ENG showed acute and chronic motor neuron damage and 129th Annual Meeting sensitive axonal neuropathy, confirmed by muscle and nerve biopsies. Brain MRI revealed cerebellar atrophy. MEP, EEG, Monday, October 4, 2004 and fundoscopy were normal. ␤-HEXB activity was unde- tectable in leukocytes. Molecular genetic studies are in Abstracts: Poster Sessions progress. ␤-HEXB deficiency should be considered in differ- ential diagnosis of juvenile MND, also for prognostic rea- sons: indeed, studies with animal models indicate substrate deprivation as a potential treatment for ␤-HEXB deficiency. FUNCTIONAL GENETICS WALKING TOUR

1. Transgenic Mouse Model for the Human GLUT1- 3. Effect of Tau and ApoE Genotypes on Age at Deficiency Syndrome Onset and Age at Death in Progressive Supranuclear Charles Heilig, Vasilis Koliatsos, Jehuda Sepkuty, Palsy Kathleen Heilig, Shenglin Chen, Minghui Xiang, Yasuhiko Baba, Yoshio Tsuboi, Keith A. Josephs, Donald Price, James Fox, Martin Pomper, David Borchelt, Natalie Cookson, Zbigniew K. Wszolek, and and Alena Savonenko; Baltimore, MD Dennis W. Dickson; Jacksonville, FL; Fukuoka, Japan; and The human GLUT1-deficiency syndrome (GLUT1DS) is Rochester, MN characterized by mutations that decrease GLUT1 expression OBJECTIVE: To assess the effect of tau and ApoE geno- or produce dysfunctional GLUT1 protein, resulting in re- types on age at onset (AAO) and age at death (AAD) of duced glucose transport across the blood-brain barrier. Af- pathologically confirmed progressive supranuclear palsy fected individuals appear normal at birth, but have hypogly- (PSP). METHODS: Fifty-two pathologically proven PSP corrachia, and eventually exhibit developmental delay, cases that lacked any other prominent neurodegenerative dis- acquired microcephaly, recurrent seizures, abnormal coordi- order were taken from the PSP Brain Bank and enrolled. nation ,and hindlimb spasticity. We produced GLUT1- Tau and ApoE genotypes were examined using DNA iso- deficient transgenic mice with an antisense-GLUT1 trans- lated from frozen brain tissue. The distribution and severity gene that is widely expressed, reducing GLUT1 in of Alzheimer type neurofibrillary degeneration was also esti- developing brain, heart, and kidney. Transgenics appeared mated with Braak NFT staging. Clinical information was normal at birth. At 3 weeks of age, many exhibited ataxia gathered from available clinical records. The relationship of and developmental delay, followed by seizures, hindlimb tau and ApoE genotypes to AAO and AAD was assessed us- spasticity, and adult brain weights 45% below normal. They ing the Mann-Whitney U-test. RESULTS: PSP cases with had grossly impaired function on the rotorod test, front-limb H1/H1 and e4 genotypes (n ϭ 8) exhibited significantly ear- and hind-limb grasp tests, open-field motor activity, and gait lier AAO (59.5 Ϯ 4.6 years) and AAD (67.0 Ϯ 5.0 years) testing. CSF glucose concentrations and CSF/blood glucose ϭ 18 than those without H1/H1 and e4 genotypes (n 7) (AAO ratios were reduced 71% and 68%, respectively. FDG PET 67.0 Ϯ 5.4, AAD 77.1 Ϯ 10.1 years, p Ͻ 0.03, respec- revealed markedly reduced glucose uptake in several brain tively), or those with H1/H1 but no e4 genotypes (n ϭ 37) areas, including the neocortex and cerebellum. Affected (AAO 64.9 Ϯ 7.6, p Ͻ 0.05, AAD 72.8 Ϯ 7.1 years, p Ͻ transgenics had frequent seizure activity at baseline, which 0.02). There were no differences in Braak NFT stages or increased substantially with 6 hr of fasting. Conclusion: We disease duration associated with each genotype. CONCLU- produced GLUT1-deficient mice with a phenotype mimick- SIONS: A genetic phenotype of tau H1/H1 and ApoE e4 ing GLUT1DS. They should be useful for determination of genotypes influences the prognosis in PSP (earlier symptom- the mechanisms and potential treatments for the abnormal atic disease onset and shorter survival). Y.B. is a recipient of phenotype and seizures. Robert and Clarice Smith Fellowship award.

2. GM2 Gangliosidosis Manifesting as Familial Motor 4. Neuroprotective Effect of Insulin-Like Growth Neuron Disease Factor-I against Glutamate- and Axotomy-Induced Gabriella Silvestri, Anna Modoni, Enzo Ricci, Motor Neuron Death Mauro Lo Monaco, Fiorella Piemonte, Pietro A. Tonali, Yasuo Iwasaki, Osamu Igarasshi, Yasumitsu Ichikawa, Alessandro Salviati, and Mario Sabatelli; Rome, Italy and Joe Aoyagi, and Ken Ikeda; Tokyo, Japan Verona, Italy Insulin-like growth factor-I (IGF-I) is a potent survival factor GM2 gangliosidosis (Sandhoff disease) is a lisosomal disorder for motor neurons that is being investigated as a possible due to ␤-hexosaminidase subunit (␤-HEXB) deficiency. Its therapeutic agent for amyotrophic lateral sclerosis (ALS).To most frequent clinical manifestation is indistinguishable from examine the possible neuroprotective effect of IGF-I in vitro Tay Sachs’disease. Other clinical forms include juvenile-onset and in vivo, the following experiments were conducted. In spinocerebellar ataxia and, rarely, motor neuron diseases vitro, we analyzed the pharmacological utility of IGF-I in a (MNDs). We report a ␤-HEXB deficiency manifesting as an postnatal orgatypic culture model of motor neuron degener- autosomal recessive MND. A 62-year-old sister and a 49- ation induced by glutamate. Cultivation span was 2 weeks. year-old brother came to our observation because of progres- Treatment with glutamate resulted in a significant reduction sive limb weakness, dysarthria, and dysphagia. Their parents of motor neuron numbers.Cotreatment with glutamate and originated from a small village. Other two out of six germans IGF-I revealed a protective effect against motor neuron were affected, with onset of symptoms between 30 and 40. death. In vivo, we examined the ability of IGF-I on axoto- Both patients showed proximal muscles wasting and weak- mized spinal motor neuron death in the rat spinal cord. After ness, predominantly at lower limbs, and areflexia; the sister the postnatal unilateral section of sciatic nerve, there was ap- had lost deambulation. The brother was able to walk and proximately a 50% survival of motor neurons in the fourth showed, as a striking feature, diffuse fasciculations. EMG/ lumbar segment. In comparison with vehicle, intraperitoneal

S12 © 2004 American Neurological Association Published by Wiley-Liss, Inc., through Wiley Subscription Services injection of IGF-I for 14 days rescued spinal motor neurons. diagnosis, and genetic counseling for this severe form of ep- There was no significant relationship between rescue of mo- ilepsy. tor neuron numbers and doses of IGF-I, whether in vitro or in vivo. These in vitro and in vivo studies show that IGF-I may play an important role in the neuroprotective effect of 7. Withdrawn motor neurons, providing a rational treatment for motor neuron diseases, such as motor neuropathies and ALS. CLINICAL TRIALS

8. Rasagiline Provides Significant Symptom Benefit as 5. Autosomal Recessive Forms of Charcot-Marie-Tooth Initial Monotherapy and as Adjunct Therapy in Early Disease: Histological Phenotypes and Genotypes and Moderate-to-Advanced Parkinson’s Disease Jean-Michel Vallat, Djamel Grid, Corinne Magdelaine, Phyllis M. Salzman, Eli Eyal, Todd J. Kunkel, and Franck Sturtz, and Meriem Tazir; Limoges, France; Evry, Neil T. Malone; North Wales, PA; Netanya, Israel; and France; and Algiers, Algeria Kansas City, MO In some countries with a high prevalence of consanguineous Rasagiline (N-propargyl-1[R]-aminoindan) mesylate is a po- marriages, autosomal recessive inheritance is likely to account tent, selective, second-generation, irreversible MAO-B inhib- for more than 50% of all forms of Charcot-Marie-Tooth itor. Two multicenter, randomized, double-blind, placebo- Disease (CMT). As with the dominant forms, it is usual to controlled, 6-month trials, conducted by the PSG, analyzed differentiate the demyelinating forms (recessive CMT 1: AR- the effects of once-daily rasagiline 1 mg on Parkinson’s dis- CMT 1 or CMT 4) from the axonal forms (recessive CMT ease (PD) symptoms. The Unified Parkinson’s Disease Rat- 2: AR-CMT 2). Genetic analysis of large families with reces- ing Scale (UPDRS) was the primary efficacy measure in the sive transmission has proved to be an efficient means of dis- TEMPO study (N ϭ 404), which evaluated rasagiline mono- covering novel CMT genotypes (genes: GDAP1, MTMR2, therapy in early PD patients (mean age: 60.8 Ϯ 10.8 years; MTMR13, KIAA1985, NDGR1, periaxin, and lamin). Clin- disease duration: 1.0 Ϯ 1.24 years), and was a secondary ical and especially histological phenotypes often lead to a sus- efficacy measure in PRESTO (N ϭ 472), which evaluated picion that a specific gene is implicated. We have studied 10 rasagiline ϩ levodopa/carbidopa (LD/CD) vs. placebo ϩ nerve biopsies from patients belonging to different consan- LD/CD in moderate-to-advanced patients (mean age: guineous Algerian families. So, we will outline the character- 63.3 Ϯ 9.5 years, PD duration: 9.3 Ϯ 5.3 years). In istic lesions that may suggest the need to look for mutations TEMPO and PRESTO, rasagiline was superior to placebo in genes such as GDAP1, MTMR2, KIAA1985, and peri- for total UPDRS (p Ͻ 0.0001 and p ϭ 0.0084, respectively) axin for AR-CMT1 and in genes such as lamin for AR- and motor subscale (p Ͻ 0.0001 and p ϭ 0.0011, respec- CMT2. In two cases, the electron microscopic lesions were tively). Symptom score analyses were conducted post hoc, very unusual. At the present time, there is therefore an indi- without correcting for multiple comparisons. In TEMPO cation for nerve biopsy to orient diagnostic research in mo- and PRESTO, rasagiline reduced tremor (p ϭ 0.002 and lecular biology, which is very time-consuming and can be p ϭ 0.0021, respectively) and reduced bradykinesia (p Ͻ performed only in highly specialized laboratories. 0.0001 and p ϭ 0.0493, respectively) vs. placebo. Rasagiline patients experienced less rigidity in PRESTO (p ϭ 0.0239) vs. LD/CD ϩ placebo. These findings demonstrate signifi- 6. Progressive Myoclonus Epilepsy with Polyglucosans cant symptom benefit with rasagiline as initial monotherapy (Lafora Disease): Evidence for a Third Locus in early PD and as adjunct therapy when added to LD/CD Elayne M. Chan, Salah Omer, Mushtaq Ahmed, in advanced PD. Study supported by Teva Pharmaceutical Leslie R. Bridges, Christopher Bennett, Stephen W. Scherer, Industries. All authors are employees of either Teva Pharma- and Berge A. Minassian; Toronto, Ontario, Canada; London, ceutical Industries or Teva Neuroscience. United Kingdom; and Leeds, United Kingdom Lafora disease (LD) is an autosomal recessive disorder and CEREBROVASCULAR DISEASE the most severe form of teenage-onset progressive myoclonus epilepsy. LD is a unique type of glycogenosis with accumu- 9. Non-Hemorrhagic Mass Lesion as Presentation of lation of ER-associated, starch-like, polyglucosans-forming Amyloid Angiopathy: A Case Report Lafora bodies. A homogeneous clinical presentation exists de- Uzma Ali and Salvador Cruz-Flores; St. Louis, MO spite the presence of genetic heterogeneity. Recessive muta- tions in either of two genes cause the syndrome. EPM2A We describe a case of cerebral amyloid angiopathy presenting encodes a dual-specificity phosphatase with a carbohydrate- as a non-hemorrhagic mass lesion. A 76-year-old man with binding domain (named laforin), and EPM2B encodes a pu- Alzheimer’s disease had speech difficulty. His exam showed a tative E3 ubiquitin ligase (named malin). In total, 88% of mini-mental status exam of 18/30 and aphasia. An MRI our collection of LD families can now be accounted for by demonstrated a mass in the left frontal and temporal regions mutations in EPM2A (48%) and EPM2B (40%). We de- with increased intensity in the FLAIR images. A brain biopsy scribe a family with three members affected with classic LD revealed amyloid deposits consistent with cerebral amyloid that have no mutations in the coding regions and flanking angiopathy (CAA). The literature yielded six patients aged intronic sequences of either EPM2A or EPM2B. Linkage and 50–70 who presented with new onset seizures, focal weak- haplotype analyses exclude both loci from causative involve- ness, headache, visual disturbances, or mental status changes. ment in the disease in this family. These results indicate that Imaging demonstrated a diffuse non-enhancing, non- a third LD gene exists. Its identification will be crucial in hemorrhagic mass in all cases, most commonly in the frontal understanding the cellular pathway underlying polyglucosan region. Biopsies revealed amyloid deposits in the arteriolar formation. In addition, the description of additional genetic wall. CAA usually presents with intracerebral hemorrhage in heterogeneity in LD will improve patient diagnosis, prenatal the elderly. Non-hemorrhagic mass is an uncommon form of

Program and Abstracts, American Neurological Association S13 presentation. When a mass is present, it is usually related to ter content following large experimental ischemic stroke. At- amyloidomas or amyloid deposits associated with central ner- tenuation of increased lung water content with HS may have vous system vasculitis. The treatment of isolated CAA mass therapeutic implications for the treatment of neurogenic pul- without evidence of amyloidoma or vasculitis is not clear. A monary edema following ischemic stroke. Study supported biopsy is often required to exclude the possibility of an in- by the American Heart Association. filtrating tumor. CAA presenting as a non-hemorrhagic mass should be considered in the differential diagnosis of non- enhancing infiltrating mass lesions. 12. Clinical Characteristics of Stroke Patients Who Present within Window Period of 3 Hours: Study from 10. Final 1-Year Composite Endpoint Results for the Northwest India ARCHeR Trials: ACCULINK for Revascularization of Robinder Jeet Singh Dhillon, Ravneet Kaur Mann, Carotids in High-Risk Patients Vinneta Sethi, Yash Pal Singh, and Jeyraj D. Pandian; Richard P. Atkinson and ARCHeR Trial Collaborators; Ludhiana, Punjab, India Sacramento, CA DESIGN AND METHODS: The Department of Neurol- Carotid endarterectomy poses a significant risk for complica- ogy, Christian Medical College, Ludhiana, India conducted tions in patients with comorbidities and/or unfavorable anat- this study between September 2001 and November 2003. omy. Carotid artery stenting with embolic protection may be Stroke severity was assessed on admission with NIHSS score. an alternative therapy. METHODS: Five hundred eighty- RESULTS: A total of 489 stroke patients were seen during one patients were enrolled at 48 sites in three trials using the study period of 26 months; 72 (14.7%) presented within 3 same Guidant ACCULINK stent: ARCHeR 1 used the AC- hr, 48 (66.6%) males and 24 (33.3%) females. The mean CULINK alone; ARCHeR 2 incorporated the ACCUNET age was 59.65 years (range: 31–90 years). Mean time at pre- embolic protection device; ARCHeR 3 used the rapid ex- sentation was 90.2 min (range: 15–180 min). Thirty-five change (RX) versions of these devices. Patients had symp- (48.6%) patients presented within 1 hr, 19 (26.3%) within 2 tomatic (Ͼ50%) or asymptomatic (Ͼ80%) stenosis and hr, and 18 (25%) within 3 hr of onset. The mean NIHSS high-risk surgical or medical conditions. The primary com- score was 9.26 (range: 0–30. About 35 (48.6%) patients had posite endpoint was stroke, death, and MI at 30 days and ischemic stroke, 27 (31%) patients had intracerebral hemor- ipsilateral stroke at 12 months. RESULTS: Thirty-day major rhage and 6 (6.9%) subjects presented with TIA. Only 5 stroke or death was 3.8%, 2.5%, and 2.8% for ARCHeR (6.9%) patients received rTpA after complete evaluation. trials 1, 2, and 3, respectively. Periprocedural death, all Thrombolysis couldn’t be given in 10% of the subjects be- stroke or MI, was 7.6%, 8.6%, and 8.3% for ARCHeR trials cause the drug was too expensive. Patients who had weakness 1, 2, and 3, respectively. The 1-year primary composite end- (p Ͻ 0.024) and facial palsy (p Ͻ 0.01) were more likely to point was 8.3% and 10.2% for ARCHeR trials 1 and 2, present within 60 min of stroke onset. CONCLUSION: respectively. Acute ACCULINK device success was greater Only 14.7% patients reached the hospital within 3 hr, and than 98% in all trials. Results of this trial support carotid 6.9% of them received rTpA. stenting with embolic protection as an acceptable treatment option for the surgical high-risk patient. Study supported by Guidant. Consultant to Guidant assisted with carotid stent and intracranial stent trials, including service on DSMB. 13. Cost Reduction Strategy for Secondary Prevention of Stroke Using Cost-Minimization Analysis of Antiplatelet Drugs 11. Lung Water Is Increased following Experimental Maria Lourdes I. Donato and Brian Silver; Cleveland, OH Stroke: Effect of Treatment with Hypertonic Saline and Detroit, MI Toung J.K. Toung, Jonathan Lin, Yi Chang, and INTRODUCTION: Many efficacious antiplatelet agents are Anish Bhardwaj; Baltimore, MD available today; however, its widespread use has been limited INTRODUCTION: Pulmonary edema is associated with by their prohibitively high cost. The goal of this study was brain injury, including large ischemic strokes. Osmotherapy (1) to determine the direct cost incurred with the use of each with hypertonic saline (HS) treatment attenuates cerebral antiplatelet drug and (2) to compare the total costs associated edema associated with ischemic stroke. In a well- with prescription of antiplatelet drugs. METHODS: Cost- characterized animal model of large ischemic stroke, we minimization analysis of total costs was done. Total medica- tested the hypothesis that there are increases in lung water tion costs included additional expenses for treatment of ad- that are attenuated with HS treatment. METHODS: verse effects after multiplying treatment cost with NNT. Halothane-anesthetized male Wistar rats (n ϭ 53) were sub- RESULTS: Cost of treatment with an antiplatelet drug for 2 jected to permanent middle cerebral artery occlusion years was as follows: aspirin, $36.50; cilostazol, $2,671.80; (MCAO). At 6 hr following MCAO, rats were treated in a extended release dipyridamole-aspirin combination (DP- blinded, randomized fashion with either an intravenous in- ASA), $2,978.40; clopidogrel, $3,007.60; and ticlopidine, fusion (0.3 mL/hr) of 0.9% saline (n ϭ 27) (NS) or 7.5% $3,460.20. The total cost to prevent one stroke in 2 years of HS (n ϭ 26) for 48 hr. Serum osmolality and lung water treatment was as follows: aspirin, $4,306.50; cilostazol, content (wet-to-dry ratios) were measured at the end of the $45,420.60; DP-ASA, $54,768.80; ticlopidine, $60,863.40; experiment as well as in naı¨ve controls (n ϭ 12). RESULTS: and clopidogrel, $87,220.40. CONCLUSION: Aspirin is Lung water content was significantly increased in rats follow- the most cost-effective antiplatelet agent for secondary stroke ing MCAO treated with NS (77.3 Ϯ 0.4%; 311 Ϯ 4 prevention by a substantial margin. The alternative drugs at mOsm/L) (mean Ϯ SEM) as compared to naı¨ve controls their current prices dramatically increase costs to prevent one (75.5 Ϯ 0.2%; 302 Ϯ 1 mOsm/L). Treatment with HS at- stroke. Given the cost savings, other interventions such as tenuated lung water content (74.8 Ϯ 0.1%; 360 Ϯ 7 blood pressure control might have a greater impact on the mOsm/L). CONCLUSIONS: There is increase in lung wa- recurrence of stroke given a fixed budget.

S14 Annals of Neurology Vol 56 (suppl 8) 2004 14. Development of Inhibition of Platelet Recruitment 16. Granulocyte Colony-Stimulating Factor Promotes over Time with Clopidogrel Added to Aspirin in Angiogenesis Leading to the Long-Term Functional Prevention of Recurrent Stroke Recovery in Focal Cerebral Ischemia Larry D. Brace, Dilip Pandey, Joan Martellato, and Soon-Tae Lee, Kon Chu, Keun-Hwa Jung, Hee-kwon Park, Cathy M. Helgason; Chicago, IL Kyung-bok Lee, Manho Kim, and Jae-Kyu Roh; Seoul, BACKGROUND: Aspirin and clopidogrel inhibit platelet Republic of Korea aggregation (pltagg) and recruitment (pltrecr) to a degree. Granulocyte colony-stimulating factor (G-CSF) is a neuro- METHODS: Thirty ischemic stroke patients had pltagg and protective agent and promotes angiogenesis in tumor and pltrecr studies. Studies were performed at 14 days while the hindlimb ischemia. We studied the effect of G-CSF on an- patient took aspirin ec 325 mg. At day 30, 60, and 90, as- giogenesis and neurological recovery after cerebral ischemia. pirin and clopidogrel 75 mg/day was taken since day 14. After induction of transient focal ischemia by intraluminal Pltagg was performed using a PAP4 aggregometer with ara- thread occlusion (n ϭ 54), rats were randomly assigned to be chidonic acid, ADP, epinephrine, and collagen (Helgason, injected G-CSF (50 ␮g/kg, i.p.) or saline from 2 hr after Stroke, 1993). Pltrecr was performed using established ischemia and for 3 days. BrdU was injected from day 1 and method (Santos, J. Clin. Invest., 1991) that included pro- every day afterwards for 14 days. Infarct volume was mea- aggregatory contribution of red blood cells when generation sured using TTC at 24 hr after ischemia. On day 14, angio- mixtures were stimulated by fibrillar collagen. Analysis of genesis and neurogenesis were measured using FITC-dextran, variance was used to compare platelet inhibition between as- BrdU, anti-vWF, anti-EBA, and anti-Tuj-1 staining. We pirin and combination therapy. Longitudinal regression was performed behavioral tests for 35 days every week. On day performed to estimate pltrecr inhibition over time. RE- 35, Nissl staining was performed. G-CSF treatment reduced SULTS: We observed that clopidogrel was favored for inhi- infarct volume by 47% (p Ͻ 0.01). Vascular density and Ͻ Ͻ ϩ ϩ bition of ADP (p 0.001), that collagen (p 0.032) in- double-labeled cells for BrdU vWF in the ipsilateral stri- duced pltagg, and that there was maximum pltrecr inhibition Ͻ ϭ atum were significantly increased. Cerebral atrophy was re- (p 0.002) for all methods. A significant (p 0.004) de- duced, and behavior tests showed better recovery from day gree of pltrecr inhibition occurred over time. CONCLU- 14 to day 35 (p Ͻ 0.01). In this study, we provide evidences SION: Addition of clopidogrel significantly enhanced inhi- that G-CSF induces long-term functional recovery in focal bition of pltagg and recruitment. Inhibition of platelet ischemic model, which might be due to neuroprotective and recruitment significantly increased over time with clopi- angiogenic effects of G-CSF. dogrel. Increased efficacy of clopidogrel over time is not pre- viously described. Study supported by Bristol Myers Squibb/ Sanofi Pharmaceuticals Partnership.

17. Cognitive Outcomes 1 and 3 Years after Coronary Artery Bypass Grafting Compared to Nonsurgical Controls 15. Intracranial Infectious Aneurysms: Clinical Features, Management, and Outcome Ola A. Selnes, Maura A. Grega, Lou M. Borowicz, Sudheeran Kannoth, Rajesh B. Iyer, Sanjeev V. Thomas, Sarah J.E. Barry, William A. Baumgartner, Scott L. Zeger, B.J. Rajesh, C. Kesavadas, V.V. Radhakrishnan, and and Guy M. McKhann; Baltimore, MD P. Sankara Sarma; Trivandrum, Kerala, India Decline in cognitive performance, both in the immediate PURPOSE: Intracranial infectious aneurysms (IAs) are infre- postoperative period and up to 5 years after coronary artery quent, but life threatening. Available literature is sparse and bypass grafting (CABG) has been reported. However, few management guidelines unclear. We studied clinical presen- studies have compared the performance of those undergoing tation and outcome of IAs for prognostication and evolving CABG with appropriate controls. We prospectively com- management strategies. METHODS: Clinical details were pared the cognitve outcomes of 140 CABG patients and 92 extracted from medical records of persons with IAs managed nonsurgical controls (NSCs) (those with coronary artery dis- between 1976 and 2003. RESULTS: Twenty-nine IAs were ease but no surgery). At baseline (preoperatively), 3 months, identified in 25 patients (mean age: 24.8years; males: 7). In- 1 year, and 3 years, a battery of neuropsychological tests was fection source was cardiac (10), meningitis (12), orbital cel- administered and analyzed by individual test scores as well as lulitis (2), and uncertain (1). Eighteen cases were bacterial, by summary z-scores for the domains of verbal memory, vi- four fungal, and three tuberculous. Aneurysms involved ca- sual memory, attention, visuoconstruction, executive func- rotid circulation (19) and vertebrobasilar circulation (10). tion, language, and motor and psychomotor speed. Within- Fifteen were distal and 14 proximal. Location of IAs proxi- subject changes in z-scores were used for the longitudinal mally in meningitis and distally in infective endocarditis was comparisons. The cognitive performance of both CABG and statistically significant. Of sixteen patients treated medically, NSC patients improved from baseline to 3 months. Both 7 recovered, 6 needed surgery, and 3 died. Five other pa- groups continued to improve between 3 months and 3 years, tients underwent early surgery. Greater age, meningitis, fun- with no evidence of statistically significant decline in the gal etiology, and vertebrobasilar location had statistically sig- CABG group. These results indicate that postoperative de- nificant mortality, but aneurysm size was insignificant. cline in cognition after CABG returns to normal by 3 Mortality after medical or surgical treatment did not differ. months. Cognitive decline 3 years and beyond CABG may CONCLUSION: Characteristics and prognosis of IAs differ be more closely associated with chronic cerebrovascular dis- according to etiology. Medical treatment would require close ease than previous exposure to cardiopulmonary bypass. monitoring because over half of them either required surgery Study supported by the Dana Foundation, the NINDS, and or ended fatally. the NIH.

Program and Abstracts, American Neurological Association S15 18. Stroke Family History Is Not a Determinant of 20. Involvement of Medullary Autonomic Regions in 90-Day Outcomes: The Ischemic Stroke Genetics Study Dementia with Lewy Bodies James F. Meschia, Doug Case, Robert D. Brown, Eduardo E. Benarroch, Ann M. Schmeichel, Phillip A. Low, Scott Silliman, Jose Merino, Thomas G. Brott, Bradley F. Boeve, and Joseph E. Parisi; Rochester, MN Bradford B. Worrall, Michael Frankel, John Hardy, and Stephen S. Rich; Jacksonville, FL; Winston-Salem, NC; Dementia with Lewy bodies (DLB) may manifest with Rochester, MN; Charlottesville, VA; Atlanta, GA; and prominent autonomic impairment, mimicking multiple sys- Bethesda, MD tem atrophy (MSA). We studied the medulla of six cases with neuropathologically confirmed DLB (ages: 77–84 years, BACKGROUND: Sroke-prone rat genomic studies show three cases with history of orthostatic hypotension [OH]), six that infarct volume is genetically regulated. Genes regulating cases with MSA (ages: 54–70 years), and six age-matched human infarct volume and outcomes are unknown. METH- controls. Fifty-micron sections of the medulla were immuno- ODS: We used the Ischemic Stroke Genetics Study (ISGS) stained for tyrosine-hydroxylase, tryptophan hydroxylase, to explore the relationship between stroke family history and choline acetyl transferase, and ␣-synuclein, and analysis was outcomes. Family histories were assessed prospectively for focused on the ventrolateral medulla (VLM) and raphe nu- stroke-affected, first-degree relatives (AFDRs). Certified ad- clei. In DLB cases, there were Lewy bodies and dystrophic judicators assessed deficit using the NIH Stroke Scale neurons in the VLM, but the numbers of catecholaminergic (NIHSS). Outcomes were assessed at 90 days post-stroke us- ing the Barthel Index (BI), Oxford Handicap Score (OHS), and serotonergic VLM neurons were not significantly re- and Glasgow Outcome Score (GOS). Analyses were adjusted duced, regardless the presence of OH. All groups were de- for pre-stroke OHS, enrollment NIHSS, and age. RE- pleted in MSA. Cholinergic neurons in the ventrolateral nu- SULTS: By 3/04, 300 patients were enrolled. Median age cleus ambiguus were reduced in MSA but not in DLB. was 65 years. There were 134 women. Of the 300 patients, There were Lewy bodies and dystrophic neurons in the raphe 177 (59%) patients had no AFDR; 91 (30%) had one; and in all DLB cases; cell numbers were reduced in the raphe 32 (11%) had 2ϩ. For patients with 0, 1, or 2ϩ AFDRs, obscurus and in raphe pallidus, but less severely than MSA. mean NIHSS scores were 4.05, 3.41, and 2.94, respectively These results suggest that DLB affects medullary autonomic (p ϭ 0.512). At follow-up, patients with 0, 1, or 2ϩ AFDRs areas but much less than MSA. In DLB, OH may be due had mean BI scores of 88.7, 90.9, and 90.5, respectively primarily to involvement of sympathetic preganglionic (p ϭ 0.59); mean OHS scores of 1.42, 1.38, and 1.23, re- and/or ganglion neurons rather than VLM neurons. Study spectively (p ϭ 0.67); and mean GOS scores of 1.55, 1.49, supported by National Institute of Neurological Disorders and 1.19, respectively (p ϭ 0.60). CONCLUSION: Inher- and Stroke (PO1 NS32352-P2). ited determinants of outcome differ from inherited determi- nants of risk. Study supported by NINDS R01 NS42733.

DEMENTIA AND AGING 21. Frequency and Severity of Subcortical Ischemic Hyperintensities in Amnestic Mild Cognitive 19. Diabetes Mellitus, Change in Motor Function, and Impairment Incident Disability in Old Age Christian Bocti, Howard M. Chertkow, Lenny Babins, Zoe Arvanitakis, Robert S. Wilson, Julia L. Bienias, and Nora Kelner, Fu-Qiang Gao, and Sandra E. Black; Montreal, David A. Bennett; Chicago, IL Quebec, Canada and Toronto, Ontario, Canada BACKGROUND: Diabetes is common and associated with BACKGROUND: Some studies suggest that subcortical hy- significant morbidity, but few studies have prospectively as- perintensities (SHs) are associated with executive functions sessed the relation of diabetes to motor function and disabil- deficits in Alzheimer’s Disease (AD) and normal aging, but ity. OBJECTIVE: To evaluate the relation of diabetes to there is little data available on amnestic mild cognitive im- change with respect to motor function and incident disabil- pairment (aMCI). OBJECTIVE(S): To determine the fre- ity. DESIGN/METHODS: Participants were 922 older quency and severity of SHs in aMCI and to study its cogni- Catholic nuns, priests, and brothers (mean age: 75 years; tive correlates. METHODS: We applied a standardized MRI 32% men) enrolled in the Religious Orders Study. For up to visual rating scale to assess SH burden. Forty-one MCI pa- 10 years, they had detailed annual evaluations, which in- tients without stroke/TIA history and 25 age-matched nor- cluded a self-report disability measure (Katz) and mal controls (NCs) underwent standardized neuropsycholog- performance-based measures of manual dexterity (Purdue Pegboard) and lower limb function (composite of gait and ical evaluation. Severity of SH was rated on a 4-point scale balance tasks). RESULTS: Analyses controlled for age, sex, for 10 brain regions, on proton density and T2-weighted ax- and education. Diabetes, present in 144 (15.6%) partici- ial MRI (Wahlund, Stroke, 2001). RESULTS: Reliability was excellent (0.94). The mean global score for NCs was 2.3 Ϯ pants, was associated with worsening manual dexterity (pa- Ϯ ϭ ϭ rameter estimate ϭϪ0.09; SE ϭ 0.04; p ϭ 0.01) and lower 2.1 compared to 4.2 3.7 for aMCI (F(1,68) 6.2; p limb function (parameter estimate ϭϪ0.04; SEϭ 0.02; p ϭ 0.02). Only 22% of subjects were free of any SHs (aMCI- Ͼ 0.02). During follow-up, 27% of participants became depen- low); 34% had a global score 2 S.D. from the mean of dent in at least one activity of daily living according to the NCs (aMCI-high). When these two groups were compared, Katz measure. Risk of incident disability was 47% greater in the aMCI-high group was older(p ϭ 0.04), but there was no those with diabetes compared to those without it (hazard ra- difference for education and disease duration, and no differ- tio ϭ 1.47; 95%CI: 1.04, 2.08). CONCLUSION: Diabetes ence in executive functions or any other cognitive domains. is associated with declining motor function and the develop- CONCLUSIONS: There is a high prevalence of SHs in ment of disability in old age. Study supported by Supported aMCI, but an expanded cohort will be investigated to clarify by the National Institute on Aging, P30 AG10161, R01 cognitive effects. Study supported by a postdoctoral training AG15819. award from the Alzheimer Society of Canada to Dr. Bocti.

S16 Annals of Neurology Vol 56 (suppl 8) 2004 22. Subjective Memory Complaint: Harbinger of 24. Depression in Frontotemporal Dementia Is Disease or Marker of Higher Intellectual Level? Associated with Decreased Left Temporal Lobe 5HT1a Laura Bracco, Angela Sforza, Carolina Piccini, Receptor Density Valentina Bessi, Benedetta Nacmias, and Sandro Sorbi; Tiffany W. Chow, Shinichiro Takeshita, Peggy L. St. Jacques, Florence, Italy Morris Freedman, Nicolaas P.L.G. Verhoeff, Sandra Black, and Jeffrey Meyer; Toronto, Ontario, Canada To reach a better understanding of Subjective Memory Complaint (SMC) as a harbinger of a pathological process, WAY-PET imaging labels central serotonin 1a receptors and we evaluated demographic characteristics, premorbid intelli- allows their quantification in living subjects. Because post- gence, case history, neuropsychological profile, and ApoE ge- mortem and pharmacologic responsivity indicate a role for notype in 48M and 84F (mean age: 64.8 Ϯ 8.6 years) com- serotonin in anxious, depressive, and obsessive-compulsive plaining mild memory deficits and 8M and 12F controls symptoms arising from frontotemporal lobar degeneration (mean age: 66.5 Ϯ 8.7 years). A direct conversation and a (FTLD), we are examining patterns of serotonin 1a receptor density in these patients (n ϭ 5) vs. age-matched controls judgement of cognitive performance allowed us to classify ϭ patients in four groups: SMC with (n ϭ 31) or without (n 4). Depressive and obsessive-compulsive symptoms were frequent (80%) in the FTLD sample. FTLD subjects (n ϭ 21) anxious-depressive features, mild cognitive impair- with depression had decreased serotonin 1a receptor density ment (MCI, n ϭ 24), and early Alzheimer’s disease (AD, in left and not right temporal lobe compared against controls n ϭ 36). Groups were compared using ANOVA with Bon- ϭ ␹2 (one-tailed t-test, p .03). Our preliminary data imply that ferroni post-hoc multiple comparisons and analysis. Neu- analysis of further subjects may reveal asymmetric serotoner- ropsychological test scores significantly distinguished AD gic activity patterns localized to frontal or temporal regions from the other groups (p Ͻ 0.01). SMC cases with or with- Ͻ associating with the neuropsychiatry of FTLD. Study sup- out anxious-depressive symptoms were significantly (p ported by NIA grant 1 F32 AG022802-01. 0.02) younger, more educated, and brighter, and presented less ApoE e4 allele (16%) in comparison with AD and MCI (30%). These data could indicate a very precocious disease 25. Increased Rivastigmine Response with More Rapid awareness — not tapped by usual neuropsychological mea- Rate of Change in Alzheimer’s Disease sures standardized on more aged and less educated people — Martin Farlow, Gary Small, and Peter Quarg; Indianapolis, or, alternatively, the presence of a nonpathological, nonpro- IN; Los Angeles, CA; and Basel, Switzerland gressive disorder, as may be suggested by the different ApoE genotype distribution. Follow-up studies could clarify this Cholinesterase inhibitors are widely used in Alzheimer’s dis- situation. ease. A patient group needing particular attention is the one that caregivers characterize as having more noticeable change, who often experience faster disease progression. We aimed to investigate whether rivastigmine has greater benefits in “no- ticeable change” patients compared with “gradual change” 23. Androgen Receptor Distribution in Hippocampal patients. Data from placebo-controlled studies were pooled. Subfields in Aging and Alzheimer’s Disease Control groups received placebo for 6 months before enter- Fen-Lei F. Chang and Benecia C. Hong-Goka; Fort Wayne, ing open-label extensions, during which time they received IN and Fresno, CA rivastigmine. With the use of data from the double-blind control groups, patients were identified with “noticeable Testosterone has been prescribed increasingly for potential change” (Ն4 point decline on ADAS-cog within the previ- anti-aging effects. Studies have suggested possible neuropro- ous 6 months), or “gradual change.” Responses were mea- tection against the development of Alzheimer’s disease (AD). sured over 26 weeks during open-label extensions. Modelling We studied autopsied brains from 58 non-AD males de- and simulation methods were used to obtain a p value cor- ceased in the fifth (40–49, n ϭ 9), sixth (n ϭ 10), seventh rected for possible regression-to-the-mean bias, and 679 con- (n ϭ 9), eighth (n ϭ 16), and ninth decades (n ϭ 14), and trol patients entered the open-label extensions. Although 43 AD males in the seventh (n ϭ 10), eighth (n ϭ 16), and both groups benefited from rivastigmine in the open label ninth decades (n ϭ 17). Androgen receptor (AR) was visu- phase, patients with “noticeable change” showed greater alized using a polyclonal AR antibody (PA1-110, Affinity, treatment responses, with a between-group difference of 3.2 Golden, CO). Optical density was measured stereologically points on the ADAS-cog after 26 weeks. The change in slope with the Bioquant system. AR immunoreactivity was mostly of symptom progression differed significantly between the ϭ cytoplasmic in the pyramidal cells with some neuronal pro- groups (p 0.029). Rivastigmine may provide even greater cesses and glial staining. Subfield CA2 had the highest AR treatment benefits in “noticeable change” patients, compared density (F ϭ 12.62; p Ͻ 0.0001). The AR density in the with patients experiencing “gradual change.” Study sup- non-AD males was lowest in the sixth decade between ages ported by Novartis Pharma AG. of 50 and 59 (F ϭ 7.09; p Ͻ 0.001). This was followed by a rise in the seventh decade suggesting a compensatory mech- anism in aging. Male patients with AD had lower AR density 26. Longitudinal Study of Cognition Change during than non-ADs across seventh to ninth decades (F ϭ 27.18; the Menopausal Transition p Ͻ 0.0001), suggesting that AD may start to develop if Jong-Ling Fuh, Shuu-Jiun Wang, Shin-Jung Lee, and compensatory receptor upregulation fails to occur. Our data Shiang-Ru Lu; Taipei, Taiwan, Taiwan; Ann Arbor, MI; would support a role of testosterone in aging and AD and Kaohsiung, Kaohsiung, Taiwan through an AR-mediated mechanism. Study supported by To characterize the changes in cognition that occur during the VA Central California HCS Hospital and the UCSF- menopausal transition, we conducted a longitudinal Fresno Alzheimer’s and Memory Center, Indiana University population-based study in Kinmen, Taiwan. We recruited all Foundation. women aged 40 to 54, premenopausal, no hormone replace-

Program and Abstracts, American Neurological Association S17 ment therapy (HRT), and no hysterectomy. A total of 694 28. Homocysteine, Brain Atrophy, and White Matter eligible women participated in the baseline study, and 573 Disease in Alzheimer’s Disease and Cerebral Amyloid women (83%) completed follow-up 18 months later. After Angiopathy excluding 78 women who received hysterectomy or HRT. Mahmut E. Gurol, Teodoro Bottiglieri, Ramon Diaz-Arrastia, The resulting sample was composed of 495 subjects, 114 of Eric E. Smith, Chana R. Engel, Steven M. Greenberg, and whom (23%) progressed to perimenopause. The women who Michael C. Irizarry; Boston, MA and Dallas, TX remained premenopausal were younger than those who be- came perimenopausal (42.7 Ϯ 2.3 vs. 45.1 Ϯ 3.0 years, p Ͻ BACKGROUND: Accumulating data link plasma homocys- 0.01). The cognitive measures included the Auditory-Verbal teine (Hcy), radiographic measures of ischemia or neurode- Learning Test, visual memory, verbal fluency, the Trail Mak- generation, and cognitive impairment. Little data are avail- ing Test, and digit span. All follow-up cognitive scores were able regarding neuroimaging correlates of Hcy in Alzheimer’s only slightly higher than baseline measures, except the Trail disease (AD) and cerebral amyloid angiopathy (CAA). OB- Making Test. The changes of visual memory (total score: 80; JECTIVE: To investigate the relationship of Hcy to white Ϫ0.2 vs. Ϫ2; p ϭ 0.01) and verbal fluency (0 vs. Ϫ1.1; p ϭ matter disease (WMD) and brain atrophy in AD/mild cog- 0.04) differed between the perimenopausal and premeno- nitive impairment (MCI) and CAA. METHODS: Plasma pausal women. After adjustment, menopausal transition was Hcy was determined in 39 subjects with AD, 21 with MCI, still a slight but significant factor of visual memory change and 49 with CAA-related intracerebral hemorrhage. MRIs 2 ϭ (R 0.03) but not in verbal fluency. Our study supported were graded for cortical atrophy (CAtr), ventricle/brain ratio the idea that menopausal transition is not accompanied by a (VBR), periventricular (PVH), and subcortical (SWMH) significant cognitive decline. Study supported by grants from white matter hyperintensities using validated scales from the the National Health Research Institute (NHRI-GT- Rotterdam Study. RESULTS: In AD/MCI, Hcy strongly EX89P923C, NHRI-GT-EX90-8923PC, and NHRI-EX91- correlated with CAtr (r ϭ 0.65, p Ͻ 0.001) and moderately 8923PC). with PVH (r ϭ 0.41, p ϭ 0.001), SWMH (r ϭ 0.39, p ϭ 0.002), and VBR (r ϭ 0.47, p Ͻ 0.001). These associations persisted when adjusted for age, creatinine, folate, vitamin B12, and hypertension. CAA subjects had lower Hcy (p ϭ 27. Changes in Activities of Daily Living among 0.003) but more PVH (p ϭ 0.004) and SWMH (p Ͻ Dementia Patients Treated with Galantamine 0.001) than AD/MCI. Among CAA subjects, Hcy correlated Serge Gauthier, Marie Martin, Bonnie Blaisdell, and with VBR (r ϭ 0.43, p ϭ 0.002) but not PVH or SWMH. Shane Kavanagh; Montreal, Quebec, Canada; Lincoln, RI; CONCLUSION: Hcy is associated with WMD and atrophy and Beerse, Belgium in AD. The relationship with WMD does not persist in the BACKGROUND: Alzheimer’s disease (AD) is characterized presence of advanced CAA. by decline in cognition and deterioration in activities of daily living (ADLs). Galantamine has demonstrated efficacy on cognition and global assessments in clinical trials. OBJEC- TIVE: To explore the effect of galantamine on ADLs. METHODS: Data from four randomized, placebo- 29. Long-Term Trials: Who Volunteers? controlled trials covering mild/moderate AD (GAL-INT-1, Lindy E. Harrell, Edward Zamrini, Nickie Brust, and GAL-INT-2, GAL-USA-1) and AD and concomitant cere- Alford Bartolucci; Birmingham, AL brovascular disease (CVD) or probable vascular dementia (GAL-INT-6) were included. The Disability Assessment for To try to answer this question, we examined some of the Dementia (DAD) was used to assess ADLs. Analyses em- demographics of normal older adults and patients with mild ployed last-observation carried forward (LOCF) and AN- cognitive impairment (MCI) and Alzheimer’s disease (AD) COVA with baseline DAD as a covariate. Psychometric anal- participating in an NIA-funded Alzheimer’s disease center. yses explored associations between patient characteristics and Of 345 patients, 177 suffered from AD and 63 from MCI, progression on the DAD. RESULTS: Galantamine demon- and 105 were normal controls (NCs). Of these, 63%, 65%, strated statistically significant effects on the DAD in three and 74% were female AD, MCI, and NCs, respectively (p Ͻ Ͻ trials: GAL-INT-1, GAL-INT-2, and GAL-INT-6 (p 0.003). Whites voluntered more often than African Ameri- 0.05). The largest treatment difference was observed in the cans in all groups (AD, 87%; MCI, 63%; NCs, 74%; p Ͻ AD ϩ CVD subgroup of GAL-INT-6 (LOCF mean: 5.5 Ϯ ϭ ϭ 0.001). Mean age was higher in the AD group (73 8.6; points; SE: 1.9; p 0.004; n 265). Pooled analyses across SD) than both MCI (68 Ϯ 8.5) and NCs (64 Ϯ 7.4) (p Ͻ all four trials for patients with AD or AD ϩ CVD showed 0.0001). When examined by decade, AD patients were older significant treatment effects at 3 months (mean: 2.9; SE: 0.7; (Ͻ60, 9%; 60–69, 17%; 70–79, 54%; 80–89, 17%; Ն90, p Ͻ 0.001; n ϭ 1145) and 6 months (LOCF mean: 2.6; SE: ϭ ϭ 2%) than MCI (11%; 48%; 32%; 8%; 2%, respectively) and 0.9; p 0.005; n 1044). CONCLUSION. Galantamine Ͻ has a statistically significant effect on ADLs for patients with NCs (33%; 38%; 26%; 3%; 0%, respectively) (p 0.0001). AD or AD ϩ CVD. Study supported by Janssen Pharma- Family history of dementia was similiar among all groups ceutica. Serge Gauthier has received honoraria from Johnson (positive; AD 66%; MCI 58%; normals 56%). Depression & Johnson Pharmaceutical Research and Development for was more common in NCs (23%) than AD ( 6%) and MCI speaking and participation in meetings. Marie Martin and (2%) (p Ͻ 0.001). At initial evalution, none of the groups Bonnie Blaisdell’s research was supported by funding from had signs or symptoms of Parkinsonism. These results sug- Janssen Pharmaceutica. Shane Kavanagh is an employee of gest that age and depression need to be taken into consider- Janssen Pharmaceutica and holds stock in Johnson & John- ation when doing statistics. Study supported by NIA 2P50 son. AG16582.

S18 Annals of Neurology Vol 56 (suppl 8) 2004 30. Diagnostic Confidence in the Clinical Diagnosis DEGENERATIVE DISEASES of Frontotemporal Dementia and Alzheimer’s Disease Judith L. Heidebrink, Steven E. Arnold, Nancy R. Barbas, 32. Late-Onset Depression and Parkinsonism in Two Christopher M. Clarke, Charles S. DeCarli, Sisters: Heterozygote Carriers for Wilson’s Disease William J. Jagust, R. Scott Turner, Roger Higdon, Gian Pietro Sechi, Giovanni Antonio Cocco, Luca Deiana, Robert A. Koeppe, and Norman L. Foster; Ann Arbor, MI; Giulio Rosati, Alessandra Errigo, and Giovanni Pes; Philadelphia, PA; Sacramento, CA; and Seattle, WA Sassari, Italy OBJECTIVES: To determine the confidence expert clini- Mutations in ATP7B gene cause Wilson’s disease (WD) in cians have in distinguishing frontotemporal dementia (FTD) homozygotes and compound heterozygotes; no adverse clin- from Alzheimer’s disease (AD) without brain imaging. ical consequence has ever been recognized in heterozygote METHODS: A dementia specialist blinded to clinical and carriers. We studied two sisters, Sardinian patients, each a pathological diagnosis prepared summaries of the complete medical history and serial clinical examinations of 45 patients heterozygote carrier for WD, which had the onset of severe with pathologically confirmed FTD (14 patients) or AD (31 depression at 69 years in one sister and 68 years in the other. patients). Brain imaging results were not included. The sum- Rigido-akinetic parkinsonism occurred 2 years later in both maries were sent to six neurologists at three AD research cen- subjects. Brain MRI showed mild cortical and subcortical at- ters. These neurologists were asked to independently decide rophy. They didn’t have a family history of WD, Kayser- whether each case had FTD or AD and to indicate their Fleischer ring, alterations in serum ceruloplasmin and copper degree of diagnostic confidence (very, somewhat, or uncer- levels, urinary copper excretion, or hepatic markers. The se- tain). RESULTS: Twenty-six cases (58%) were designated as quence of the whole ATP7B gene revealed a heterozygous diagnostically uncertain by at least one clinician. The diag- carrier state in both patients for the Ϫ441/Ϫ427 deletion at nosis of FTD had greater uncertainty (28% on average) and the 5Ј-UTR region. No other functional mutations could be lower accuracy (66%) than the diagnosis of AD (9% uncer- revealed, except for the V1140A polymorphism, which tainty, 84% accuracy, p Ͻ 0.01). Overall, raters were very doesn’t affect the gene expression. The occurrence of the confident in 49% of their diagnoses (range: 33–55%), some- same late-onset phenotype with similar temporal course in what confident in 36% (24–55%), and uncertain in 15% both sisters strongly indicates that the occurrence of the het- (4–24%). CONCLUSIONS: Even dementia specialists have erozygous carrier state and the appearance of the neuropsy- considerable uncertainty in distinguishing FTD from AD chiatric disorders may not be incidental. We are planning an based solely on clinical information. Diagnostic confidence epidemiological study to clarify if the heterozygous carrier may be lower among nonspecialists and could hinder the use state for WD may be a risk factor for the development of a of disease-specific recommendations and treatments. Study supported by NIH grants AG16976, AG08671, AG10129, late-onset parkinsonism. AG10124, and AG22394.

33. The Q&E Is More Sensitive Than the Clock 31. Dementia with Lewy Bodies: Subtypes in a Large Community-Based Autopsy Dementia Sample Draw, Mini-Cog, and Six-Item Screener in the James B. Leverenz, Mathew Kraybill, Thomas J. Montine, Detection of Mild Dementia James D. Bowen, Wayne C. McCormick, Walter A. Kukull, Paul Dash, Allan Troupin, Jessica Thomson, and Eric B. Larson, and Debby W. Tsuang; Seattle, WA Mary Knowlton; New Orleans, LA and Spokane, WA It has been suggested that dementia with Lewy bodies (DLB) Several “micro-mental” dementia screening tests have been is the second most common dementia subtype. However, proposed as alternatives to the MMSE, but have not been there is limited data on the frequency of DLB-associated pa- directly compared. The Q&E is a brief test that scores en- thology in community- or population-based dementia sam- coding, temporal orientation, verbal fluency, and recall. The ples. We addressed this issue by examining DLB-associated Addenbrooke’s Cognitive Examination (ACE) has been pathology in a community-based sample of dementia. shown to have excellent sensitivity and specificity for demen- ␣-Synuclein (ASN) immunostaining was performed in 208 tia, and the clock draw, mini-cog, six-item screener and cases of dementia. Fifty-two percent of this sample had ASN MMSE scores can be extracted from it. The Q&E and the abnormalities. The majority of these cases (73%) had coex- ACE were administered by a trained medical assistant to 180 istent pathology of AD (AD-DLB), whereas the remainder patients being evaluated in Dr. Troupin’s memory clinic. (27%) had ASN abnormalities without AD (DLB alone). Alzheimer’s patients with MMSE scores of Ͼ20 were classi- Cognitive testing revealed more severe memory dysfunction fied as mild. A Q&E score of Ն4 (specificity about 95% in in AD-DLB, but more frontal lobe dysfunction in DLB normal elderly (Dash, unpublished)), was defined as abnor- alone. A comparison of demographics found that AD-DLB ε mal. Of 80 patients clinically diagnosed with mild Alzhei- cases were more likely to be female and carry the APOE 4 Ϯ allele. Overall, demographic, clinical, and genetic character- mer’s (average MMSE: 25.3 2.4), the Q&E identified istics of the AD-DLB group were similar to those in AD, 84%, compared with 65% for the mini-cog, 55% for the while the DLB alone characteristics were more similar to six-item, and 41% for the clock draw. The Q&E was supe- Ͻ those observed in Parkinson’s disease (PD). We suspect that rior (p 0.05, overall McNemar’s test) to the three other DLB may include at least two pathophysiological subtypes, screening tests. The Q&E’s superiority was particularly evi- one linked to AD (AD-DLB), and the other to PD (DLB dent in the very mildest patient group; of 40 Alzheimer’s alone). Study supported by Veteran’s Affairs and the Na- with MMSE scores of Ն26, the Q&E picked up 72% versus tional Institutes of Health. the mini-cog’s 48%.

Program and Abstracts, American Neurological Association S19 34. Severity and Rate of Progression of Clinical 36. Initial Evaluation of the Frequency of the Restless Disability in Adrenomyeloneuropathy Patients Legs Syndrome and Sleep Complaints among Patients Prachi Dubey, Hugo W. Moser, Lena Bezmam, with Amyotrophic Lateral Sclerosis Larissa Keldiyarova, Ali Fatemi, Richard O. Jones, and Glen P. Greenough, Jeffrey A. Cohen, Wilfred R. Pigeon, and Gerald V. Raymond; Baltimore, MD Peggy M. Simon; Lebanon, NH OBJECTIVE: Adrenomyeloneuropathy (AMN) is an adult INTRODUCTION: The restless legs syndrome (RLS) is variant of X-linked adrenoleukodystrophy, characterized by characterized by extremity discomfort associated with a desire progressive disability; however, not much is known about the to move. Amyotrophic lateral sclerosis (ALS) patients often rate of progression of clinical disability. METHODS: have sleep complaints. METHODS: ALS clinic patients Twenty-two AMN males (mean age: 40.6 Ϯ 10.1 years) agreeing to participate were screened for RLS (International were followed for a mean duration of 3.6 Ϯ 3 years. Kaplan– Restless Legs Study Group criteria). Participants completed Meier survival plots were used to analyze time elapsed from self-assessment questionnaires. RESULTS: Ten subjects par- ticipated, and 50% met all four criteria for RLS. The Sleep onset of symptoms to onset of severe disability (reaching Disorders Questionnaire subscore means (standard devia- EDSS score 6). RESULTS: Mean age of onset of symptoms Ϯ Ϯ tions) were as follows: periodic limb movement disorder was 29 7 years. Mean EDSS at last follow-up was 5.2 (PLMD), 23.4 (5.1); narcolepsy, 26.4 (7.1); and psychiatric 1.5. Ten patients developed cerebral demyelination. The me- sleep disorders, 22.5 (8.4). Epworth Sleepiness Scale mean dian time from onset of symptoms to reach an EDSS of 6 was 11.7 (4.5) with 70% of scores in the abnormal range of was 13.4 years for the entire cohort and 9 years for cerebral Ͼ9. The Sleep Impairment Index mean was 14.5 (7.6) with AMN. In the entire cohort, 25% patients were expected to 70% having moderate-severe insomnia. The Zung Depres- develop severe disability within 7 years and 75% within 20.6 sion Scale mean was 69.2 (11.8) with 70% of subjects having years of start of symptoms. CONCLUSIONS: The rate of moderate-severe depression. DISCUSSION: Using Parkin- progression of disability in AMN is moderately rapid. The son’s disease (PD) as a benchmark, the prevalence of RLS patients with the cerebral form of the disease appear to and degree of sleepiness among ALS patients are greater. ALS progress far more rapidly. These results provide an estimate patients had elevated indices for PLMD, narcolepsy, and psy- of disease severity and progression needed for planning clin- chiatric sleep disorders, which are greater than reported in ical trials, which employ EDSS as an outcome measure for PD. This study indicates that treatable sleep problems are efficacy evaluation. Study supported by the Johns Hopkins prevalent among ALS patients and may decrease the quality University School of Medicine General Clinical Research of life. Centers (grant #M01-RR00052).

37. Non-Invasive “Phenotyping” of Patients with Spinocerebellar Ataxia Type 3 and Spinocerebellar Ataxia Type 6 by Molecular Imaging 35. Short-Term Hyperglycemia Produces Oxidative W.D. Heiss, A. Thomas, L. Schoels, M. Abele, J. Kessler, Damage and Apoptosis in Neurons E. Kalbe, O. Lenz, R. Hilker, J. Rudolf, T. Klockgether, and Andrea M. Vincent, Lisa L. McLean, Carey Backus, and A.H. Jacobs; Cologne, Germany; Bochum, Germany; and Eva L. Feldman; Ann Arbor, MI Bonn, Germany Dorsal root ganglia neurons in culture die through pro- BACKGROUND: To study differences in cerebral glucose grammed cell death when exposed to elevated glucose, pro- metabolism and neuronal integrity in patients with spinocer- viding an in vitro model system for the investigation of the ebellar ataxia type 3 (SCA3) and spinocerebellar ataxia type 6 (SCA6). PATIENTS/METHODS: Multitracer PET ([18F]- mechanisms leading to diabetic neuropathy. This study ex- 11 amines the time course of programmed cell death induction, FDG, [ C]FMZ), MR imaging, and neuropsychological ϭ the regulation of cellular antioxidant capacity, and the pro- testing were performed in patients with SCA3 (n 8; mean age: 52.6 Ϯ 10.3 years), SCA6 (n ϭ 7; 53 Ϯ 13.8) and tective effects of antioxidants in neurons exposed to hyper- ϭ Ϯ glycemia. We demonstrate that the first 2 hr of hyperglyce- normal controls (n 17; 53.4 14.0). Groups were com- mia are sufficient to induce oxidative stress and programmed pared by SPM. RESULTS: All patients had a similar cere- bellar syndrome (Klockgether score: 12.1 Ϯ 5.8 (SCA3) vs. cell death. With the use of fluorimetric analysis of reactive 10.0 Ϯ 4.3 (SCA6)). Patients with SCA3 tended to have an oxygen species (ROS) production, in vitro assays of antioxi- earlier onset (36.1 Ϯ 11.5 vs. 46.2 Ϯ 12.8 years) and a dant enzymes, and immunocytochemical assays of cell death, longer disease duration (13.9 Ϯ 9.7 vs. 8.0 Ϯ 10.5 years). we demonstrate superoxide formation, inhibition of aconi- Neuropsychological testing detected impaired visuospatial tase, and lipid peroxidation within 1 hr of hyperglycemia. processing, executive functions, and verbal and working These are followed by caspase-3 activation and DNA frag- memory both in SCA3 and SCA6. Glucose metabolism was mentation. Antioxidant potential increases by 3–6 hr, but is lowered in frontal areas (SCA3, SCA6), in the cerebellum insufficient to protect these neurons. Application of the an- (SCA6), and in the brainstem (SCA3). Neuronal integrity tioxidant ␣-lipoic acid potently prevents glucose-induced ox- was markedly disturbed in the cerebellum and in frontobasal idative stress and cell death. The study identifies cellular areas in SCA6. CONCLUSION: Reduced cerebellar FMZ- therapeutic targets to prevent diabetic neuropathy. Study binding is pathognomic for SCA6 indicating early neurode- supported by Juvenile Diabetes Research Foundation Center generation. Mild alterations in SCA3 rather indicate neuro- for the Study of Complications of Diabetes, Program for nal dysfunction. Therefore, non-invasive phenotyping of Understanding Neurological Disease. SCA3 and SCA6 is possible by PET.

S20 Annals of Neurology Vol 56 (suppl 8) 2004 38. Minocycline Delays Motoneuron Degeneration in 40. Protective Effect of Copaxone in Mouse Models of an Adult Rat Model of Facial Nerve Injury ALS Depends on Genetic Background and Gender Ken Ikeda, Jo Aoyagi, Yasumitsu Ichikawa, Osamu Igarashi, Albert C. Ludolph, Birgit Schwalenstoecker, Ruth Danzeisen, Kazuhiko Watabe, Tsuyoshi Sakamoto, and Yasuo Iwasaki; and Stefan Waibel; Ulm, Germany Tokyo, Japan For animal models of ALS, the G 93A (Gly3Ala) mutation Minocycline slows progression of motoneuron disease in mu- of the Cu/Zn SOD is most commonly used. In contrast, tant superoxide dismutase-transgenic mice.Our purpose is to drug effects in hybrid mice can be obscured by the naturally large variation in phenotype; however, they probably model evaluate whether this drug protects motoneurons following the human population more realistically. Copaxone (Cop-1) facial nerve avulsion of adult rats.The right facial nerve was is an FDA-approved drug for the treatment of multiple scle- avulsed at the stylomastoid foramen in Fischer 344 male rats rosis that has been shown to activate a range of self-reactive (12–14 weeks old). Rats were administered 0.1% minocy- T-cells. Previously, we have shown that Cop-1 can improve cline hydrochloride or regular food for 4 weeks (each n ϭ 7). motor function and extend lifespan in B6.Cg-Tg(SOD1- Daily intake of diet was 10–15 g/100 g of body weight, and G93A)1Gur/J) inbred mice. These animals have a relatively loss of food was 10–15 % during food processing. Daily mild disease progression, and survive until about day 220. doses of minocycline were calculated as 100 mg/kg. At 4 We have subsequently tested the efficacy of Cop-1 in B6SJL- weeks postoperation, the lower pons was stained with cresyl- TgN(SOD1-G93A)1Gur (Jackson Laboratories) hybrid violet. The number of facial motoneurons was counted, and mice, animals that die untreated around day 130. Here, ϩ the survival ratio (the number of lesion side / the number of Cop-1 improves motor function and extends life span ( 8 non-lesion side ϫ 100 %) was determined. Immunostaining days) only in female animals, but has no effect in male mice. of microtubule-associated protein-2, GFAP, phospho-p44/ Also, we could demonstrate that this effect is dose- dependent. Our findings strongly indicate that the benefit of p42 and p38 mitogen-activated protein kinase (MAPK), and Cop-1 depends on the genetic background, the gender, and isolectin B4 were done.Compared to vehicle, minocycline the potential immunological profile of transgenic mice. treatment suppressed the loss of motoneurons (p Ͻ 0.01) and preserved the neuronal network.Avulsion induced several p44/p42 MAPK-positive motoneurons.Those motoneurons 41. Role of CD40 in Amyotrophic Lateral Sclerosis and microglial activation, but not astrocytosis, were inhibited Tatsusada Okuno, Yuji Nakatsuji, Atsushi Kumanogo, in minocycline-treated rats.Our data support that minocy- Masayuki Moriya, Harutoshi Fujimura, Hitoshi Kikutani, cline attenuated motoneuron death and reduced microglia and Saburo Sakoda; Suita, Osaka, Japan and Toyonaka, activation in facial nerve injury of adult rats. Osaka, Japan There is increasing evidence that an inflammatory process in association with reactive gliosis may play an important role in the pathogenesis of amyotrophic lateral sclerosis (ALS). One of the recent key findings consistent with an inflamma- 39. Increase of Intracellular Zinc Inhibits Energy tory response in ALS is a marked increase in spinal cord Production in Motor Neurons Expressing Mutant cyclooxygenase-2 (COX2), which is regarded as a valuable Superoxide Dismutase therapeutic target of ALS. We investigated the expression of Hyun-Jung Kim, Jong-Min Kim, Woo-Mi Cho, CD40 in the spinal cord of a transgenic mouse model of ALS immunohistochemically, and its relevance to COX2 up- Jong-Ha Park, Jung-Jun Sung, Manho Kim, and regulation. The expression of CD40 was observed in both Kwang-Woo Lee; Seoul, Korea reactive microglias and astrocytes in the spinal cord of trans- Altered zinc metabolism in relation to the mutant superoxide genic mice, and COX2 was colocalized in those glial cells. dismutase (SOD1) has been suggested as the toxic gain of COX2 was induced in microglias and astrocytes in vitro by function for the familial ALS (FALS). Our study aimed to CD40 stimulation with agonistic antibody. CD40 stimula- investigate the effect of zinc and energy production on mu- tion in primary spinal cord cultures induced motor neuron 2ϩ death, which was reduced significantly by COX2 selective tant SOD1-induced motor neuronal death. Zn was treated inhibitor. Thus our results suggest that CD40, which is up- in the motoneuron-neuroblastoma hybrid cells constitutively regulated in reactive glia in ALS spinal cord, leads to an in- expressing human SOD1 with wild-type or mutations. Intra- ϩ duction of COX2 and contributes to motor neuron death. cellular Zn2 was increased at 4 hr followed by reactive ox- ϩ ygen species (ROS) generation at 8 hr after Zn2 treatment. The viability decreased after 24 hr in the cells expressing mu- 2ϩ 42. Increased Expression of Vascular Endothelial tant SOD1. This Zn -induced death was attenuated by Growth Factor in Skin Biopsies of Patients with broad caspase inhibitor, calpain inhibitor, or anti-oxidant. ϩ Amyotrophic Lateral Sclerosis To further prevent Zn2 -induced neuronal death, energy ϩ Seiitsu Ono, Toshihiro Yamazaki, Tougo Irie, substrates, NAD catabolism inhibitor, and pyruvate dehy- Hiromi Shiraishi, Koji Wakayama, Megumi Suzuki, and drogenase co-factors were tested. Energy substrates and Natsue Shimizu; Ichihara, Chiba, Japan ϩ ϩ NAD catabolism inhibitor attenuated Zn -induced neuro- BACKGROUND: Several studies of skin in patients with nal death. These results indicate that intracellular zinc over- amyotrophic lateral sclerosis (ALS) have shown unique mor- load increase ROS production and cell death in motor neu- phological and biochemical alterations. Vascular endothelial rons expressing mutant SOD1. A defect in cellular energy growth factor (VEGF) is expressed in many tissues and is production through inhibition of glycolysis and the tricar- rapidly upregulated during hypoxia. It has been shown re- oxylic acid cycle may involve a mechanism by which mutant cently that deletion of the hypoxia response element in the SOD1 causes motor neuronal death in some forms of FALS. VEGF promotor causes motor neuron degeneration in mice

Program and Abstracts, American Neurological Association S21 with neuropathological features reminiscent of ALS in hu- striatal Bcl-2 levels and age (18–99 years) was observed. Stri- mans. METHODS: We have performed a quantitative im- atal Bcl-2 distribution was heterogeneous, with levels (ng/␮g munoreactive study of VEGF in skin biopsy samples from protein, n ϭ 25) in nucleus accumbens (0.051 Ϯ 0.004) Ͼ the left upper arm of 11 patients with ALS and from 11 caudate (0.033 Ϯ 0.003) Ͼ putamen (0.024 Ϯ 0.002). controls with other neurodegenerative diseases matched for Throughout rostrocaudal caudate/putamen in the older sex and age. RESULTS: The immunoreactivitiy of VEGF (Ͼ50 years, n ϭ 10) but not the younger subjects (n ϭ 10), was strongly positive in the epidermis and in some blood Bcl-2 level increased significantly dorsoventrally by approxi- vessels and glands of the reticular dermis in all ALS patients. mately 20%, whereas there was a nonsignificant trend for These findings became more conspicuous as ALS progressed. increasing Bcl-2 rostrocaudally in caudate. CONCLUSION: Its optical density in ALS patients (6.22 Ϯ 2.91) was signif- The striking inverse relationship between intrastriatal Bcl-2 icantly higher (p Ͻ 0.001) than in controls (1.65 Ϯ 0.61). level in normal brain and dopamine loss in PD patients sug- Furthermore, there was a significant positive relationship gests a role of Bcl-2-involved events in the aetiology of PD (r ϭ 0.84; p Ͻ 0.001) between the immunoreactivity and and, possibly, a benefit of Bcl-2-mimicking agents in slowing duration of illness in ALS patients. CONCLUSIONS: down the degeneration process. Study supported by the Cen- VEGF was found to be significantly upregulated in skin sam- ter for Addiction and Mental Health. ples from ALS patients.

45. Differences in Cortical Excitability and Selective 43. Clinical Features of Multiple System Atrophy in Neuronal Vulnerability between Sporadic and Japan: MSA-C Is the Most Common Manifestation of Homozygous D90A SOD1 Amyotrophic Lateral MSA in Japan Sclerosis Hiroyuki Soma, Ichiro Yabe, Asako Takei, Naoto Fujiki, and Martin R. Turner, Abena Osei-Lah, Alexander Hammers, Hidenao Sasaki; Sapporo, Hokkaido, Japan Ammar Al-Chalabi, Christopher E. Shaw, Peter M. Andersen, David J. Brooks, Kerry R. Mills, and P. Nigel Leigh; London, The clinical features of 100 patients (57 men and 43 United Kingdom and Umeå, Sweden women) diagnosed as probable multiple system atrophy (MSA) are described. Diagnosis was based on consensus cri- Excitotoxicity is one mechanism proposed in the pathogen- teria. Autonomic symptoms were the initial features in 18% esis of amyotrophic lateral sclerosis (ALS). Patients homozy- of the patients, but had subsequently developed in 100% at gous for the D90A SOD1 gene mutation (homD90A) have a latest follow-up. The most frequent autonomic symptom was unique phenotype, associated with prolonged survival com- bladder disturbance. Cerebellar ataxia was the initial feature pared with sporadic ALS (sALS) patients. This study has in 65% of the patients, but had subsequently developed in used cortical transcranial magnetic paired stimulation to 98% at latest follow-up. Eighty-eight percent of our subjects demonstrate that a group of 11 homozygous homD90A pa- were classified into MSA-C. Parkinsonism was the initial fea- tients have preserved cortical inhibitory pathways, compared ture only in 6%, although subsequently developing in a fur- to the increased cortical excitability seen in the simultaneous ther 39% of cases. Twelve percent of MSA were classified study of a group of 28 sALS patients, when both are com- into MSA-P. Cerebellar ataxia was present in 83% of pa- pared with 24 controls. A unique and parallel visualization of tients with MSA-P and parkinsonism in 33% of patients the cortical GABAA receptor in subjects from both ALS pa- with MSA-C. Previous studies described that MSA-P was the tient groups in which [11C]flumazenil PET was used, has most common manifestation of MSA in a Western popula- demonstrated a marked bilateral relative reduction in cortical tion. However, in our study, the proportion of MSA-C was binding in the sALS compared with the homD90A patients. high, and MSA-P was relatively infrequent in Japan. This This is presumed to reflect neuronal loss and/or reduced different frequency among different ethnic groups suggests GABA-ergic inhibitory influence. The areas of greatest re- that genetic factors may contribute to determine clinical phe- duction were found within motor association areas, particu- notype of MSA. Study supported by a grant for research on larly the superior parietal regions of the sALS patients. This ataxic disease from the Ministry of Health and Welfare of may suggest a distinct cortical vulnerability in the homD90A Japan. patients, with implications for understanding their unique phenotype and the slower progression of disease. Study sup- ported by the Wellcome Trust, the Medical Research Coun- 44. Inverse Relationship between Intra-Striatal cil, and the Motor Neurone Disease Association. M.R.T. is Distribution of Bcl-2 Protein in Normal Human Brain supported through a Wellcome Trust Clinical Research Fel- and the Pattern of Dopamine Loss in Parkinson’s lowship. D.J.B. receives infrastructure finance from the Med- Disease ical Research Council. The King’s MND Care and Research Junchao Tong, Mark Guttman, and Stephen J. Kish; Toronto, Centre receives financial support from the Motor Neurone Ontario, Canada Disease Association. OBJECTIVE: Idiopathic Parkinson’s disease (PD) is charac- terized by an uneven striatal dopamine loss, with putamen 46. Ratio of Mutant/Normal SOD1 Is an Indicator loss Ͼ caudate Ͼ nucleus accumbens, and dorsal loss Ͼ ven- for the Progression of Familial ALS tral. To establish whether the anti-death protein Bcl-2, Yoichi Yamamoto, Takako Sato, Toyofumi Nakanishi, which promotes neuronal differentiation and axonal regener- Fuminobu Sugai, Kei Fukada, Seiichi Nagano, ation, might play a role in the specific heterogeneous dopa- Akira Shimizu, and Saburo Sakoda; Suita, Osaka, Japan and mine terminal loss in PD, we measured intrastriatal Bcl-2 Takatsuki, Osaka, Japan protein distribution in normal human striatum. METH- ODS: Intrastriatal distribution of Bcl-2 (three dorsoventral Familial ALS is caused by the toxic gain-of-function of and rostrocaudal levels) was determined by quantitative im- SOD1 mutant protein. Studies on the clinical course of each munoblotting in 20 autopsied normal brains. RESULTS: A mutation suggested that the age at onset of muscle weakness significant positive correlation (R ϭ 0.48; n ϭ 40) between varied greatly but the duration of illness appeared to be rel-

S22 Annals of Neurology Vol 56 (suppl 8) 2004 atively consistent for a particular mutation. However, it is afraid to undergo the tapering. Three (12%) patients had not investigated why the disease duration varies among mu- normal brain MRI and normal EEG, requested the tapering, tations. We analyzed erythrocytes of 11 patients with FALS and remained seizure-free. One (4%) patient who had nor- using liquid chromatography electrospray ionization mass mal brain MRI and normal EEG requested the tapering but, spectrometry to estimate the turnover of the mutant pro- six months later, had a generalized tonic-clonic seizure. It teins. Four cases, whose mutant/normal SOD1 in erythro- appears from this brief study that the major factor in the cytes was 0, progressed to respiratory failure within 2 years tapering of AEDs in 2-year, seizure-free epileptic patients is from onset, whereas the remaining 7 cases, whose mutant an updated abnormal EEG. A second important factor is the SOD1 proteins were detectable in erythrocytes, went to re- patients’ acceptance of the AED tapering. spiratory support or died of respiratory failure or were still alive without respiratory support after 2 years from onset. Our results suggested that the rapid turnover of mutant 49. Anti-Epileptic Property of Bilateral Subthalamic SOD1 proteins caused rapid progress of the disease course. Stimulation in a Patient with Parkinson’s Disease Boulos-Paul W. Bejjani, Mazen G. Jabre, and George Nohra; Byblos, Lebanon EPILEPSY BACKGROUND: Subthalamic stimulation (STN DBS) is effective in the treatment of advanced Parkinson’s disease 47. Absence of LGI1 Mutations in Familial Mesial (PD) and suppresses seizures in diverse animal models of ep- Temporal Lobe Epilepsy Patients with or without ilepsy. OBJECTIVE: We report the dual efficacy of STN Auditory Hallucinations DBS on intractable epilepsy and severe parkinsonism in a AmanPreet Badhwar, Lemuel Racacho, Eliane Kobayashi, patient with Parkinson’s disease. METHODS: A 47-year- Daniela D’Agostino, Francois Dubeau, Frederick Andermann, old, right-handed woman with a history of PD and epilepsy Dennis Bulman, and Eva Andermann; Montreal, Quebec, underwent STN DBS a year ago resulting in the marked Canada and Ottawa, Ontario, Canada improvement of all parkinsonian symptoms. Before surgery, Familial temporal lobe epilepsy (FTLE) can be subdivided she had a severe disabling PD (UPDRS-III: 52/108) with into mesial (FMTLE) and lateral (FLTLE) FTLE. Whereas severe dyskinesias and motor fluctuations, despite treatment FMTLE has been associated with polymorphisms in five dif- optimization. Her long epilepsy history was characterized by ferent genes, LGI1 gene(chromosome 10q) mutations have intractable generalized myoclonic seizures, with more than been demonstrated in several FLTLE families. Simple partial two fits per week, despite treatment with Valproate, Clonaz- seizures with AH is a hallmark of FLTLE. To date, we have epam, and Lorazepam. RESULTS: After surgery, there was identified a few FMTLE patients with auditory hallucina- an 85% improvement of parkinsonian symptoms and the pa- tions (AHs), usually in the context of experiential phenom- tient became seizure free with normalized EEG. Levodopa ena. Our aim was to determine if (1) patients with FMTLE was stopped; she was maintained on Pergolide monotherapy and with (2 patients) or without (16 patients) AHs, and (2) (0.5 mg/day); Valproate dose was reduced by 25%; Clonaz- sporadic TLE patients with AHs (3 patients) have LGI1 mu- epam was maintained; and Lorazepam was withdrawn. tations. In the 21 patients, mean age of seizure-onset was CONCLUSIONS: Subthalamic stimulation was effective in 15.7 years (range: infancy to 52 years of age). Seizure types controlling severe PD and refractory epilepsy. In addition to included simple partial, complex partial, and occasional sec- its role in the pathophysiology of movement disorders, the ondary generalization. AHs were present in 24% of patients; subthalamic nucleus seems to be implicated in epilepsy. febrile seizures, in 20%; and deja-vu in 13%. Forty percent had intractable seizures. Hippocampal atrophy was present in 56% and gliosis in 33%. No mutations of the LGI1 gene 50. Oscillatory Activity Originating at Network Lesion were identified. We identified two known and one novel Boundaries: A Model for Early Posttraumatic Epilepsy SNP. Our results demonstrate that AHs in FMTLE patients Elan L. Ohayon, Maxim Bazhenov, Terrence J. Sejnowski, is not due to LGI1 mutations, and additional gene(s) might Igor Timofeev, Paul W. Tsang, Donald S. Borrett, be involved in the aetiology of FMTLE with AHs and spo- Hon C. Kwan, and McIntyre W. Burnham; La Jolla, CA; radic TLE with AHs. Toronto, Ontario, Canada; and Quebec City, Quebec, Canada Anatomical damage to neuronal networks can lead to sub- 48. Tapering of Antiepileptic Drugs in 2-Year, stantial alterations in system dynamics. An archetypal exam- Seizure-Free Patients with Partial and Secondarily ple, for which the pathophysiological mechanisms remain Generalized Epilepsy largely unknown, is early posttraumatic epilepsy. Changes in Juan C. Barrera and Cynthia L. Harden; Scranton, PA and intrinsic cell properties are often postulated to be the causal New York, NY factors. However, localized changes in network structure may Gradual tapering of antiepileptic drugs (AEDs) in 2-year, be sufficient to explain the effects of lesions on brain dynam- seizure-free patients with partial and secondarily generalized ics without assuming changes to cell properties. We demon- epilepsy is a common practice among neurologists, but little strate this principle in computational models (ranging from is known about patients’ acceptance. In a prospective study, 900 to 10,000 cells) in which certain balanced conditions are patients with partial onset epilepsy, who were seizure-free for disturbed by the introduction of even a small lesion. Re- 2 years, were older than 18 years, and were on monotherapy, duced feedback between boundary cells after lesioning lowers and who had updated normal brain MRI and updated nor- mutual damping effects, thereby allowing for high-amplitude mal EEG, were included. The tapering of the AEDs was elic- synchronous activity to begin at the lesion boundary. Once ited in 8–12 weeks. Twenty-five patients fulfilled the selec- this activity is initiated it may propagate far beyond the site tion criteria. Thirteen (52%) patients had normal brain MRI of damage. This study suggests that phenomena such as hy- but abnormal EEG and could not be tapered. Eight (32%) perexcitability and synchrony following lesions or cell death had normal brain MRI and normal EEG but they were may be due to changes in network connectivity, which

Program and Abstracts, American Neurological Association S23 would explain the increased risk of early seizures following MOVEMENT DISORDERS trauma. These principles may also underlie changes in EEG accompanying other types of cell loss in the CNS, such as 53. Baseline Characteristics of the Prospective Alzheimer’s, Parkinson’s, and CJD. Study supported by the Huntington at Risk Observational Study Cohort Canadian Institutes of Health Research – Institute of Neu- Kevin M. Biglan and PHAROS Investigators; Baltimore, MD rosciences and by a Mental Health and Addiction Ohayon BACKGROUND AND OBJECTIVE: Prospective Hun- Doctoral Research Award. tington at Risk Observational Study (PHAROS) enrolled clinically unaffected adults at risk for Huntington’s disease (HD) who chose not to undergo presymptomatic DNA test- 51. Long-Term Seizure Control of AEDs after ing. The earliest and gene-specific clinical signs in this cohort Epilepsy Surgery will apply to therapeutic trials aimed at postponing the onset Dieter Schmidt; Berlin, Germany of HD. DESIGN/METHODS: Research participants in- cluded unaffected adults at 50% risk for HD, 26 to 55 years Although seizure outcome while taking antiepileptic drugs old, who agreed to longitudinal evaluations and blinded de- (AEDs) after temporal lobe surgery is well known, it less termination of HD gene status. Demographic and clinical clear how many patients are seizure-free for several years features were assessed using the Unified Huntington’s Dis- without taking AEDs. According to a recent review, one in ease Rating Scale (UHDRS). RESULTS: Between July 1999 three seizure-free surgical patients suffers a seizure recurrence and January 2004, 1001 research participants were enrolled after planned AED discontinuation (Schmidt et al., 2004). A at 43 sites in North America. The cohort, mean age 41.8 Ϯ follow-up review of the literature included 13 retrospective 7.3 years, was disproportionately female (68.8%), highly ed- and 5 prospective observational studies published since 1980 ucated (15.0 Ϯ 2.6 years), and employed (95.8%). Motor that provided data on long-term seizure control of AEDs. UHDRS scores were near the floor of the scale (2.8 Ϯ 4.3), No randomized controlled trials were found. Following tem- and only 1% of participants were judged to have manifest poral lobe surgery, approximately one in three to four pa- HD. Depression was more commonly reported in women tients can currently be shown to be seizure-free for 5 years (33.3%) than men (18.3). CONCLUSIONS: The PHAROS without AEDs (25%, mean of eight studies in adults, 95% cohort is predominantly female and more highly educated CI: 21–30%, mean 31% of three studies in children and and employed than the at-risk HD population as a whole. adolescents, 95% CI: 20–41%). However, 55% of patients Manifest HD was rare at baseline. Longitudinal follow up is free of disabling seizures (including patients with persistent in progress. The authors do not have any personal financial auras) were still on AEDs 5 years after surgery. A random- interest in this research, which was supported by the Na- ized controlled trial of AED discontinuation in patients who tional Institutes of Health (HG 02449), the Hereditary Dis- have been seizure free for 2 years on AEDs after temporal ease Foundation, the High Q Foundation, and the Hunting- lobe surgery may be able to show that the outcome reported ton’s Disease Society of America. here was too pessimistic.

52. Diagnostic Value of Basic Tests (History Taking, Routine EEG, MRI, and Video EEG Monitoring) for 54. Differential Impact of D1 and D2 Dopamine the Decision to Perform Temporal Lobe Epilepsy Receptor Stimulation on Bladder Function in Surgery Parkinson’s Disease Sabine G. Uijl, Karel G.M. Moons, Johan B.A.M. Arends, Livia Brusa, Filomena Petta, Vincenzo Moschella, Jaime Parra, Alexander C. Van Huffelen, and Paolo Stanzione, Pietro Tiraboschi, and Enrico Finazzi-Agro`; Frans S.S. Leijten; Utrecht, Netherlands; Heeze, Netherlands; Rome, Italy and Milan, Italy and Heemstede, Netherlands BACKGROUND AND OBJECTIVE: In addition to motor BACKGROUND: Candidates for temporal lobe epilepsy impairment, most patients with Parkinson’s disease (PD) dis- (TLE) surgery were subjected to several diagnostic tests. We play urinary disturbancies (urgency, increased frequency, quantified to what extent the decision for surgery can be and/or incontinence). Because animal studies have suggested made with widely available tests only. METHODS: We used that stimulation of D1 dopamine receptors inhibits bladder a population-based retrospective study, assessing diagnostic voiding, while that of D22 receptors facilitates micturition, accuracy of patient history, routine EEG, MRI, and video we investigated whether the addition of sulpiride (a D2 an- EEG monitoring, separately and in combination, in relation tagonist) to L-dopa (a mixed D1/D2 agonist) might improve to the decision for TLE surgery, including ROC analyses of bladder dysfunction in PD patients. SUBJECTS AND the diagnostic workup. RESULTS: The outcome was the de- METHODS: We examined a cohort of 60 patients with cision to perform surgery in 117 patients and not to perform mild PD (Hohen and Yahr score Ͻ2.5) and urinary urgency, surgery in 84 patients. The ROC area, including all diagnos- all of whom were evaluated with urodynamic studies in tic tests, was 0.70. Of 33 patients with concordant unilateral washout condition and after acute administration of temporal abnormalities on MRI and video EEG, 5 were not carbidopa/L-dopa (50/200 mg). Thirty of them were addi- eligible for surgery. Of the operated patients, 92 showed uni- tionally assessed after acute administration of the same dose lateral temporal abnormalities on MRI; of these, 60 had dis- of carbidopa/L-dopa plus either 25 or 150 mg of sulpiride. cordant abnormalities on routine EEG. CONCLUSIONS: RESULTS: Increased bladder overactivity induced by L-dopa Basic tests perform moderately in the decision for TLE sur- was reversed by the addition of 150 mg of sulpiride. No gery. There is no subgroup of patients in which the decision significant improvement was conversely observed with coad- for surgery can always be made, on the basis of these tests ministration of 25 mg of sulpiride. CONCLUSIONS: In alone. Patients should not be rejected for surgery because of keeping with animal studies, our findings imply that urinary discordant routine EEG results. Study supported by the dysfunction seen in PD patients is worsened by D2 receptor Netherlands Epilepsy Foundation. stimulation.

S24 Annals of Neurology Vol 56 (suppl 8) 2004 55. Apathy and Psychosis in Early Onset Parkinson 57. Botulinum Toxin Serotype A Compared to B in Disease Cervical Dystonia: Randomized, Double-Blind, Parallel Anjan Chatterjee, Elan D. Louis, Helen Mejia-Santana, Study Howard Andrews, Juliette Harris, Cheryl Waters, Blair Ford, Cynthia L. Comella, Joseph Jankovic, Sue Leurgans, Steven Frucht, Stanley Fahn, Ruth Ottman, and Wenqing Fan, Teresa Chmura, and Karen S. Marder; New York, NY the Dystonia Study Group; Chicago, IL and Houston, TX OBJECTIVE: We assessed the prevalence and clinical corre- Two serotypes of botulinum toxin (BoNTA and BoNTB), lates of apathy and psychosis in early vs. late onset Parkin- approved for treatment of cervical dystonia (CD), were com- son’s disease (EOPD [onset age Յ50 yrs] vs. LOPD). pared with respect to maximal efficacy, duration, and adverse METHODS: Apathy and psychosis (UPDRS-1) were de- events in a randomized, double-blind, parallel study. Subjects Ͻ Ն fined as dichotomous variables (score or 2). Patients were evaluated in a blinded fashion at baseline, 4 weeks, and were also administered the modified mini-mental status exam at 2–4-week intervals thereafter until they lost 80% of clin- (mMMSE). Logistic regression models examined each out- ical effect or completed 20 weeks of observation. CD severity come in analyses controlling for age, age at onset, gender, was measured with the Toronto Western Spasmodic Torti- marital status, ethnicity, disease duration, severity of collis Rating Scale (TWSTRS), and adverse events were as- illness(UPDRS-2), education, mMMSE, depression, and sessed by a structured interview. There were 122 subjects medications. RESULTS: Thirty-five of 243 (14.4%) EOPD (BoNTA, n ϭ 63; BoNTB, n ϭ 59) enrolled and analyzed and 18 of 268 (6.7%) LOPD patients had psychosis, in the study from 19 centers. Similar magnitude of improve- whereas 29 (11.9%) EOPD and 30 (11.1%) LOPD patients ment in TWSTRS score from baseline (42.7 (9.7)) was had apathy. In the logistic model, EOPD vs LOPD was not found at week 4 for both BoNTA (⌬ TWSTRS ϭ 11.2 associated with either outcome. Psychosis in EOPD corre- (7.2)) and BoNTB (⌬ TWSTRS 11.3 (8.1)) (p Ͻ 0.0001). lated with age (B ϭ 0.1, p ϭ 0.001), age at onset (B ϭ BoNTA had a longer duration of benefit (BoNTA, 14 Ϫ0.17, p ϭ 0.001), and mMMSE (B ϭϪ0.1, p ϭ 0.03), weeks; BoNTB, 12.1 weeks; p ϭ 0.025). Dysphagia whereas apathy correlated with age (B ϭ 0.1, p ϭ 0.002), (BoNTA, 5%; BoNTB, 37%; p ϭ 0.002) and dry mouth mMMSE (B ϭϪ0.1, p ϭ 0.004), depression (B ϭ 2.2, p ϭ (BoNTA, 5%; BoNTB, 43%; p Ͻ 0.0001) were more fre- 0.001), and being single (B ϭ 1.1, p ϭ 0.03). CONCLU- quent with BoNTB. Despite comparable maximal benefit, SIONS: The prevalence of apathy and psychosis are similar in EOPD and LOPD. In EOPD, measures of disease dura- BoNTA had fewer adverse events and a longer duration of tion and/or severity are associated with psychiatric symp- effect. Study supported by an unrestricted research grant to toms. Study supported by RO1 NS36630 (Dr. Marder, PI). the Dystonia Study Group by Allergan Pharmaceuticals.

56. A Novel Anti-GAD-Antibody-Positive Neurological 58. Age-Related Influences on the Clinical Syndrome of Generalized Dystonia Responding to Characteristics of New-Onset Hallucinations in Immunotherapy Parkinson’s Disease Patients Abhijit Chaudhuri and Peter O. Behan; Glasgow, Scotland, Christopher G. Goetz, Joanne Wuu, Linda Curgian, and United Kingdom Sue Leurgans; Chicago, IL Stiff-person syndrome is the prototype anti-GAD-antibody- OBJECTIVE: We sought to determine the influence of pa- positive neurological disorder. We report here a unique case tient age on sensory (pure visual vs. nonvisual or mixed vi- of multifocal and generalized dystonia associated with anti- sual/nonvisual) characteristics of new-onset hallucinations in GAD-antibody. This patient, who is of Scottish descent and without a family history, has been followed up for 17 years. PD. METHODS: We utilized data sets from a 6-year lon- She had first presented at the age of 16 with foot dystonia, gitudinal study of 60 PD patients who had no hallucinations progressing over a period of 2 years to severe generalized dys- at baseline. We re-interviewed them at 6, 18, 48, and 72 tonia refractory to anti-cholinergics and levodopa. She re- months to assess presence and type of hallucination that de- quired to be paralyzed and ventilated because of her contin- veloped as the first form of hallucination. We analyzed data uous dystonic muscle spasms. Her electrophysiology was by Wilcoxon rank-sum test. RESULTS: Over 72 months, 37 negative for stiff-person syndrome. All secondary causes of of 60 patients developed hallucinations. The hallucinations dystonia were excluded, and she was successfully treated with were pure visual in 18, nonvisual in 9, and mixed visual/ immunotherapy using plasma exchange, corticosteroids, and non-visual in 10. At the time of first hallucination, patients long-term azathioprine. She is susceptible to relapses related whose hallucinations were nonvisual or mixed were signifi- to severe physical exertion, atopy, and infection, but she re- cantly older than those with purely visual hallucinations mains responsive to corticosteroid therapy. We suggest that (mean age 69.8 Ϯ 8.3 vs. 61.9 Ϯ 10.6; p ϭ 0.031). Disease some cases of dystonia may have an immunopathogenic basis duration in the two groups, however, was statistically com- similar to stiff-person syndrome, a movement disorder of au- parable (9.6 Ϯ 4.4 vs. 12.9 Ϯ 8.6 years). CONCLUSIONS: toimmune origin. It may be useful to consider anti-GAD- Though classically described as visual, hallucinations in PD antibody test in the absence of other primary or secondary frequently involve other sensory modalities. It is possible that causes of dystonia and in those who are refractory to con- age-related disinhibition facilitates wider cortical activation in ventional treatment because of possible therapeutic implica- PD and potentiates aberrant signaling that invokes other tions. Study supported by the David and Frederick Barclay types of hallucinations besides the classic visual forms. Study Foundation. supported by the Parkinson’s Disease Foundation.

Program and Abstracts, American Neurological Association S25 59. Serotonin Transporter Gene Polymorphisms and 61. Genomic Sequence Analysis of the DYT3 Region Hallucinations in Parkinson’s Disease on Human Chromosome Xq13.4 Jennifer G. Goldman, Christopher G. Goetz, Satoshi Makino, Ryuji Kaji, Maiko Tomizawa, Elizabeth Berry-Kravis, Sue E. Leurgans, Lili Zhou, and Masataka Nishimura, Shinnichi Matsumoto, Daisy Tabuena, Chinton Desai; Chicago, IL Elma Maranon, Marita Dantes, Lillian V. Lee, Satoshi Ando, and Gen Tamiya; Isehara, Kanagawa, Japan; Tokushima, OBJECTIVE: To investigate serotonin transporter gene (5- Tokushima, Japan; Iloilo, Panay, Philippines; and Quezon HTT) polymorphisms and hallucinations in Parkinson’s dis- City, Philippines ease (PD). BACKGROUND: Dopaminergic overactivity does not sufficiently explain hallucinations in PD. Atypical X-linked dystonia-parkinsonism (XDP) is an endemic disease anti-psychotic receptor profiles suggest serotonergic involve- presenting with severe torsion dystonia and subsequent par- ment. Two functional 5-HTT polymorphisms influence the kinsonism. The disease gene, DYT3, was previously reported serotonin transporter protein: a promoter VNTR (short allele to have a linkage to human chromosome Xq13.1. However, — lower transporter levels than long allele) and intron 2 the DYT3 gene and its causative mutation is not fully delin- VNTR (10 allele — reduced transcription relative to 12 al- eated. To find all variants within the DYT3 region, we em- ployed a genomic sequence analysis. We first constructed a lele). METHODS: We studied 44 cases with PD and BAC contig using XDP patients’ DNA, which consisted of chronic hallucinations and 44 controls with PD without hal- eight BAC clones and covered 462,651 bp in the DYT3 crit- lucinations, matched for age and dopaminergic therapy. ical region between the GJB1 and CXCR genes. The DYT3 DNA isolated from blood was genotyped by PCR. Genotype region also includes eight other genes, ZNF261, NONO, and allele frequencies were compared using Mantel–Haens- Melusin, TAF 250, ING1-like, FLJ23071, OGT, and ACRC zel, ␹2, and Wilcoxon signed-rank tests. Statistical signifi- II Ͻ genes. Subsequently, we determined the entire genomic se- cance was p 0.05. RESULTS: No significant differences quence of the DYT3 region by the shotgun sequencing strat- occurred between genotype distribution and allele frequency egy with an average 5-fold redundancy. As a result, 169 vari- for either the 5-HTT promoter or intron 2 VNTR polymor- ants were found in the DYT3 region, including many base phisms. No difference was seen between cases and controls substitutions, small indels, and some chromosome rearrange- when comparing subjects with the least (s/s 10/10) and most ments. This was 20 times as many as the number of variants (l/l 12/12) serotonin transporter. CONCLUSIONS: Our reported previously. After listing these variants, we per- case-control study does not support an association of 5-HTT formed expression analyses, by northern hybridization and polymorphisms with hallucinations in PD. These polymor- quantitative RT-PCR, and we found a hitherto unrecognized phisms may have greater association with anxiety and affec- candidate gene in which patient-specific mutations of these tive disorders than psychosis. Alternatively, individual sero- variants were located. Study supported by a COE grant from tonin receptors rather than the transporter may affect the Japanese Ministry of Science, Culture, Education, and hallucinations and psychosis. Study supported by the Parkin- Sports. son’s Disease Foundation.

62. Uncoupling between Glucose Metabolism and 60. Cervical Radiculomyeloptahy and Parkinson’s Cerebral Blood Flow in Patients with Spinocerebellar Disease: Does an Added Neurological Comorbidity Ataxia Affect UPDRS and Hoehn and Yahr Scores? Yasushi Kato, Kaname Matsumura, Yuri Nakagawa, Ilia Itin, Christopher G. Goetz, and Sue Leurgans; Yutaka Naito, Yugo Narita, Kan Takeda, and Chicago, IL Shigeki Kuzuhara; Tsu, Mie, Japan OBJECTIVE: We sought to assess the added impact of cer- We compared the glucose metabolism of the cerebellum, which was measured by using FDG-PET, and the rCBF, vical radiculomyelopathymyelopathy on Parkinson’s disease- 99m Ј related impairment. METHOD: Using case-control method- which was measured by using Tc(V)oxo-1, 2-N,N - ology, we screened our database to identify seven patients ethylenedylbis-L-cysteine, diethyl ester (ECD) SPECT in with PD and cervical myelopathy corroborated by the MRI three patients with SCA (two cases of multisystem atrophy with cerebellar ataxia and one case of SCA3). In SCA pa- findings. Two controls with PD and no radiculopmyelopathy tients, PET showed a significant hypometabolism of glucose matched for age of onset and the duration of PD were ran- (control vs. SCD by 70.0%, p Ͻ 0.001) in the cerebellum. domly selected from the database. We compared the motor SPECT showed a significant decreased rCBF in the cerebel- function and the rate of deterioration in UPDRS and Hoehn lum (control vs. SCD by 82.6%, p Ͻ 0.001). On the other and Yahr scales over 1 year in the two groups using Wil- hand, both in controls and patients with SCD, the cerebel- coxon signed-rank test. RESULTS: The mean ages of onset lum/cerebrum ratio of glucose metabolism was significantly and duration of PD were equivalent between cases and con- lower than that of the rCBF (controls, p Ͻ 0.001; SCD, p Ͻ trols. At baseline, there was no significant difference in UP- 0.01).These data suggest that glucose metabolism was more ϭ ϭ DRS (p 0.17) and Hoehn and Yahr (p 0.24) between severely involved than the rCBF in cerebellum in SCA pa- the two groups. After 1 year, specific PD impairment did not tients. This may suggest that in the cerebellum in SCA pa- progress in either group, and the myelopathy did not affect tients, glucose hypometabolism occurs before the decrease of PD standard assessments. CONCLUSION: In this series, the rCBF. It is concluded that PET can demonstrate patho- the superimposition of myelopathy on PD affected neither logical changes in the cerebellum better than SPECT and UPDRS nor Hoehn and Yahr scores. PD scales appear to thus is more sensitive and useful for the clinical evaluation of reliably capture parkinsonian features despite other neurolog- SCA. The uncoupling between cerebral blood flow and glu- ical comorbidity. cose metabolism may be characteristic of SCA.

S26 Annals of Neurology Vol 56 (suppl 8) 2004 63. Voxel-Based Relaxometry: Application to Multiple- 65. Identification and Characterization of a Novel System Atrophy Biomarker That Specifically Predicts Parkinson’s Thomas Klockgether, Martina Minnerop, and Karsten Specht; Disease Bonn, Germany and Julich, Germany Giulio M. Pasinetti; New York, NY Voxel-based morphometry (VBM) is an MRI-based method In ongoing surface-enhanced laser desorption ionization-mass that allows the analysis of densities of grey and white matter spectrometry (SELDI-MS) studies aiming at establishing bi- tissue within T1-weighted images. We here present a novel ological markers of Parkinson’s disease (PD) onset and pro- morphometric method, voxel-based relaxometry (VBR). In gression, we identified a 4.6-kDa anionic protein species VBR, the relaxation rate of each voxel is estimated from whose content is selectively and consistently elevated in the cerebral spinal fluid (CSF) of PD, relative to neurologically multi-echo T2-weighted images without segmentation of im- normal control (NC) cases. On the basis of peptide sequence ages into grey and white matter. Subsequently, SPM is used analysis, we identified this 4.6-kDa anionic protein as derm- to perform a voxel-wise comparison of the relaxation rates cidin (DCD-1). We generated a quantitative DCD-1 ELISA between groups. In a group of cerebellar multiple-system at- assay to validate our SELDI-MS evidence that DCD-1 may rophy patients (MSA-C), relaxation rates were significantly be a novel CSF biomarker for PD. We found that DCD-1 increased in the cerebellum and brainstem. Compared with ELISA immunoreactive material content in CSF was elevated the alterations detected by VBM, the abnormalities were in medicated PD cases (n ϭ 27), relative to age-matched NC more widespread and pronounced. In parkinsonian MSA pa- cases (n ϭ 10) (PD vs. NC; p Ͻ 0.05; t-test). Using “re- tients (MSA-P), VBR similarly showed alterations in the cer- ceiver operating characteristic” analysis, we were able to dis- ebellum that were more pronounced than those detected by tinguish PD from NC cases with 81% sensitivity and 100% VBM. In addition, VBR showed increased relaxation rates in specificity. Finally, we found that the DCD-1 immunoreac- the basal ganglia, in particular in the lateral parts of the pu- tive material in the CSF of PD cases was highly sensitive tamen, whereas VBM did not consistently show abnormaili- (81%) and specific (98%) in discriminating PD from pro- ties in the basal ganglia of MSA-P patients. In conclusion, gressive supranuclear palsy cases, which is a major challenge VBR is more sensitive than VBM in detecting cerebellar and for differential diagnosis of PD. Thus, our studies provide a brainstem atrophy in MSA. In addition, VBR reveals abnor- basis for the design of a much-needed biological diagnostic malities within the basal ganglia that are not detected by test for PD. Study supported in part by PCM Lifescience and the Michael J. Fox Foundation (G.M.P.). VBM.

NEUROGENETICS 64. NEMO Binding Domain Inhibits the Formation of Cytoplasmic Inclusions: Phosphorylated I␬B␣ as Its 66. Presenilin-1 Alzheimer’s Disease Mutations: Do Target Protein Is a Novel Component of Lewy Bodies Synaptophysin Disturbances Play a Role in the Pathophysiology? Kazuyuki Noda, Toshiaki Kitami, Wei Ping Gai, Tamer Abdelhak, Thomas W. Smith, Linda Nee, Poul Henning Jensen, Keiji Tanaka, Nobutaka Hattori, and Mike Wong, and Carol F. Lippa; Philadelphia, PA; Yoshikuni Mizuno; Bunkyo, Tokyo, Japan; Bedford Park, Worcester, MA; and Bethesda, MD South Australia, Australia; and Aarhus C, Denmark Synaptic disturbances may play a key role in the pathophys- OBJECTIVE: We sought to determine whether immunore- iology of Alzheimer’s disease (AD). We previously demon- activities for phosphorylated I␬B␣ (pI␬B␣) and SCF com- strated plaques, similar to cotton wool plaques, in plex are localized in Lewy bodies (LBs). METHODS: We presenilin-1 (PS-1) AD cases with the C410Y mutation. examined immunohistochemical analysis of postmortem These plaques show reduced ␤-amyloid and ␶. The current brain tissues from sporadic PD and dementia with LBs investigation determines whether there is differential synap- (DLB). Furthermore, accumulation of pI␬B␣ was investi- tophysin staining in these plaques. We examined 6-micron gated after addition of MG132 for 24 hr in SH-SY5Y cells. sections of the medial temporal lobe from 13 patients with We investigated whether inhibition of I␬B␣-kinase (IKK) AD using an antibody to synaptophysin (Boehringer- has an effect on inclusion formation and cell death, using Mannheim, with microwave enhancement). Postmortem de- Ͻ selective IKK-inhibitory peptide corresponding to the lays were 10 hr. Plaques showing increased immunoreac- NEMO-binding domain (NBD) that interacts within both tivity for synaptophysin (relative to the background gray IKKs. RESULTS: We showed that pI␬B␣ is localized in matter) were observed in all C410Y cases. Occasional synap- LBs. In SH-SY5Y cells using MG132, we found the tophysin plaques were observed in cases with other PS-1 mu- tations. Plaques with decreased synaptophysin immunoreac- ubiquinated inclusions that were also immunoreactive for ␬ ␣ tivity were occasionally present in A246E PS-1 cases in the pI B and SCF complex. The cell-permeable NBD peptide context of a synaptophysin-positive neuritic reaction. In spo- reduced the frequency of cytoplasmic inclusions containing radic AD, plaque immunostaining did not stand out. We ubiquitin and pI␬B␣ but not the cell viability loss. CON- ␬ ␣ conclude that plaques in C410Y cases may show increased CLUSION: We showed that pI B was involved in LBs in synaptophysin immunoreactivity. This raises several possibil- PD and DLB cases. Finally, we note that protein aggregation ities, including the following: 1) PS-1 misprocessing influ- due to proteasomal dysfunction may be an important mech- ences synaptophysin (or synaptic protein) expression; 2) anism in the formation of LBs. Furthermore, we indicated C410Y plaques induce synaptic in growth, or 3) synaptic that cytoplasmic inclusions are independent from the dopa- density is decreased in regions surrounding these plaques. minergic cell death. Study supported by the Robert Potamkin Foundation.

Program and Abstracts, American Neurological Association S27 67. Clinical Experience on 156 Cases of Adult-Onset 69. Alternative Splicing May Contribute to Tissue- Neurological and Psychiatric Lysosomal and Specific Phenotype in Aprataxin-Related Ataxia Peroxisomal Genetic Metabolic Diseases: Diagnostic Makito Hirano, Yoshiko Furiya, Shingo Kariya, and Strategy Satoshi Ueno; Kashihara, Nara, Japan Nicole A. Baumann, Jean-Claude Turpin, Mireille Lefevre, Early-onset ataxia with ocular motor apraxia and hypoalbu- and Benoit Colsch; Paris, France minemia (EAOH) is the most commonly observed Genetic neurometabolic lysosomal and peroxisomal diseases autosomal-recessive cerebellar ataxia in Japan,and it is caused can manifest for the first time during adolescence and/or by mutations in the aprataxin gene. A wide range in severity adulthood. Their presentation may be that of a degenerative of clinical symptoms, including ataxia, disturbed eye move- disease of the central nervous system (for example, spastic ment, neuropathy, and dementia, imply that the mutant paraparesia for adrenoleukodystrophy, spinal muscular atro- gene causes the various degrees of functional deficits in indi- phy for GM2 gangliosidosis, and psychiatric troubles vidual tissues, indicating that factors other than the gene mu- “pseudo-schizophrenic” for metachromatic leukodystrophy). tation contribute to the phenotype of EAOH. Alternative In recent years, we have found 67 cases of X-linked adreno- splicing is a widespread mechanism for regulating gene ex- myeloneuropathy (equally in hemizygote males and hetero- pression and generating isoform diversity. We have recently zygote females); 21 cases of metachromatic leukodystrophy found six splice-variant transcripts of aprataxin. In the (either with spinocerebellar ataxia or with mainly a psychiat- present study, the quantitative analyses showed that a total ric symptomatology); 11 cases of Niemann-Pick type C (pre- of seven variant transcripts encoding three variant proteins senting either with spinocerebellar symptomatology or with were expressed predominantly in tissues spared in EAOH. psychiatric symptoms), 7 cases of GM2 gangliosidosis (pre- Each variant protein bound to wild-type protein with dif- senting as Kugelberg–Welander disease, dystonia, and some- ferent binding affinity. A disease-causing mutant protein times psychiatric manifestations), 20 cases of Fabry’s disease reduced binding ability to the variant proteins. Thus, the (rarely starting by a cerebro-vascular accident); and 30 cases alternative splicing increases the molecular diversity of of Gaucher disease (including 3 with neurological manifesta- aprataxin and the expression profiles may partially account tions). We have established a clinical diagnostic strategy. It is for the tissue-specific phenotypes. This study was supported particularly important for genetic counseling. Also, many of by a grant-in-aid for scientific research from the Ministry of these diseases start being accessible to enzyme substitutive Education, Culture, Sports, Science, and Technology of Ja- therapy or to metabolic inhibitors. Study supported by the pan. European Leukodystrophy Association (ELA) and the Vain- cre les Maladies Lysosomales (VML Association).

70. Early-Onset Parkinsonism in Heterozygous Parkin Mutation Carriers 68. ␣-1-Antichymotrypsin Gene Polymorphism and Rivka Inzelberg, Puiu Nisipeanu, Ralph L. Carasso, Susceptibility to Multiple-System Atrophy Sergiu C. Blumen, Nobutaka Hattori, and Yoshiko Furiya, Makito Hirano, Shingo Kariya, Yoshikuni Mizuno; Hadera, Israel; Haifa, Israel; Takuya Nakamuro, Ryusuke Matsumura, and Tokyo, Japan Naonobu Futamura, and Satoshi Ueno; Kashihara, The PARK-2 phenotype has been described in carriers of Nara, Japan various mutations in both alleles of the parkin gene. Muta- Multiple-system atrophy (MSA) is a sporadic, progressive tions in a single allele of parkin are thought to represent a neurodegenerative disease, characterized by a clinically com- susceptibility gene for idiopathic late-onset Parkinson’s dis- plex combination of cerebellar, pyramidal, extrapyramidal, ease. We herein describe the clinical features of heterozygous and autonomic disorders. Despite accumulated knowledge in parkin mutation carriers. Eight sporadic parkinsonian pa- pathohistology, little is known about the genetic risk factors tients (onset Ͻ50 years) and 10 patients belonging to two for their onset. Recent studies have demonstrated neurode- families with consanguineous parents were examined. DNA generation of MSA and Parkinson’s disease (PD) may be at- was extracted from blood leukocytes and screened for all tributed to the accumulation of ␣-synuclein in the brain tis- known parkin mutations. Nine familial patients carried ho- sues, implying the common pathomechanism in the onset of mozygous parkin mutations (deletion exon 3; deletion A at the two diseases. The genetic polymorphisms that are asso- nucleotide position 202). One familial patient carried a ciated with PD are reported in the different races and several heterozygous A 202 deletion. Age at onset was 65 years, countries; ␣-1-antichymotrypsin (ACT) in the signal peptide and the clinical picture consisted of mild tremor only. The (Ϫ15 Ala to Thr) gives three genotypes, ACT-AA, AT, and homozygous carriers of the same mutation presented in TT, in which the ACT-AA genotype may increase the risk of their fourth decade. Three sporadic patients carried het- PD. In this study, we investigated the polymorphism of erozygous mutations: 1197 (exon 10) C-to-T point muta- ACT gene in MSA, and found a higher frequency than in tion, hetero-deletion exon 7, and hetero-deletion exon 4. controls. Further comparison revealed that MSA with Clinical onset was at 13, 31, and 49 years with tremor, foot ACT-AA showed shorter disease course (50.3 Ϯ 15.4 dystonia, and hemiparkinsonism, respectively. We suggest months) with earlier onset (52.3 Ϯ 4.7 years), than non- that heterozygous mutations in a single allele of the parkin ACT-AA MSA (72.2 Ϯ 16.6 months, 57.3 Ϯ 6.7 years). gene may present with early onset parkinsonism, possibly Thus, the ACT-AA genotype is a plausible risk factor and due to parkin haploinsufficieny or the influence of addi- modulating factor for MSA. tional genes.

S28 Annals of Neurology Vol 56 (suppl 8) 2004 71. Accurate and Expedited Diagnosis of Amyloidotic perimental systems. Study supported by the Italian Ministry Transthyretin Neuropathy: Proteomic and Genomic of Health, Fondazione Telethon. Approach Christopher J. Klein, Chang H. Kim, P. James B. Dyck, Steve R. Zeldenrust, Harold R. Bergen, John F. O’Brien, Angelito I. Nepomuceno, Malinda L. Butz, Stephen N. Thibodeau, David C. Muddiman, and 73. Previously Unidentified MECP2 Open Reading Peter J. Dyck; Rochester, MN Frame Defines a New Protein Isoform Relevant to Rett Syndrome INTRODUCTION: Although identification of amyloid Gevork N. Mnatzakanian, Hannes Lohi, Iulia Munteanu, from biopsied tissue remains an important diagnostic tech- Simon E. Alfred, Takahiro Yamada, Patrick J.M. MacLeod, nique, the further characterization of the underlying protein Julie R. Jones, Stephen W. Scherer, Carolyn N. Schanen, abnormality, mutant transthyretin (TTR) monoclonal light Michael J. Friez, John B. Vincent, and Berge A. Minassian; chains (primary, AL), is problematic. The low sensitivity and Toronto, Ontario, Canada; Victoria, British Columbia, specificity probably relate to the small size of amyloid depos- Canada; Greenwood, SC; and Wilmington, DE its, low affinity of antibodies, and nonspecific binding of protein markers. Better testing is needed. METHOD: Mass Rett syndrome is a common neurodevelopmental disorder in spectrometry with electrospray ionization (MS-ESI) was per- females. It is caused by mutations in exons 3 and 4 of the formed on TTR from patients’ serum with varied TTR amy- four-exon MECP2 gene in about 80% of patients. In the loidosis (6); gelsolin amyloidosis (6); and others (22). All pa- known transcript of the gene, termed MECP2A, all four ex- tients consented, as was confirmed by our institutional ons are utilized, the translation start site is in exon 2, and review board, and they were diagnosed at the Mayo Clinic exon 1 and most of exon 2 form the 5Ј-untranslated region. Peripheral Nerve Center. MS-ESI and TTR DNA analysis We describe a novel MeCP2 isoform, termed MECP2B, was blinded. RESULTS: MS-ESI predicted the correct TTR which encodes a novel N-terminus originating in exon 1. We amino acid change in all patients: F33C, T60A-two patients, quantified the expression levels of the two transcripts and L58H, G47E, S77Y and G6S polymorphism in four unaf- found that MECP2B expression is 10 times higher than fected by amyloidosis. No control patients had MS-ESI or MECP2A in adult human brain. Subcellular localization ex- DNA abnormality. CONCLUSION: MS-ESI analysis of periments showed that MeCP2B, similar to MeCP2A, is TTR protein was sensitive and specific. Throughput was found principally in the nucleus. Mutation screening of 19 rapid (20 minutes), and small volumes (Ͻ1 mL) could be Rett syndrome patients with no known mutations, resulted assessed. This approach does have limitations. Several rare in two patients with deletions in exon 1. Mutations unique variants are either isobaric with wild-type TTR or result in to this isoform and absence of mutations, to date, specific to small mass differences. A proteomic and genomic approach is the previously recognized protein, indicate a primary role for proposed. Study supported in part by the National Institute the newly discovered molecule in the pathogenesis of Rett of Neurological Disorders and Strokes (NS36797), the Mus- syndrome. Study supported by the Canadian Institutes of cular Dystrophy Association, and the Mayo Gene Discovery Health Research–Neuromuscular Research Partnership. Shared Resource (Mayo Comprehensive Cancer Center Grant) from the National Cancer Institute (CA15083).

74. Molecular Studies of Infant Spinal Muscular 72. Molecular and Functional Analyses of Drosophila Atrophy in Cuba Homologues of Autosomal-Dominant Hereditary Spastic Yuset Montejo, Ana M. Acevedo, Tatiana Zaldivar, and Paraplegia Genes Spastin and Atlastin Rosa Guerra; Havana, Cuba Andrea Martinuzzi, Genny Orso, Alessia Gazziero, INTRODUCTION: Spinal muscular atrophies (SMA) are Mariagiovanna Rossetto, and Andrea Daga; Conegliano, TV, autosomal-recessive diseases leading to symmetrical muscle Italy and Padova, PD, Italy weakness and wasting of voluntary muscles, The SMN gene The hereditary spastic paraplegias (HSPs) encompass a rare is located in the 5q 11.2-13.3 region, which contains several and diverse spectrum of disorders that are normally charac- copies of marker genes. OBJECTIVES. To find deletions at terized by progressive spastic weakness of the lower extremi- the SMN1 gene and to perform a prenatal diagnosis in ties. Two loci (SPG4 and SPG3a) account for the majority women with a family history of SMA. PATIENTS AND of autosomal-dominant HSPs. SPG4 codes for the spastin METHODS: Fifty-eight Cuban families as well as 17 preg- and SPG3a for atlastin, two proteins of unknown function. nant, with amniotic liquid examination at 19 weeks of preg- Both proteins are conserved across species and exhibit signif- nancy, were studied. The DNA was extracted according to icant homology to proteins in Drosophila melanogaster.We micro salting-out methods. Deletions of exons 7 and 8 for have identified the Drosophila homologues of spastin and at- the SMN gene were detected through the direct method and lastin, and have generated transgenic flies overexpressing ei- haplo-identification with the micro-satellite markers of chro- ther D-spastin or D-atlastin. We have also obtained the si- mosome 5q as an indirect method. The molecular polymer- lencing of both genes by inheritable RNA interference ase chain reaction technique was used for those. RESULTS: approach, and have generated transgenic lines expressing Twenty-nine patients (50% of the sample) were found to pathological versions of the D-spastin and D-atlastin cDNAs. have deletions. Nine of the prenatal diagnoses (52.9%) were The phenotypes elicited by expression of these transgenes are positive. CONCLUSIONS: Half the patients and pregnan- reminiscent of the human pathology and will be presented in cies were detected to have the deletion, proving the useful- detail. Our work demonstrates that Drosophila can be used ness of the diagnostic methodology performed. The molecu- successfully to describe crucial aspects of human disease, such lar studies of SMA have helped increase the quality of life of as the nature of the mechanism underlying pathogenetic mu- the Cuban family and to bring genetic counselling to af- tations, that are much more difficult to tackle in other ex- fected families.

Program and Abstracts, American Neurological Association S29 75. Point Mutations of the p150 Subunit of Dynactin 77. Multiple Sclerosis Prevalence in Israeli Ethnic (DCTN1) Gene in Amyotrophic Lateral Sclerosis Groups: Evidence That Lifestyle Influences Risk Christoph Muench, R. Sedlmeier, Thomas Meyer, Milton Alter, Esther Kahana, Nelly Zilber, and Ariel Miller; Vivien Homberg, Anne D. Sperfeld, Anja Kurt, J. Prudlo, Philadelphia, PA; Ashkelon, Israel; Jerusalem, Israel; and G. Peraus, Clemens O. Hanemann, G. Stumm, and Haifa, Israel Albert C. Ludolph; Ulm, Germany; Munich, Germany; Factors that cause MS may be inferred where frequency dif- Berlin, Germany; and Hamburg, Germany fers among groups in the same area. Israel’s diverse popula- Several reports have shown that functional abnormalities of tion, excellent medical facilities, detailed census data, and dynein and dynactin contribute to the pathogenesis of selec- updated National MS Register allowed determination of MS tive motor neuron degeneration. We performed a mutation prevalence country-wide. Age-adjusted prevalence/100,000 screening of the p150 subunit of dynactin (DCTN1) and the population in Israeli-born Jews (56.7) and in Jewish immi- cytoplasmic dynein heavy chain (DNCHC1) genes in 250 grants from Europe/America (54.8) was highest. Christian Arabs in Israel, who lead a more Western lifestyle than other patients with amyotrophic lateral sclerosis (ALS) and 150 Arabs, had a higher prevalence (39.4) than Moslem Arabs unrelated controls. Protein coding exons 5 to 14 of the (13.1). Druze, an ancient non-Jewish sect, and Bedouins had DNCHC1 gene and each of the 31 coding exons of significantly lower prevalence (8.9 and 5.6, respectively). DCTN1 were PCR-amplified and screened for sequence al- Israeli-born African/Asian Jews reared in Israel’s Westernized terations by heteroduplex analysis and sequencing (SCE- culture had a higher rate (52.0) than their immigrant fore- 9610, Spectrumedix). Heterozygous missense mutations of bears from Arab countries (26.1). Thus, a Western lifestyle the DCTN1 gene were detected in one apparently sporadic factor may increase MS risk; alternatively, one associated case of ALS, one individual with familial ALS, two patients with a traditional Arab lifestyle may be protective. Age at with familial ALS, and two unaffected relatives in the same which childhood infections are acquired is proposed as a can- kindred. The sequence variants were excluded in 150 non- didate environmental factor. Thus, differences in MS fre- neurological controls. The mutation screening of the quency in Israel among Christian and Moslem Arabs, Druze, DNCHC1 gene in the same group of patients did not reveal and Bedouins, reported here for the first time, as well as abnormalities in the coding exons 5 to 14 as disclosed by differences among Jewish immigrant and native-born Jewish heteroduplex analysis. We propose that the allelic variants of subgroups, may help identify the environmental factor(s) in- the DCTN1 gene may represent a previously unknown fluencing MS risk. Study supported by the National Multi- genomic risk factor for ALS. ple Sclerosis Society.

78. Magnetization Transfer MRI Study of Deep Gray NEUROIMMUNOLOGY AND MULTIPLE Matter Involvement in Multiple Sclerosis SCLEROSIS Rohit Bakshi, Andrew J. Fabiano, Jitendra Sharma, Baljinder Singh, Zeenat Jaisani, and Robert Zivadinov; 76. Reappraisal of Lhermitte’s Sign in Multiple Boston, MA and Buffalo, NY Sclerosis Gray matter involvement in multiple sclerosis (MS) is of Adnan Hameed Al-Araji and Joel Oger; Vancouver, British growing interest regarding disease pathogenesis. Magnetiza- Columbia, Canada tion transfer (MT), an advanced MRI technique, is sensitive Lhermitte’s sign (LS) is clearly a symptom of and is to disease in normal appearing MS brain tissue. We tested if strongly linked to MS. Our aim is to reassess its frequency MT detected subcortical gray matter abnormalities in pa- ϭ in MS, assess neuroradiological correlations, and propose a tients with MS (n 60) vs. age-matched normal controls ϭ working definition. This is a cross-sectional, controlled (NL, n 20). Magnetization transfer ratio (MTR) maps study done at the UBC MS Clinic-Vancouver. Patients were produced from axial proton density, conventional spin- with CDMS and normal controls were assessed through echo, 5 mm gapless slices covering the whole brain. A region structured interviews. Cervical MRIs were reviewed when of interest (ROI) approach derived MTR histograms for the available. The cohort included 229 patients and 77 normal left/right caudate, putamen, globus pallidus, thalamus, and normal-appearing white matter (NAWM). Whole brain controls. Ninety-six (42%) patients reported LS but none MTR was obtained after removal of CSF pixels. Mean whole of the controls. All patients who reported LS described a brain and NAWM MTR were lower in patients with MS rapidly spreading, short-duration sensation; in all it was re- than normal controls (p Ͻ 0.001) and mean whole brain lated to neck movement. In 93/96, it was felt at the back of MTR was lower in secondary progressive (SP, n ϭ 10) than the neck with or without radiation to the lower back. The relapsing-remitting (RR, n ϭ 50, p Ͻ 0.001) patients with sensation was electric-like in only 77%. Others included MS. However, none of the gray matter ROIs showed differ- tingling (12), buzzing (4), and miscellaneous (6). All re- ences in MS vs. NL, RR vs. SP, or SP vs. NL. We conclude viewed cervical MRIs done in 20 patients with LS were that MT is relatively insensitive to disease in the deep gray abnormal. None of the MS patients with a normal cervical matter nuclei despite showing sensitivity for whole brain or MRI had LS.We conclude that LS is highly prevalent in white matter disease in MS. Study supported by research MS and has a high correlation with abnormalities on the grants to R. Bakshi from the National Institutes of Health cervical MRI. We suggest continuing to call LS a “sign” to (K23 NS42379-01), the National Multiple Sclerosis Society emphasize its high localizing value. A working definition is (RG 3258A2/1), and the National Science Foundation proposed. (DBI-0234895).

S30 Annals of Neurology Vol 56 (suppl 8) 2004 79. Visual Evoked Potentials and Brainstem Auditory autoimmune-inflammatory process. Study supported by the Evoked Potentials in Patients with Multiple Sclerosis Wadsworth Foundation and the Betty Yablin Grant for Re- and Cerebral Periventricular White Matter Small Vessel search in Multiple Sclerosis. Ischemic Disease Juan C. Barrera, Cynthia L. Harden, and Gail E. Solomon; Scranton, PA and New York, NY 81. Progressive Grey and White Matter MTR Abnormality in Early Relapsing-Remitting MS Abnormal visual evoked potentials (VEPs) and brainstem au- Gerard R. Davies, Daniel R. Altmann, Waqar Rashid, ditory evoked potentials (BAEPs) do not avoid the need for Declan T. Chard, Colette M. Griffin, Gareth J. Barker, lumbar puncture (LP) searching for cerebrospinal fluid Alan J. Thompson, and David H. Miller; London, (CSF) oligoclonal bands (OCB) for the diagnosis of clinically United Kingdom definite, laboratory-supported (CD LS) MS. In a retrospec- tive study, patients were selected if they had periventricular In early relapsing-remitting multiple sclerosis (RRMS), ab- white matter lesions. All patients had brain magnetic reso- normality in normal-appearing grey and white matter nance imaging (MRI) (with or without contrast), fluid- (NAGM and NAWM) can be detected with the magnetiza- attenuated inversion recovery (FLAIR) technique, diffusion- tion transfer ratio (MTR). However, it remains uncertain weighted imaging (DWI), VEPs, and BAEPs. Patients with whether such changes progressively worsen prior to the onset strong evidence for MS underwent LP for CSF and serum of permanent disability and at what stage such abnormalities OCB testing. Fourteen patients posing a diagnostic dilemma begin. Twenty-three RRMS patients (mean disease duration: were selected. Four patients with CD LS MS had abnormal 1.9 years; expanded disability status scale: 0–3.0) and 19 brain MRI, normal VEPs, normal BAEPs, positive CSF, and healthy controls were imaged yearly for 2 years using a mag- negative serum OCB. Five patients with CD LS MS had netization transfer imaging sequence (21 patients and 10 abnormal brain MRI, abnormal VEPs, normal BAEPs, pos- controls were imaged at 2 years). Patient-vs.-control differ- itive CSF, and negative serum OCB. Two patients with CD ences and change over time were assessed using a hierarchical LS MS had abnormal brain MRI, normal VEPs, abnormal regression model, adjusting for changes in brain volume. BAEPS, positive CSF, and negative serum OCB. Three pa- Baseline NAWM and NAGM MTR were reduced in pa- tients with cerebral periventricular small vessel ischemic dis- tients vs. controls (p Ͻ 0.001 and p ϭ 0.004, respectively). ease had abnormal brain DWI-MRI, abnormal VEPs, and In patients (but not in controls) NAWM and NAGM MTR normal BAEPs. Abnormal VEPs and BAEPs may lead to declined progressively: Ϫ0.10 pu/year, p ϭ 0.001 and CSF and serum OCB testing. Ϫ0.18 pu/year, p Ͻ 0.001. Backward extrapolation of the linear regression model suggested that NAWM abnormality began 2.9 years before symptom onset and that NAGM ab- 80. Attenuation of Chronic Experimental Autoimmune normality began shortly after the first attack. Progressive Ecephalomyelitis by Intraventricular Transplantation of MTR abnormalities in NAWM and NAGM occur in pa- Neural Spheres tients with early RRMS and minimal disability. The onset of Tamir Ben-Hur, Ofira Einstein, Rachel Mizrachi-Kol, NAWM abnormality may predate symptom onset. Study Nikolaos Grigoriadis, Dimitrios Karussis, Iris Lavon, supported by the Multiple Sclerosis Society of Great Britain Ionas Milonas, and Oded Abramsky; Jerusalem, Israel and and Northern Ireland. Thessaloniki, Greece AIM: We examined the clinical, neuropathological, and im- 82. Case-Control Study of Myelin Oligodendrocyte munological effects of neural sphere transplantation in Glycoprotein and CD45 Polymorphisms in Multiple chronic experimental autoimmune ecephalomyelitis (EAE), Sclerosis in Verona, Italy an animal model of multiple sclerosis. METHODS: Multi- Macarena Gomez-Lira, Sarah Ottaviani, Silvia Mazzola, potential neural spheres from newborn GFP-transgenic Alessandro Salviati, Alberto Gajofatto, Emanuela Turri, mouse were transplanted intraventricularly to MOG-induced Anna Fiumani, Giuseppe Moretto, Luciano Deotto, chronic EAE in C57Bl/6 mice. Sham- and sphere- Nicola Rizzuto, and Maria Donata Benedetti; Verona, Italy transplanted animals were scored clinically and sacrificed at days 18 and 80 post-induction for histopathological analysis. We are conducting an epidemiologic study on mulitiple scle- Demyelination and axonal pathology were assessed by Klu- rosis (MS) in the province of Verona, Italy, which includes a ver–Barrera staining, amyloid precursor protein immunohis- case-control study of myelin oligodendrocyte glycoprotein tochemistry, and Bielschowski staining. Inflammation was (MOG) and CD45 polymorphisms in the first consecutive quantified by counting perivascular infiltrates, CD25ϩ cells, 150 MS prevalent cases and in 150 controls from the same and CD62Lϩ cells and by image analysis of ICAM-1 and geographic area. MS was defined according to criteria de- LFA-1 immunohistochemistry. Lymphocyte proliferation was fined by McDonald (2001), and controls were selected from examined in vitro by [3H]thymidine incorporation. RE- blood donors. Screening for MOG gene polymorphism SULTS: EAE attracted transplanted cell migration into white G511C (Val142Leu) and for CD45 polymorphism C77G matter tracts. Neural sphere transplantation attenuated the was performed. The frequency of MOG G511C was similar clinical course of chronic EAE and reduced demyelination in cases and controls, both groups having a low proportion and axonal pathology. Neural sphere transplantation inhib- of CC homozygosis and a high proportion of GG homozy- ited the inflammatory brain process, increased brain regula- gosis. We found the well-known association between HLA- tory CD25ϩ T cells, and decreased infiltrate-associated ax- DRB1*1501 and MS (38% of cases vs. 15% of controls, onal damage. Addition of neural spheres to EAE-derived OR ϭ 3.28, p Ͻ 0.0001). We then analyzed MOG poly- lymphocytes in vitro inhibited their proliferative responses to morphism after stratifying controls subjects by HLA- ConA and MOG and reduced MOG-induced production of DRB1*1501 positivity: in positive controls CC frequency interferon-␥. CONCLUSIONS: Neural sphere transplanta- was 13.3% vs. 5.6% in negative controls. This finding sug- tion attenuates clinical and pathological features of chronic gests a possible linkage disequilibrium between these two EAE. The graft effect is mediated by modulation of the loci. Further analysis in a larger sample will investigate the

Program and Abstracts, American Neurological Association S31 tendency towards a protective effect of MOG polymorphism. ment of MS and other neuroinflammatory conditions. Study Study supported by the Italian Foundation of Multiple Scle- supported by the Fogarty International Research Collabora- rosis. tion Award.

83. Neuropathology in Intramedullary Sjogren’s Syndrome Mark D. Garwood, Erik K. St. Louis, Praful M. Kelkar, and 85. Audit of the Registered Cause of Death in Mark A. Granner; Iowa City, IA Patients with Multiple Sclerosis in Northern Ireland BACKGROUND: Sjogren’s syndrome is a systemic autoim- Orla M. Gray, Lik T. Lim, and Stanley A. Hawkins; Belfast, mune disorder that infrequently presents with an inflamma- Northern Ireland, United Kingdom tory myelopathy similar to that seen in multiple sclerosis. Few systematic audits of the accuracy of recording death Previously reported neuropathology from autopsy cases in rates statistics have been performed. We used the Northern Sjogren’s myelopathy has shown vasculitic pathology. OB- Ireland Multiple Sclerosis Registry, containing patients with JECTIVE: To report unique neuropathology in a case of multiple sclerosis (MS) who attended neurology outpatients Sjogren’s myelopathy. MATERIALS/METHODS: Case re- clinics between 1950 and 1980, entered by Dr. Harold Mil- port with tissue pathology from spinal cord and salivary lar. Patients who had died were linked with the Register of gland biopsies. RESULTS/CASE REPORT: A 66-year-old Deaths. Of 1,931 patients, 850 had died. Preliminary results woman presented with relapsing weakness, paresthesias, and on 350 cases revealed that MS was noted on the death cer- hyperreflexia over 18 months. MRI demonstrated patchy en- hancing expansile lesions extending along the entire spinal tificate in 50.5% of cases, but in only 48.5% of these was it cord. Clinical signs and imaging abnormalities remitted in- the underlying cause of death. Of patients in whom MS was completely with repeated steroid courses. She ultimately the cause of death, respiratory disease was documented as the worsened over 2 weeks prior to presentation, progressing to mode of death in 89.3%. When MS was contributing to paraplegia and anesthesia below T5. SSA, SSB, and minor death but was not the cause, the cause of death was respira- salivary gland biospy were consistent with Sjogren’s syn- tory in 42.6%, cardiac in 31.6%, neoplastic in 14.6%, and drome. Given clinical progression despite steroid therapy and urinary sepsis in 5.6%. In conclusion, MS was the cause of radiographic cord expansion, a spinal cord biopsy was per- death in 24.5% of patients, most commonly associated with formed to exclude neoplasm, with findings of demyelination, respiratory complications. MS was not documented on the relative axonal preservation, and cellular infiltration by foamy death certificates of 49.5% of patients with known MS, in- CD68-stained macrophages. There was no pathologic evi- dicating that a mortality survey based on death certificates dence of vasculitis. Treatment with cyclophosphamide was alone would be inaccurate. Study supported by the Irish In- initiated, but no improvement occurred over a 6-month stitute of Clinical Neurosciences. follow-up. CONCLUSIONS: Intramedullary Sjogren’s syn- drome can be caused by demyelination without vasculitis, expanding the spectrum of known pathophysiology in CNS Sjogren’s syndrome. 86. Cerebrospinal Fluid Biomarkers in Patients with Multiple Sclerosis and Significant Cognitive Impairment 84. Chemokines in a Novel Model of Brain Immune- Carolina Ionete, Marjorie Padula, Kathleen Healey, Mediated Inflammation Bernd W. Scheithauer, and Katerina Markopoulou; Omaha, Andrzej R. Glabinski, Bartosz Bielecki, Tracey Newman, NE and Rochester, MN V. Hugh Perry, and Richard M. Ransohoff; Lodz, Poland; Southampton, United Kingdom; and Cleveland, OH Multiple sclerosis (MS) has long been considered a white matter disease. Recently, axonal loss, brain and spinal cord Important mediators involved in formation of inflammatory atrophy, and gray matter have been implicated in disease foci in multiple sclerosis (MS) are chemoattractant cytokines pathogenesis, and increased cerebrospinal (CSF) tau protein (chemokines). In this study, we analyzed the expression of has been reported (Kapaki et al., 2000). We report four cases chemokines and their receptors in a novel experimental with secondary progressive MS and moderate-severe cogni- model of delayed-type hypersensitivity in the brain. The cel- tive impairment in which the CSF tau/A␤42 ratio (AD- lular composition of inflammatory focus in this model is very MARK, Athena Diagnostics) was obtained. MS diagnosis similar to that observed in MS lesions, but having the precise was based on the Posner and Patty criteria, the presence of timing and localization of the lesion facilitates analytic study of the mechanisms of lesion formation. Chemokine and che- white matter lesions on MRI, oligoclonal bands, and in- mokine receptor gene expression was analyzed by quantita- creased IgG synthesis rate in CSF. MRI scans revealed atro- phy with a frontal and temporal predominance and periven- tive Rnase Protection Assay (RPA) at different time points ␤ after intracerebral BCG injection. We observed upregulation tricular white matter lesions. The tau/A 42 ratio in the CSF of chemokines RANTES and MIP-1␤ as well as chemokine was consistent with a diagnosis of Alzheimer’s disease (AD). receptors CCR1, CCR2, CCR5, and CX3CR1 in the brain. Mini-Mental State Examination (MMSE) scores revealed Chemokine receptors CCR3 and CCR4 were not upregu- moderate to severe cognitive impairment; however, neuro- lated in this model. The first peak of inflammatory gene ex- psychological testing revealed a pattern inconsistent with pression was observed at day 20, and the second at day 40. AD. The association of MS cases with cognitive impairment This biphasic chemokine and chemokine receptor upregula- and a tau/A␤42 ratio consistent with AD raises the possibil- tion correlated with biphasic pathological findings observed ity that a common neurodegenerative mechanism underlies in this model. This observation validates the brain BCG- cognitive impairment in AD and MS. Alternatively, it may induced model of inflammation as a useful tool for analyzing reflect a lack of specificity of the tau/A␤42 ratio as a biomar- how to achieve therapeutic targeting of chemokines for treat- ker for AD.

S32 Annals of Neurology Vol 56 (suppl 8) 2004 87. Depression in Multiple Sclerosis and Its Relation of a polymorphism in the PAF-R gene (A224D) with sus- to Functional Abilities ceptibility for Japanese MS. The missense mutation, which Yasuo Iwasaki, Ken Ikeda, Hiroaki Iguchi, Kiyokazu Kawabe, displays a partial but significant reduction of PAF-induced and Toshiki Fujioka; Tokyo, Japan intracellular signals, was determined by PCR-RFLP. DNA OBJECTIVE: Depression is common in multiple sclerosis samples from 217 MS patients and 245 healthy controls (MS) and contributes to cognitive dysfunction. Diagnosing were collected. Fifty-five patients clinically displaying selec- depression in MS and initiating appropriate treatment is im- tive involvement of the optic nerve and spinal cord were clas- portant. METHOD: We studied 48 patients with MS to sified as opticospinal MS (OS-MS), whereas the other 162 elucidate the nature and frequency of depressive state by showing disseminated involvement of the central nervous comparing a group of MS patients against age- and system as conventional MS (C-MS). The frequency of D al- education-matched normal controls. We also examined the leles in C-MS was significantly higher than those in healthy relationship between severity of the illness and depressive controls (11.7% vs. 6.9%, p ϭ 0.0258), and the frequency state. Patients completed the Zung self-rating depression of AD/DD genotypes in C-MS also tended to be higher than scale (SDS), underwent a complete neurological evaluation, those in healthy controls. However, no statistically significant and were asked to rate their state of neurological well-being on a scale of 1 (poor) to 5 (normal). Neurological disabilities differences were found in the frequencies of genotypes or al- were measured using EDSS. Correlations between SDS leles between OS-MS and healthy controls. These results score,self-rating scale, and EDSS were performed. RE- suggest that a reduction of PAF-induced intracellular signals SULTS: The mean SDS scores were higher in MS than in based on the missense mutation may contribute to the sus- those of controls. There was no correlation betwenn SDS ceptibility for Japanese C-MS. score and EDSS. However, there was a good correlation be- tween SDS score and self-rating assessment. CONCLU- SION: A self-rating assessment may provide a valuable means of ascertaining depression in MS. NEUROMUSCULAR DISEASE

88. Exploring the Relationship of Relapsing Myelitis 90. Sporadic Inclusion-Body Myositis as a with Neuromyelitis Optica (Devic’s Disease) and Conformational Disorder: Novel Role of Misfolded Multiple Sclerosis Proteins and Proteasome Inhibition in Sporadic Anu Jacob, Richard Nicholas, Kumar Das, and Mike Boggild; Inclusion-Body Myositis Pathogenesis Liverpool, Merseyside, United Kingdom Valerie Askanas, W. King Engel, Pietro Fratta, BACKGROUND: A small series of patients with relapsing Gaetano Vattemi, Fred W. Van Leeuwen, Elly M. Hol, and myelitis (RM) not meeting criteria for MS or NMO have Kelvin J. A. Davies; Los Angeles, CA and Amsterdam, been described. We compare the features of 12 RM patients, Netherlands with a cohort of 17 patients of NMO to explore this rela- tionship. RESULTS: Fifty-eight percent of RM and 76% of Sporadic inclusion-body myositis (s-IBM) is the most com- NMO patients were female with similar ages and ages of mon muscle disease of older persons and leads to severe dis- onset. Patients with NMO seemed more disabled (87% vs. ability. Pathologic features include muscle fibers containing 50%). Spinal MRI identified identical spindle-shaped lesions cytoplasmic ubiquitinated, congophilic proteinaceous aggre- in both groups. OCB was positive in 55% of RM patients, gates.Two major types of aggregates contain either and in 26% of those with NMO. The length of lesions in amyloid-␤ (A␤) or phosphorylated tau (p-tau). Our newest those with positive OCB was smaller. One patient with RM studies demonstrated the following: (1) Endoplasmic reticu- showed delayed VERs but had absent OCB. Good response lum (ER) stress and “unfolded protein response” (UPR). to immunosuppressants was seen in both groups, especially UPR is considered a protective mechanism involving in- in those without OCB. DISCUSSION: RM may not be a creased synthesis of ER chaperones in response to accumu- homogenous entity. It probably has three subgroups: (1) a lated misfolded proteins. (2) Association of mutant ubiq- spinal variant of MS with positive OCBs and smaller spinal ϩ1 ϩ1 uitin, UBB , with A␤ and p-tau aggregates. UBB cord lesion lengths; (2) a distinct disease, with normal VERs, absent OCBs, and other autoantibodies; and (3) a “forme indicates “molecular misreading,” which designates acquired, fruste” of NMO with subclinical or delayed visual tract in- non-DNA-encoded dinucleotide deletions occurring within volvement. Subclassification of RM into these subtypes may mRNAs. Aberrant transcripts can be translated from the de- ϩ help optimize treatment. Study supported by Serono Phar- letion onward into the 1 reading frame to produce abnor- mal proteins, typically in an aging cellular environment. maceuticals. ϩ UBB 1 can inhibit the “ubiquitin-proteasome system.” (3) Proteasomal dysfunction, evidenced by: a) increased and ac- 89. Single Nucleotide Polymorphism of Platelet- cumulated subunits of the 26S proteasome; b) decreased pro- Activating Factor Receptor in Japanese Multiple teasomal activity; and c) accumulated “aggresomes,” identi- Sclerosis fied by ␥-tubulin, which form when a cell’s capacity to Manabu Osoegawa, Ryuji Miyagishi, Hirofumi Ochi, degrade misfolded proteins through the 26S proteasome sys- Masaaki Niino, Seiji Kikuchi, Toshiyuki Fukazawa, and tem is decreased. Unique, for a muscle disease, this repertoire Jun-ichi Kira; Fukuoka, Japan and Sapporo, Japan of abnormalities suggests that misfolded, potentially toxic Platelet-activating factor (PAF) is reported to be elevated in proteins play a novel role in s-IBM pathogenesis. Study sup- cerebrospinal fluid and plasma of patients with multiple scle- ported by grants to V.A. from the National Institutes of rosis (MS), and PAF receptor (PAF-R) is reported to be up- Health (MERIT Award AG16768), the Muscular Dystrophy regulated in MS lesions. Thus, we evaluated the association Association, and the Myositis Association.

Program and Abstracts, American Neurological Association S33 91. Comparison of Motor Transcarpal Conduction IgM antibody activities in GBS, chronic inflammatory demy- Velocity with Sensory Conduction Techniques in elinating polyneuropathy (CIDP), and multifocal motor neu- Diagnosis of Carpal Tunnel Syndrome ropathy (MMN). The effects of nine different kinds of phos- Ming-Hong Chang; Taichung, Taiwan pholipids were examined. In contrast with anti-GM1 IgG antibody activities, no phospholipid provided significant en- OBJECTIVE: Comparing the sensitivity of motor transcar- hancement on anti-GM1 IgM antibody activities in GBS. pal conduction velocity (TCV) with those of sensory tech- Only the mixture of lysophosphatidylcholine (LPC) had an niques in electrodiagnosis of carpal tunnel syndrome (CTS). enhancing effect on anti-GM1 IgM activities in CIDP and METHODS: This study included 360 CTS hands and 150 MMN. On the other hand, anti-GM1 IgM antibody activi- normal hands. We determined and calculated: motor TCV; ties in GBS, CIDP, and MMN were decreased as well as motor and sensory distal latencies (DL) for thumb (M1), in- anti-GM1 IgG in GBS when the antigen was a mixture of dex (M2), and ring finger (M4); sensory TCV for index fin- GM1 and sphingomyelin (SM). The effects of phospholipids ger; and sensory latency differences between median-radial on the anti-GM1 IgM antibody activities were completely (M-R) and median-ulnar (M-U) nerves. Normal limits were different from those on IgG. The decrease of the activity by calculated from mean plus or minus 2.5 standard deviations. the addition of SM to GM1 antigen in ELISA may be com- The sensitivities of each test were compared. RESULTS: mon to the anti-GM1 antibodies in autoimmune neuropa- Among the 360 hands with suspected CTS, 32 hands (8.9%) thies. had normal electrodiagnostic studies and 328 (91.1%) had at least one abnormal electrodiagnostic study. Among the 328 hands with abnormalities, 249 (61.2%) had abnormal motor 94. Analysis of Differentially Expressed Genes in DL and 306 (85%) had abnormal motor TCV. The sensi- Denervated Skeletal Muscle tivity for M1 was 81.7%, and 75.8% for M2, 80.8% for Takahiro Jimi, Yoshihiro Wakayama, Yoko Matsuzaki, M4, 87.5% for M-R, 88% for M-U, and 80.3% for sensory Akihiko Unaki, Hajime Hara, Masahiko Inoue, and TCV. CONCLUSION: TMCV is a valuable motor conduc- Seiji Shibuya; Yokohama, Japan tion technique for the diagnosis of CTS, suggesting that studying motor TCV could increase the diagnostic yield; To examine effects of neural factors on gene expression in however, latency differences between median-ulnar or -radial skeletal muscle, we analyzed differential mRNA expression nerves are the best techniques for a diagnosis of CTS. Study under denervated conditions. Experimentally denervated rat supported by a grant from NSC 92-2314-B-075A-006. muscle was prepared by partial removal of the unilateral sci- atic nerve and, 72 hr later, excision of the extensor digitorum longus muscle. The total RNA was extracted from both nor- 92. Is the Serum Cobalamin Assay the Best Predictor mally innervated and experimentally denervated muscles. As of Vitamin B12 Deficiency? probes, the RNA from innervated muscle and that from the Jamie T. Haas, Florian P. Thomas, and Laurence J. Kinsella; denervated one was labeled with Cy5 and fluorescein, respec- St. Louis, MO tively. Both probes were combined and competitively hybrid- ized to 0.4 million ready-made DNA microbeads (Takara- Previous studies suggest that only 1% of individuals with a Bio). On the surface of each DNA microbead, cDNA Ͼ serum cobalamin (Cbl) of 300 pg/mL have methylmalonic fragments consisting of one kind of rat skeletal muscle acid (MMA) elevation consistent with a deficiency state. We mRNA were fixed. After hybridization, the microbeads were studied the relationship between Cbl and MMA levels in pa- analyzed by a cell sorter. A two-color dot plot indicated the tients with neurological symptoms or signs consistent with area where differential upregulation of expressed genes in the Cbl deficiency. We reviewed the records of patients seen in denervated condition occurred. The microbeads in the target neurologic consultation with suspected B12 deficiency whose area were isolated by the cell sorter. Among 50 genes iso- serum Cbl and MMA levels were measured. We identified lated, several noticeable genes, including thioredoxin, Myf-6, 37 patients with both levels determined within 4–5 months and dynein, were upregulated in denervated condition. These of each other prior to treatment. Thirty-four (91.9%) had genes may be useful in understanding neural effects on skel- Ͼ Ͼ normal Cbl levels ( 200); 17 (44.7%) had Cbl levels 300. etal muscle and prove to be applicable samples in further Of the 34 with normal Cbl, 26 (76.5%) had elevated MMA studies, including microarray analysis. Study supported by a Ͼ Ͼ ( 243 nmol/L). Of the 17 with Cbl 300, 12 (70.6%) had grant-in-aid for scientific research (C-2-14570619) from the elevated MMA. Most (67%) values were less than two times Ministry of Educaton, Culture, Sports, Science, and Tech- the upper limit of normal. MMA is more frequently elevated nology, Japan. in patients with low normal and normal Cbl levels than pre- viously reported. This may indicate that serum Cbl is an in- adequate measure of B12 deficiency. It might be prudent to 95. GD1a-GD1b Complex: New Target Antigen in measure MMA along with Cbl in patients with suspected Guillain–Barre´ Syndrome B12 deficiency. Ken-ichi Kaida, Daiji Morita, Mami Kanzaki, Keiko Kamakura, Kazuo Motoyoshi, Minako Hirakawa, and Susumu Kusunoki; Tokorozawa, Saitama, Japan and Osaka- 93. Effects of Phospholipids on the Activity of Anti- Sayama, Osaka, Japan GM1 IgM Antibodies in Autoimmune Neuropathies Antibodies to gangliosides are present in the acute-phase sera Minako Hirakawa, Daiji Morita, Shoji Tsuji, and of about 60% of patients with Guillain–Barre´ syndrome Susumu Kusunoki; Osaka, Japan and Tokyo, Japan (GBS). It is known that glycosphingolipids form clusters ex- We earlier reported the increase of anti-GM1 IgG antibody tensively in the plasma membrane. No antibodies to the gan- activities in Guillain–Barre´ syndrome (GBS) in ELISA by the glioside complex with clustered glycoepitopes, however, have use of a mixture antigen of GM1 and a phospholipid such as been reported. We found antibodies specific for a complex of phosphatidic acid (PA) instead of GM1 alone. In this study, gangliosides GD1a and GD1b (GD1a/GD1b) in sera from 8 we investigated the effects of phospholipids on anti-GM1 of 100 patients with GBS. They had high titers of antibodies

S34 Annals of Neurology Vol 56 (suppl 8) 2004 to a mixture of GD1a and GD1b (GD1a/GD1b) with little and in the foot. In another patient with the anti-GQ1b IgG or no reactivity to either GD1a or GD1b in ELISA. TLC antibody, the sweat output was absent in the foot. The re- immunostaining by the use of those sera showed specific sults suggest that the presence of IgG antibodies against gan- staining of the overlapping portion of GD1a and GD1b. gliosides with the disialosyl residue is associated with the pro- Clinical analysis on the seven patients whose detailed clinical found abnormality in QSART. Those antibodies may play data were available showed that anti-GD1a/GD1b antibody- some role in the post-ganglionic autonomic dysfunction. positive patients tended to have severe disabilities at peak (six patients were bed-ridden and three needed artificial ventila- tion) and cranial nerve deficits (six patients), especially bul- 98. Peripheral Nerve Demyelination: Consensus bar palsy (five patients). Clustered epitopes of the ganglioside Research Criteria Transformed to Linear Regression complex in the plasma membrane may be targeted by such Criteria Using Height an antibody, and interaction between the antibody and gan- Paul J. Maccabee, Larry P. Eberle, and Keewhan Choi; glioside complex may induce the neuropathy. Brooklyn, NY and New York, NY Standard consensus research criteria (CRC) (Cornblath et al., 96. Current Perception Threshold Test Is Useful in Neurology, 1991) that define peripheral nerve demyelination Detecting Small Fiber Neuropathy in the clinical laboratory do not take height into account. Nam-Hee Kim, Kwang-Woo Lee, and Seong-Ho Park; Nevertheless, the significant linear correlation of height vs. F Seongnam-si, Gyeonggi-do, Korea and Seoul, Seoul, Korea response latency, motor conduction velocity (CV), and pos- sibly motor terminal latency is well documented. We now BACKGROUND: Small fiber neuropathy (SFN) is com- propose and test a simple, direct transformation of CRC to mon, but it is frustrating to clinicians because of the enig- linear regression criteria using height. Conservative CRC de- matic diagnosis with minimal signs and normal nerve con- myelinating limits derived from a normal population duction studies. Therefore, the development of quantitative (posterior-tibial nerve parameters) are: (1) expressed as a Z techniques to assess small fiber function is important for score, (2) carried over to linear regression analysis of latency more accurate diagnosis. DESIGN/METHOD: We evalu- (or CV) vs. height (using regression mean and standard de- ated the diagnostic sensitivity of current perception threshold viation), and (3) converted back into msec (or M/Sec) across (CPT) in 30 patients suspected of SFN. Three different CPT a range of heights, giving demyelinating Z regression (DZR) frequencies (5, 250, and 2,000 Hz) selectively activated each criteria. In progressive axonal neuropathies (17 limbs) and subset of nerve fiber (afferent C, A␦, and A␤). RESULTS: lumbosacral radiculopathy (39 limbs), no latency or CV was Among the patients, 93% had abnormal CPT, whereas 60% demyelinated by CRC or DZR. In CIDP, diagnostic F re- had abnormal neurologic signs, 36% had Valsalva response, sponse sensitivity rose from 4/19 (CRC) to 14/19 (DZR) and 51% had SSR. All patients with abnormal CPT had limbs; motor CV sensitivity, from 7/22 to 10/22 limbs. In high thresholds in the peroneal site (96% had abnormal AIDP, F response sensitivity rose from 0/12 to 5/12 limbs. CPT at 250 Hz; 46% at 5 Hz; 68% at 2000 Hz) and more Direct transformation of CRC to DZR criteria may signifi- severe grades at the small fiber specific frequencies. The per- cantly improve detection of demyelinating neuropathy. oneal CPT at 250 Hz was most valuable (AUC: 0.961) for detecting SFN on the receiver-operating characteristic (ROC) curve. CONCLUSION: The small myelinated fiber dysfunction in SFN might be more prominent than small 99. Low Frequency of Cardiac Conduction unmyelinated fiber, considering the highest sensitivity and Abnormalities in Myotonic Dystrophy Type 2: 10-Year AUC of 250 Hz and low sensitivity of Valsalva response and Follow-Up Study SSR. CPT is highly effective in documenting dysfunction in Giovanni Meola, Valeria Sansone, Annamaria Pazzi, SFN. Ralf Krahe, and Luigi De Ambroggi; San Donato Milanese, Milan, Italy and Houston, TX BACKGROUND: We have demonstrated that the only 97. Quantitative Sudomortor Axon Reflex Test in EKG abnormality in a small number of patients with myo- Patients with Autoimmune Neuropathies tonic dystrophy type 2 (DM2) was a prolonged QRS dura- Yoshimasa Kuzumoto, Mikihiro Kihara, Mitsuaki Shioyama, tion over 6 years. AIMS: To confirm that cardiac conduction Yoshiyuki Mitsui, and Susumu Kusunoki; Osaka-sayama, abnormalities are infrequent in patients with DM2 compared Osaka, Japan to those in myotonic dystrophy type 1 (DM1) in a larger Anti-ganglioside antibodies are frequently present in the sera cohort of patients and for a longer period of time. MATE- from patients with such autoimmune neuropathies as Guil- RIALS AND METHODS: Thirty-three patients with genet- lain–Barre´ syndrome and may be involved in the pathoge- ically confirmed DM2 and 70 patients with DM1 were sub- netic mechanism. The autonomic dysfunction sometimes oc- jected to 12-lead standard EKG, 24-hr EKG Holter curs in autoimmune neuropathies. The result of the monitoring, and echocardiograms at initial examination and quantitative sudomotor axon reflex test (QSART), which at mean follow-up of 10.2 years Ϯ 4.6. RESULTS: Whereas evaluates the post-ganglionic sudomotor axon quantitatively, patients with moderately severe DM1 developed cardiac con- can be used as one parameter of autonomic dysfunction. We duction abnormalities (first-degree AV block: n ϭ 28; BBB: performed QSART for 17 patients with autoimmune neu- n ϭ 22; first-degree AV block and BBB; n ϭ 9; PM im- ropathies. Recordings were made in two sites: left distal leg plantation: n ϭ 6), none of our patients with DM2 devel- and foot. We compared the results with the pattern of anti- oped severe cardiac conduction abnormalities. The only ab- ganglioside antibodies. In 9 of 17 patients, the sweat output normality was prolonged QRS duration over time, which was decreased in the distal leg and/or in the foot. Among was not associated with cardiac symptoms or signs. CON- those 9 patients, in three patients with the anti-GQ1b IgG CLUSIONS: Our data confirm that DM2 should be consid- antibody, and in one patient with the anti-GD1b IgG anti- ered a relatively benign disorder compared to DM1. This has body, the sweat output was decreased both in the distal leg important prognostic and therapeutic implications.

Program and Abstracts, American Neurological Association S35 100. Molecular Therapy for Familial Amyotrophic 102. Inoculation with Lipids from Mycoplasma Lateral Sclerosis pneumoniae-Induced Production of Antibodies against a Timothy M. Miller, Richard A. Smith, Brett P. Monia, Major Myelin Glycolipid, Galactocerebroside Thomas P. Condon, Koji Yamanaka, Christian S. Lobsiger, Daiji Morita, Minako Hirakawa, Shoji Tsuji, Madeline M. Butler, C. Frank Bennett, and Kazuhiro Matsuda, and Susumu Kusunoki; Osakasayama, Don W. Cleveland; San Diego, CA and Carlsbad, CA Osaka, Japan; Bunkyo-ku, Tokyo, Japan; and Chuo-ku, Tokyo, Japan Mutations in Cu/Zn Superoxide Dismutase (SOD1) account Antibody against galactocerebroside (Gal-C), a major myelin for a subset of patients with familial amyotrophic lateral scle- glycolipid, has been reported to be a demyelinating factor. rosis (ALS). The toxicity of mutant SOD1 is likely to involve We previously reported that the anti-Gal-C antibodies are a gain of function. Thus diminishing the amount of mutant frequently present in the acute phase sera of Guillain–Barre´ protein would be expected to ameliorate the disease. Anti- syndrome (GBS) subsequent to Mycoplasma pneumoniae in- sense oligonucleotides that specifically target the expression fection. Molecular mimicry between the glycolipids in M. of SOD1 messenger RNA (mRNA) were infused into the pneumoniae and Gal-C has been indicated. In this report, we right lateral ventricle of rats. Capillary gel electrophoresis investigated whether anti-Gal-C antibody production is in- demonstrated 25 mcg/g or greater tissue concentration of oli- duced in sera from rabbits inoculated with the lipid fraction gos in bilateral cortex, brainstem, cervical spinal cord, tho- from M. pneumoniae (M-lipid). M-lipid was extracted from racic spinal cord, and lumbar spinal cord. Similarly, robust the cultivated M. pneumoniae (Mac strain). The respective six uptake of oligo into brain and spinal cord, including ventral rabbits were inoculated with either M-lipid or Gal-C. The horn, was demonstrated by immunocytochemistry. SOD1 antibody activity was investigated with ELISA or thin-layer mRNA and protein levels were decreased by 50–60% not chromatogram (TLC) immunostaining. IgM and IgG anti- only in brain regions near the site of infusion (right cortex), body titers were elevated in all six rabbits inoculated with M-lipid and in four of the six rabbits inoculated with Gal-C. but also in the brainstem and at all levels of the spinal cord. One rabbit inoculated with M-lipid developed transverse Therefore, antisense oligonucleotides offer an effective myelitis. TLC immunostainig showed that several glycolipids method to decrease SOD1 protein and thus the opportunity in M-lipid fraction as well as the authentic Gal-C were spe- to modify or arrest SOD1 variant ALS in humans. Accord- cifically immunostained by the anti-Gal-C rabbit antisera. ingly, we have identified oligos that suppress human Inoculation with M-lipid thus induces production of anti- A4V SOD1 mRNA and have initiated toxicology studies as a Gal-C antibodies. Molecular mimicry may be the mechanism prelude to utilization of these oligos in human ALS. Study of this antibody production. supported by the ALS Association of America, the Skaggs Clinical Scholar Program, the Scripps Research Institute (La Jolla, CA), and the Isis Pharmaceutical Corporation (Carls- 103. Expression of Peripheral Myelin Protein 22 in bad, CA). Human Central Nervous System Tatsufumi Murakami, Yutaka Oosawa, Yuko Miyazaki, and Yoshihide Sunada; Kurashiki, Okayama, Japan The expression of peripheral myelin protein 22 (PMP22) mRNA has been found in rat and mouse brain and spinal 101. Acute Burning Body Syndrome: Expanding cord, although the levels are much lower than in peripheral Spectrum of Small Fiber Neuropathy/Neuronopathy nerves. Recently, we examined a CMT1A patient who Abhay Moghekar, Michael Polydefkis, John Griffin, showed transient, abnormal, high-intensity signals in the David Cornblath, and Vinay Chaudhry; Baltimore, MD splenium of corpus callosum, pyramidal tracts, and middle OBJECTIVE: Acute onset of diffuse burning pain is not a cerebellar peduncles during the hypoglycemic coma. Accord- well-recognized presentation of small fiber dysfunction. We ingly, we hypothesized that PMP22 may be expressed in the present 11 patients with this syndrome. METHODS: Pa- human central nervous system (CNS). Northern blot analysis was performed by total RNA blots that contained several tients presenting to the Peripheral Nerve Clinic with acute Ͻ parts of the human brain, spinal cord, and peripheral nerve (peak 4 weeks) onset of dysesthesias were selected. All pa- using a 554-bp fragment of human PMP22 cDNA as a tients had standardized testing including skin biopsies. RE- probe. As two alternative PMP22 transcripts have been re- SULTS: Eleven patients (mean age: 47 years) were included. ported and the exon 1A-containing transcripts are associated Burning pain involved the entire body in seven, and face, with myelin formation, the exon 1A fragment was also used trunk, or all extremities in the rest. In eight, the onset to to examine this transcript. Total PMP22 and exon 1A- peak occurred within 24 hr. Examination was normal in six, containing mRNA was significantly detected in most parts of and showed predominant pinprick sensory loss in six, in a brain, spinal cord, and peripheral nerve. These suggest that patchy distribution. Ankle reflexes were reduced in two. PMP22 may play an important role in the human CNS. Sural SNAPs were normal in 10 and showed reduced ampli- tude in 1. Skin biopsies in nine showed reduction of intra- epidermal fiber density (five in a non-length-dependent pat- 104. Calpain Cleaves ␣-Fodrin during Muscle Fiber tern). All were considered idiopathic. On follow-up, five Regeneration in Inflammatory Myopathy were stable and four improved subjectively clinically and Ken-ya Murata, Miwa Takamure, Yoshiki Tamada, with skin biopsy. CONCLUSIONS: We present 11 patients Mitsuyoshi Azuma, and Satoshi Ueno; Kashihara, Nara, with acute onset of diffuse burning pain. Given the acute Japan and Kobe, Hyogo, Japan onset and the non-length-dependent distribution, we hy- We examine the involvement of calpains and ␣-fodrin in pothesize that this represents a sensory neurononpathy affect- muscle fiber regeneration in untreated polymyositis (PM) ing the B cells of dorsal ganglia, likely on an immune basis. and dermatomyositis (DM) patients. Serial frozen sections of

S36 Annals of Neurology Vol 56 (suppl 8) 2004 muscle biopsy specimens (10 PM, 10 DM, and 20 normal John C. Steele, a neurology resident, and Dr. J. Clifford Ri- subjects) were immunostained with antibodies against cal- chardson, who was head of the Neurology Division at To- pain, ␣-fodrin, ␤-spectrin, dystrophin, and NCAM. Muscle ronto General Hospital, investigated and described PSP in specimens were also examined by Western blotting to iden- eight patients presenting in late/middle age with supranu- tify ␣-fodrin fragments. Calpain I and II were highly ex- clear ophthalmoplegia (downward gaze), pseudobulbar palsy, pressed in the sarcolemma and the cytoplasm of NCAM- dysarthria, dystonic rigidity of neck and upper trunk, and positive regenerative muscle fibers in disease muscles, but dementia. These patients eventually died within several years. negligible in control muscles. ␣-Fodrin staining patterns dif- Then Steele described the histopathology with Dr. Jerzy Ol- fered according to the regenerative stage. Macrophages in- szewski, Chief of Neuropathology at the Banting Institute. vaded muscle fibers, in the early stages of regeneration, They noticed cell loss, gliosis, neurofibrillary tangles, granu- showed diffuse immunoreactivity for ␣-fodrin in the cyto- lovacuolar degeneration, and demyelination, particularly in plasm. In contrast, ␣-fodrin was expressed at the sarcolemma globus pallidus, subthalamic nucleus, red nucleus, substantia of muscle fibers that were negative for ␤-spectrin or dystro- nigra, superior colliculi, nuclei cuneiformis and subcuneifor- phin. In addition to normal 280-kDa fragments, Western mis, periaqueductal gray, pontine tegmentum, and the den- blot analysis revealed the presence of 150-kD fragments of tate nucleus. Dr. Richardson presented the first clinical re- ␣-fodrin that were produced by calpain cleavage, but not by port at the American Neurological Association meeting, and caspase-3 cleavage. These findings suggest that calpain Dr Olszewski presented the pathology reports at the Ameri- cleaved ␣-fodrin into 150-kDa fragments at specific stages of can Association of Neuropathology meeting in 1963. In regeneration in patients with inflammatory myopathies. April 1964, they published the report of nine patients in the Archives of Neurology. This condition later became known as Steele–Richardson–Olszewski Syndrome, a term first used by 105. Phospholipid Microparticles Incorporating Dr. Andre Barbeau in 1965. This presentation will provide Phosphatidylglycerol Inhibit Microglial Activation, original clinical and pathological pictures of PSP. Rescue Motoneurons, and Slow Disease in ALS Mice David R. Beers, Weihua Zhao, Jenny S. Henkel, Jinghong Wang, Robert J. Ray, Anthony E. Bolton, and 107. Recurrent Transverse Myelitis as a First Stanley H. Appel; Houston, TX and Mississauga, Manifestation of Systemic Lupus Erythematous Ontario, Canada Dipak P. Pandya and David S. Roby; Philadelphia, PA Recent studies suggest that the pathogenic process in amyo- Lupus transverse myelitis is a life-threatening manifestation trophic lateral sclerosis (ALS) is non-cell autonomous and of systemic lupus erythematous occurring in approximately that the immune system actively contributes to motoneuron less than 1% of patients. Recurrent transverse myelitis as a injury. Prominent pathological features of human ALS and first manifestation of SLE is very rare. We report an unusual mutant SOD1 (mSOD1) transgenic mice, an animal model case of recurrent lupus transverse myelitis as an initial man- of familial ALS, are the presence of dendritic cells and acti- ifestation of SLE. A 32-year-old, right-handed woman with vated microglia in spinal cord tissue. We have previously no medical problems was admitted with bilateral upper and shown that phospholipid microparticles incorporating phos- lower extremities numbness with tingling sensation and mild phatidylglycerol (VP025, Vasogen, Mississauga, Canada) in- upper and lower extremity weakness. Her examination was hibit neuroinflammation. In the present study, VP025 was significant for weakness of all extremities, left-sided ataxia, nontoxic to primary neuronal cultures and significantly im- hyperreflexia without clonus, and negative Babinski sign. proved the viability of motoneurons treated with peroxyni- Tests revealed ANA 1:1280, low complement levels, anti-SM trite or glutamate. In microglia and motoneuron co-cultures antibody 1:40, and CSF pleocytosis. Imaging studies re- treated with lipopolysaccharide or ALS IgG, addition of ported transverse myelitis. She had complete recovery to VP025 prevented motoneuron death. Most important, when pulse dose of solumedrol with normal subsequent imaging. injected intramuscularly into mSOD1 mice, VP025 signifi- She presentated again with a large lesion that extended from cantly delayed disease onset (95.3 Ϯ 2.3 vs. 87.4 Ϯ 1.6 days medulla to thoracic spine. She achieved a complete recovery, for PBS-injected controls; p ϭ 0.009) and prolonged survival responding to pulse-dose solumedrol, plasmapheresis, and cy- (151.3 Ϯ 4.4 vs. 133.2 Ϯ 2.7 days for controls; p ϭ 0.004). clophosphamide. Since then she has been without any re- Immunohistochemical examination of spinal cord sections lapse. She left questions unanswered, such as her triggering from these mice revealed a suppression of microglial activa- factors for myelitis, and how her immune responses were tion when compared with PBS-treated mutant mice. These modulated for such a catastrophic presentation. More re- results suggest that VP025 is a new immunomodulatory search is needed to understand the pathogenesis and treat- therapy that can inhibit immune system activation and pro- ment. tect motoneurons from injury. Study supported by Vasogen (Mississauga, Ontario, Canada), Dr. Robert J. Ray (manager, pre-clinical research, Vasogen, Canada), Dr. Anthony E. 108. C-Terminus of Hsp70-Interacting Protein Bolton (chief scientist, Vasogen, Ireland), Dr. Stanley H. Ap- Suppresses Polyglutamine Aggregation and Toxicity in pel (member, scientific advisory board, Vasogen, Canada). Vitro and in Vivo Victor M. Miller, Cynthia M. Gouvion, Michael R. Rebagliati, and Henry L. Paulson; Iowa City, IA OTHER Neuronal protein quality control depends critically on the specific and coordinated activity of molecular chaperones and 106. Historical Perspective of Progressive Supranuclear the ubiquitin proteasome pathway. The C-terminus of Palsy (Steele–Richardson–Olszewski Syndrome) Hsp70-interacting protein (CHIP), a protein with dual roles Shri K. Mishra and Vivek Misra; Los Angeles, CA as a co-chaperone and ubiqutin ligase, provides a molecular Progressive supranuclear palsy (PSP) was first recognized by link between these processes through its interactions with three physicians at the University of Toronto. In 1961, Dr. proteins in both pathways and its demonstrated ability to

Program and Abstracts, American Neurological Association S37 modulate refolding and degradation of misfolded proteins. new antiepileptic drug, also employed as prophylactic agent Protein misfolding and aggregation are implicated in the in migraine. DESIGN/METHODS: The patient is a 12- pathogenesis of many neurodegenerative diseases, including year-old white girl with a family history of migraine. By the the dominantly inherited polyglutamine (polyQ) diseases. age of 7 months she displayed two or three attacks of alter- Here we show that CHIP modulates polyQ aggregation and nating hemiplegia per week. Each attack lasted 24–36 hr and toxicity in vitro and in vivo. Overexpression of CHIP sup- subsided during sleep. Investigations included negative neu- presses aggregation of both a generalized expanded polyQ- roimaging, cardiovascular, metabolic, coagulation, and ge- fusion protein and a mutant Huntington (Htt) fragment in netic studies. An ictal video-EEG showed posterior slow Cos-7 and PC12 neural cells. In vivo, CHIP overexpression waves. She failed conventional antiepileptic and antimigraine rescues embryonic lethality in a novel zebrafish model of treatment. Topiramate was started up to 3 mg/kg/day in polyglutamine disease that exhibits glutamine repeat-length add-on with valproate and flunarizine with a follow-up of 12 dependent toxicity, developmental arrest, and protein aggre- months. RESULTS: Topiramate induced a dramatic, sudden gation. We suggest that CHIP is a critical integrator of the reduction of hemiplegic attacks up to one or two episodes cellular response to misfolded polyQ protein, and may rep- per month with milder severity. No significant adverse effects resent a promising new molecular target in the search for occurred. CONCLUSIONS: These results suggest that topi- therapies for polyQ and other neurodegenerative disorders. ramate could be efficacious and safe in treatment of alternat- Study supported by MIH/NINDS R01 NS38712. ing hemiplegia. Further studies should be needed to confirm these reports.

109. Cobalamine Deficiency with Bilateral Optic Neuropathy, Multiple White Matter Lesions, and 111. Neuropsychological Profile of Asymptomatic Normal B12 Levels Boys with X-Linked Adrenoleukodystrophy Who Had Chitharanjan V. Rao, John B. Selhorst, and Normal Brain MRI Florian P. Thomas; Saint Louis, MO Prachi Dubey, Christian Cox, Hugo W. Moser, Ali Fatemi, Lena Bezman, and Gerald V. Raymond; Baltimore, MD Visual problems are infrequent in cobalamin deficiency (CD) and rare at onset; MRIs may resemble MS. With normal BACKGROUND: Childhood cerebral X-linked adrenoleu- B12 levels in about 10%, homocysteine/methylmalonic acid kodystrophy (CCALD) is characterized by inflammatory de- (MMA) must be assayed. A patient presented with a 6-week myelination associated with cognitive dysfunction. Not history of acute-progressive, bilateral, painless visual loss. much is known about cognitive profile in asymptomatic With bilateral optic atrophy, paracentral scotomas, visual X-linked adrenoleukodystrophy (X-ALD) patients before the acuity of 20/50, no APD, and periventricular, high-intensity, onset of cerebral demyelination. METHODS: Neuropsycho- enhancing MRI lesions, MS was diagnosed. He developed logical tests including IQ (full-scale IQ, FSIQ; verbal IQ, imbalance, tingling feet, distal sensory loss, hyporeflexia, VIQ; and performance IQ, PIQ) and five cognitive domains equivocal plantars, and Romberg sign. CSF protein was 54 were performed on 61 asymptomatic X-ALD patients (age: mg/dL; cells, glucose, MBP, and immunoglobulins were nor- 6.5 Ϯ 3.4 years) with normal MRI. Standardized Z scores mal. VEP revealed P100-latency prolongation; SSEPs were relative to normative means and global Z score and summa- normal. IVMP produced no improvement. NCS/EMG indi- rizing five cognitive domains were generated. A Z score cated sensory neuropathy. Spinal MRI, CBC, MCV, folate, ՅϪ2 was considered significantly abnormal. The Wilcoxon ACE, ANA, lactate, RPR, Lyme, and phospholipid antibod- matched-pair, signed-rank test was used to assess VIQ-PIQ ies were normal. B12 was 237 pg/mL, MMA was 928 discrepancy. RESULTS: Mean Z scores for IQ and all cog- nmol/L. With no intrinsic-factor antibodies, gastrointestinal nitive domains were normal (mean Ϯ SD were FSIQ ϭ diseases, dietary deficiency, or relevant medications, and with 103.4 Ϯ 14.6, VIQ ϭ 102.49 Ϯ 13.9, PIQ ϭ 102.49 Ϯ a borderline Schilling test, the etiology of CD remained un- 15.04, language ϭϪ0.016 Ϯ 0.0.9, visuoperceptual ϭ clear. B12 supplementation improved vision, balance, and 0.27 Ϯ 0.86, visuomotor ϭϪ0.138 Ϯ 0.875, memory ϭ sensation. This illustrates a pitfall when MS is suspected. 0.006 Ϯ 0.75, executive ϭϪ0.17 Ϯ 0.8, global Z ϭ Painless bilateral visual loss, distal sensory symptoms/signs, Ϫ0.05 Ϯ 0.67). The VIQ-PIQ discrepancy was significant hyporeflexia, and non-contributory CSF raised doubts. CD (p ϭ 0.02); 70% had PIQ Ͼ VIQ. CONCLUSION: Re- can exist with normal B12 and MRIs resembling MS. Be- sults confirm and extend previous reports in a larger cohort, cause CD produces serious, treatable neurologic disease, demonstrating normal neuropsychological functions in MMA/homocysteine must be measured, particularly with asymptomatic X-ALD patients with normal MRI, suggesting B12 below 300 pg/mL. that cerebral demyelination precedes neuropsychological ab- normalities. The significant discrepancy in VIQ-PIQ, (PIQϾ VIQ) suggests that known PIQ abnormalities in PEDIATRIC NEUROLOGY CCALD occur alter onset of demyelination and that subtle verbal deficits may manifest earlier. Study supported by 110. Case of Alternating Hemiplegia of Childhood Johns Hopkins University School of Medicine General Clin- Successfully Treated with Topiramate: Follow-up of 12 ical Research Centers (grant M01-RR00052). Months Gabriella Di Rosa, Maria Spano, Giuseppina Pustorino, Valerio Bascia, Domenica L. Sgro, Maria P. Santoro, 112. Cortical Architectural Study of a Model Mouse Filippo Calamoneri, and Gaetano Tortorella; Messina, Italy of Rett Syndrome Masayuki Itoh and Tetsuya Fukuda; Kodaira, Tokyo, Japan BACKGROUND: Alternating hemiplegia is a rare syndrome of childhood, of unknown cause, characterized by recurrent INTRODUCTION: Rett syndrome (RTT) is associated hemiplegic attacks shifting from one side to the other. It has with cerebral dysfunction. It is known that a small brain and been considered as a variant of migraine and has been treated a thin cerebral cortex are the typical brain pathology of RTT. with flunarizine with partial effectiveness. Topiramate is a We focus on the cerebral cortical structure in mecp2-

S38 Annals of Neurology Vol 56 (suppl 8) 2004 mutated mice, to clarify the pathomechanism of the cortical of HCN1, HCN2, and HCN4 was detected using immuno- dysfunction of RTT. RESULTS: Ten-micrometer-thick sec- histochemistry. We observed a developmental regulation in tions on paraffin-embedded or frozen brain of hemizygote both types of voltage-gated channels in Me5 neurons, with a and wild-type males were stained with cresyl violet and with peak expression occuring in P8–12, the period immediately the antibodies for GFAP, S-100, MAP-2, and neurofilament. preceding the onset of chewing behavior. Voltage-gated ion Then we recorded ultrastructural observations. The thickness channel expression was weak in Mo5 throughout the time of the cerebral cortex of the mecp2-hemizygote male does frame sampled. Our data suggest that intrinsic membrane not increase after 4 weeks of age, whereas that of the wild- plasticity among Me5 neurons contributes to the sucking-to- type male increases. And the neuronal concentration of the chewing transition. Study supported by funding from the male does not decrease after 4 weeks of age, whereas that of Center for Early Childhood Feeding Disorders (awarded to the wild-type male decreases. Immunohistochemistry of J.T., Jr.). GFAP, S-100, MAP-2, and neurofilament shows no differ- ence between mecp2-hemizygote and wild-type male brains. DISCUSSION: We revealed that the cerebral cortex of the 115. Cerebellar Vermis Morphology in Children with mecp2-hemizygote male might be immature. It is possible Arnold–Chiari Type II Malformation that synaptic dysfunction, derived from structural and func- Michael S. Salman, Susan Blaser, James A. Sharpe, and tional abnormalities, can lead to cortical symptoms such as Maureen Dennis; Toronto, Ontario, Canada mental retardation and epilepsy. BACKGROUND: Arnold–Chiari malformation type II (ACII) is associated with reduction of posterior fossa size, cerebellar weight, and volume. Our aim was to quantify the 113. Methylmalonic Acidemia presumed reduction in vermis size with MRI. METHODS: William C. Robertson, Jr.; Lexington, KY A midsagittal brain MRI slice was selected from each of 68 Three reports of MR spectroscopy and two of findings on children with ACII (mean age: 13; 37 females). Control par- diffusion-weighted imaging (DWI) in four unrelated chil- ticipants were 28 typically developing children (mean age: dren with methylmalonic acidemia (MMA) have shown in- 14.1; 13 females). Midsagittal surface areas of the intracranial creased lactate and restricted diffusion in striatum during fossa, posterior fossa, cerebellar vermis and tonsil, vermis lob- bouts of acidosis. One patient was studied during and fol- ules I–V, and VI–VII were measured. RESULTS: Mean pos- lowing metabolic decompensation. Two siblings with MMA terior fossa area was significantly smaller (p Ͻ 0.003) in were studied during and between bouts of metabolic acidosis. ACII. However, mean vermis and tonsil areas were signifi- Brain MR on the older sibling during acidosis showed hy- cantly larger (p Ͻ 0.0001) in participants with ACII. In perintense lesions confined to globi pallidi (GP) on T-2 and ACII participants, the mean vermis lobules I–V area was DW images. DWI 6 weeks later was normal, and T-2 lesions 31% larger, and the mean vermis lobules VI–VII area was were less prominent. T-2 lesions and restricted diffusion 44% larger than in control participants (p Ͻ 0.0001). were not seen in the younger brother on day 3 of treatment CONCLUSION: The vermis is expanded, not reduced, in for acidosis. Single-voxel spectroscopy of the GP performed size in ACII on midsagittal MRI. We attribute the expansion in both children while they were asymptomatic was normal. to compressive displacement of midline structures within the A normal MR finding in the younger sibling suggests that confines of a small posterior fossa. This implies that ACII permanent changes in the striatum as seen in the older sister deformity could affect function of the vermis differently result from recurrent bouts of acidosis. Brain injury in MMA from function of the cerebellar hemispheres. Study supported probably results from inhibition of succinate dehydrogenase by KidsAction; the Spina Bifida and Hydrocephalus Associ- (SD) by methylmalonic acid. Studies have suggested that GP ation of Canada; the Research Training Competition Award; has a relative deficiency of SD which could explain their ap- the Clinician-Scientist Training Award; the Hospital for Sick parent increased vulnerability to injury in MMA. Recurrent Children, Toronto; the Vision Science Research Program bouts of acidosis appear to cause permanent injury and per- Training Award for Clinician-Scientists, Toronto Western sistent areas of T-2 hyperintensity with preferential involve- Hospital; the University of Toronto; Bloorview Childrens ment of GP. Hospital Foundation grants; and National Institute of Child Health and Human Development Grant P01 HD35946 Spina Bifida: Cognitive and Neurobiological Variability. 114. Developmental Regulation of Voltage-Gated Ion Channels in Trigeminal Neurons Suparna Saha and Jack E. Turman; Los Angeles, CA 116. Saccadic Adaptation in Children with Arnold– Chiari Type II Malformation The development of ingestive behaviors includes a transition Michael S. Salman, James A. Sharpe, Moshe Eizenman, from sucking to chewing. We hypothesize that the plasticity Linda Lillakas, Carol Westall, Teresa To, Maureen Dennis, in brainstem oral-motor circuits contributes to this transi- and Martin Steinbach; Toronto, Ontario, Canada tion. To test this hypothesis, we examined developmental changes in molecular properties of trigeminal motorneurons BACKGROUND: Saccadic adaptation is an unconscious (Mo5) and mesencephalic trigeminal neurons (Me5). One corrective change in the amplitude of saccades in response to parameter associated with rhythmical movements, such as visual errors. It is a form of motor learning. The cerebellum sucking and chewing, is neuronal bursting. Intrinsic mem- is a major participant. Arnold–Chiari type II malformation brane properties determined in part by voltage-gated sodium (ACII) is a deformity of the hindbrain. We investigated the channels and inward-rectifying currents (Ih) sculpt neuronal effects of ACII on saccadic adaptation, and correlated them bursting patterns. This study examined the developmental with MRI features of ACII. METHODS: An infrared eye expression of voltage-gated sodium channels (Nav 1.1, 1.2, tracker (El-Mar) recorded adaptation to target hypometria 1.3, 1.6, 1.7) and hyperpolarization-activated channels induced by 3° back-steps of 12° horizontal targets in 21 par- (HCN), which generate Ih currents, in postnatal day (P) ticipants with ACII and 39 control subjects aged 8–19 years. 0–15 rats. Expression of voltage-gated sodium channels and Target back-steps were triggered during primary saccades to

Program and Abstracts, American Neurological Association S39 the 12° target steps. Midsagittal MRI brain regions were pontine tumors, Guillain–Barre syndrome, and multiple scle- measured in 19 ACII participants. RESULTS: Saccadic ad- rosis. We report six cases of facial and generalized myokymia aptation was achieved in 57% of ACII participants, who had following cardiopulmonary arrest, first noted by rhythmic ac- 11.6% mean reduction in saccade amplitude, and in 67% of tivity on EEG. The implications of diffuse injury to motor control participants, who had a 13.3% mean reduction in neurons and the eventual outcome for the patients is re- saccade amplitude. The differences between the groups were viewed. Six patients aged 18 to 73 with a severe hypoxic not significant. Adaptation did not correlate with MRI event had myokymia recognized at the time of EEG record- planimetry of the cerebellum. CONCLUSION: Saccadic ad- ing as rhythmic muscle artifact. Visible facial myokymia was aptation occurs in children with ACII as young as 8 years. documented on EMG as spontaneously firing doublets and This indicates intact function of the cerebellar circuits in- multiplets in facial and limb muscles. Intraburst firing fre- volved in saccadic adaptation despite the malformation of quency varied from 45 to 250 Hz. Discharges disappeared ACII. Study supported by KidsAction; the Spina Bifida and 36–48 hr postarrest. All of the patients died within 1 week Hydrocephalus Association of Canada; the Research Training of the arrest. Myokymia reflects hyperexcitability of the mo- Competition Award; the Clinician-Scientist Training Award; tor axons, as seen with disorders of voltage-gated potassium the Hospital for Sick Children, Toronto; the Vision Science channel abnormalities, demyelination, and ischemia. The oc- Research Program Training Award for Clinician-Scientists, currence of myokymia can be caused by severe ischemia to Toronto Western Hospital; the University of Toronto; the brain and spinal cord and is due to ischemia-induced Bloorview Childrens Hospital Foundation grants; and Na- axonal hyperexcitability. Ischemia-induced myokymia is a tional Institute of Child Health and Human Development poor prognostic sign and is incompatible with survival. Grant P01 HD35946 Spina Bifida: Cognitive and Neurobi- ological Variability. Dr. M. Eizenman is the inventor of the tracker. He has shares and interest in El Mar, the manufac- 119. Effects of Active Sleep Deprivation on the turer of the eye tracker. Developing Brain M.J. Morrissey, S.P. Duntley, and A.M. Anch; Saint Louis, MO SLEEP, COMA, AND BRAIN DEATH The aim of this study was to identify a possible function of active sleep (AS), also known as rapid eye movement (REM) Ammonia Increases Interleukin-1␤؊Induced .117 sleep, in humans as a protective state during early central Inducible Nitric Oxide Synthesis Expression in C6 nervous system (CNS) development. AS is characterized by Glioma Cells high levels of CNS activity at levels comparable to waking. Xuesheng Feng, Shasha Wu, Marie Rose, Lifang Shao, and AS occupies up to 75% of the circadian cycle in developing David Geller; Pittsburgh, PA mammals (rodents from postnatal day 1 to postnatal day 14, OBJECTIVE: To examine the effect of ammonia on the reg- p1 to p14, and humans from prenatal month 7 to postnatal ulation of inducible nitric oxide synthesis (iNOS) expression year 1). Researchers have documented behavioral anomalies by rat glioma cells. BACKGROUND: Ammonia is a key fac- as a result of AS deprivation. Reduced adult brain mass has tor in the pathogenesis of hepatic encephalopathy (HE). The been observed after AS deprivation in developing rats during molecular mechanisms underlying ammonia neurotoxicity this period; however, no study to date has documented this are incompletely understood. METHODS AND RESULTS: process as it occurs. Our methodology includes utilization of Ammonia enhanced nitrate oxide (NO) production in C6 the ␣2-adrenergic receptor agonist clonidine to deprive rat glioma cells in a dose-dependent pattern within the concen- pups of AS at ages p7 to p14. The animals that were AS- tration of 1–5 mmol/mL, increasing 40–50% at concentra- deprived showed a statistically significant decrease in brain tion of 5 mmol/mL. Increases in NO production reflected mass and have stained positively for programmed cell death. significant increases in iNOS immunoreactive protein and This research has major implications with regard to deter- iNOS mRNA. Interestedly, ammonia has a minor suppres- mining the function(s) of REM sleep. sive effect on cytokine mixture (IFN␥, 100 u/mL; IL-1␤, 200 u/mL; and TNF␣, 500 u/mL)-induced NO production in C6 cells. Unlike TNF␣, ammonia has no effect on 120. Decline in Visual Vigilance in Drivers with NF-␬B DNA binding activity and activation. In contrast to Obstructive Sleep Apnea Syndrome previous reports in other cell types, ammonia alone did not Matthew Rizzo, Ida Kellison, Laura Stierman, induce iNOS expression significantly in C6 glioma cells. Rick Vanderleest, and Jon Tippin; Iowa City, IA CONCLUSION: These findings suggested that the ammo- PURPOSE: Investigate visual vigilance in drivers with ob- nia upregulates iNOS expression in C6 cells under a differ- structive sleep apnea syndrome (OSAS). BACKGROUND: ent mechanism as TNF␣. The results also indicated that Drivers with OSAS pose increased risk for car crashes due to iNOS/NO system be involved in the molecular mechanisms decreased vigilance. Studies in sleep deprivation suggest the underlying ammonia neurotoxicity such as in HE. Study problem is worse for detecting peripheral targets (Throne et supported by a grant from the National Institutes of Health al., 1999). METHOD: Fifteen licensed drivers (mean age: to Dr. Geller. 47.8 years) with OSAS drove a simulator with a 150° for- ward field of view. Drivers clicked the high beams in re- sponse to targets flashed at unpredictable intervals and loca- 118. Significance of Myokymia Associated with Severe tions along the horizon. The Stanford Sleepiness Scale Hypoxic-Ischemic Injury indexed self-rated sleepiness. RESULTS: Drivers responded Laurie Gutmann and Gauri V. Pawar; Morgantown, WV faster (p ϭ 0.027) and more accurately (p ϭ 0.007) to cen- Facial myokymia associated with spontaneous doublets and tral targets than peripheral targets. Although hit rates did not multiplets has been described following cardiopulmonary ar- differ over the drive, RT was slower in the final third com- rest. (Morris, Arch. Neurol., 1981) Other descriptions of fa- pared to the middle third (p ϭ 0.015). Sleepiness increased cial myokymia are reported with brainstem lesions, including over the drive (p Ͻ 0.001), which correlated with greater

S40 Annals of Neurology Vol 56 (suppl 8) 2004 RT on the vigilance task (p ϭ 0.029). Unlike tunnel vision, measurements. CT and MRI assessment of canal stenosis or the vigilance decrement affected central and peripheral tar- cord compression correlated significantly with admission gets similarly. CONCLUSION: Vigilance declines as a func- ASIA scores. Moreover, MRI assessment of cord compression tion of sleepiness. Our results indicate that sleepiness de- and canal stenosis was predictive of long-term neurological creases the efficiency with which drivers extract information outcome after SCI. Study supported by the Krembil Foun- from a cluttered scene, as hypothesized in some studies of dation. Part of my postdoctoral fellowship salary is supported cognitive aging (Sekuler et al., 2000). Study supported by by the Krembil Foundation. the Centers for Disease Control and Prevention.

123. Mechanisms of Hyponatremia after Spinal Cord 121. Restless Legs Syndrome in Children Injury: Clinical and Neuroanatomical Evidence for Muhammad A. Sayed, Parkash Kotagal, Disruption of Descending Renal Sympathetic Pathways Nancy Foldvary-Schaefer, and Charles Bae; Cleveland, OH Julio C. Furlan and Michael G. Fehlings; Toronto, Ontario, Canada INTRODUCTION: Restless legs syndrome (RLS) is a rec- ognized and well-described disorder in adults, yet some evi- We postulated that post-spinal cord injury (SCI) hyponatre- dence shows its onset in childhood. RLS was described in mia may partly reflect destruction of descending renal sym- children, but only in patients with ADHD. Our case series pathetic pathways (DRSPs). Accordingly, we studied the (1) includes 10 children with RLS, 40% of them without a con- incidence of hyponatremia within 2weeks post-SCI, (2) as- comitant ADHD. METHODS: We reviewed the charts of sociation of hyponatremia with SCI severity, (3) localization children with sleep disorders between 2000 and 2003.The of DRSPs, and (4) influence of DRSP integrity on serum diagnosis of RLS was established based on polysomnographic [Na]. Data of individuals with acute SCI admitted between and clinical findings. RESULTS: Out of 207 children, 10 1998 and 2000 were reviewed. Postmortem spinal cord sec- patients were diagnosed with RLS (incidence rate: 5%). The tions from cervical SCI and control cases were evaluated for mean age was 8 Ϯ 6 years. Only 30% were females, 70% myelin (LFB) and axons (NF200) 3 mm lateral and ventral had insomnia, 80% had an excessive daytime sleepiness, 60% to dorsolateral sulcus (VDLC), within corticospinal tracts had a progressive course, 40% had family history of RLS, (CST) and dorsal columns. Post-SCI hyponatremia occurred and only 60% had ADHD. Treatment including sleep hy- in 85.7% of 21 individuals (6 females, 15 males; ages: giene, Neurontin, Clonidine, and Requip, and it was com- 17–83 years). Postmortem analysis included five control menced in 90% of patients. Eighty percent of compliant pa- cases (two females, three males; ages: 30–73 years) and six tients showed different degrees of symptomatic relief, yet the individuals with severe SCI (two females, 4 males; ages: compliance rate was only 50%. CONCLUSION: These data 31–82 years). The number of preserved axons within CST supports that RLS occurs in children even in the absence of and VDLC was significantly reduced after SCI. Mean and ADHD. Clinicians should be aware that RLS can occur in lowest serum [Na] correlated directly with extent of demy- childhood and may be more common than was previously elination and inversely with number of intact axons within thought. More studies are needed to further characterize RLS VDLC. Hyponatremia is frequent and is associated with the in children. severity of SCI. The extent of destruction of VDLC is in- versely correlated with post-SCI hyponatremia, and this may reflect autonomic renal dysfunction due to disruption of TRAUMA/INJURY DRSPs. Study supported by the Krembil Foundation. Part of my postdoctoral fellowship salary is supported by the Krem- 122. Significance of Quantitative Assessment of Canal bil Foundation. Stenosis by CT Scan and MRI for Evaluation of Neurological Status and Prediction of Neurological Outcome after Spinal Cord Injury 124. Hematological Abnormalities in the Acute Stage Julio C. Furlan and Michael G. Fehlings; Toronto, after Traumatic Spinal Cord Injury Ontario, Canada Julio C. Furlan and Michael G. Fehlings; Toronto, Ontario, Canada This study evaluates the value of maximum canal compro- mise (MCC) and maximum spinal cord compression Given that autonomic innervation dominates kidneys, (MSCC) in assessing neurological status and predicting neu- spleen, bone marrow, and surrounding tissues, this study rological outcomes after spinal cord injury (SCI). All consec- evaluates (1) the hematological abnormalities within the first utive individuals with acute traumatic SCI who underwent post-SCI week and (2) the influence of age, gender, level, MRI and CT at admission between 1998 and 2000 were and SCI severity on post-injury hematological abnormalities. neurologically assessed (ASIA score) at admission and at All consecutive individuals with acute, isoleted SCI admitted follow-up (mean: 10.2 months). Data were analyzed using between 1998 and 2000 were reviewed. Data were analyzed ANOVA and linear regression. There were 22 individuals (6 using multiple linear regression. There were 24 individuals females, 16 males; ages: 17–82 years) who were surgically with acute, isolated SCI and no medical co-morbidity (7 fe- (50%) or conservatively treated for different SCI degrees males, 17 males; ages: 17–83 years; mean: 55.9 years). Ane- (ASIA A1/B2/7C/8D/4E). CT-MCC (p ϭ 0.044), MRI- mia occurred in 83.3%. Individuals with more severe SCI MCC (p ϭ 0.004), and MRI-MSCC (p ϭ 0.021) were cor- showed lower hemoglobin concentration (p ϭ 0.003). Lym- related with baseline ASIA scores. Individuals with more se- phopenia (83.3%) and leukocytoses (37.5%) were the only vere SCI had greater MRI-MCC (p ϭ 0.01), and there was abnormalities in white blood cell counts. Blood leukocyte a trend for a similar association with MRI-MSCC (p ϭ count was not correlated with age, gender, level, or severity 0.064). There were no significant differences for CT-MCC of SCI. Lower blood lymphocyte count was correlated with measurements among individuals with different ASIA scores. elderly (p ϭ 0.031), male (p ϭ 0.05), thoracic (p ϭ 0.001), Neurological outcome was correlated with MRI-MCC (p ϭ and severe SCI (p Ͻ 0.001). Thrombocytopenia occurred in 0.003) and MRI-MSCC (p ϭ 0.011), but not CT-MCC 33.3%. Lower blood platelet concentration was correlated

Program and Abstracts, American Neurological Association S41 with elderly (p ϭ 0.059) and severe SCI (p ϭ 0.007). Ane- following peptide administration. Brain TNF␣ RNA was re- mia, lymphopenia, and thrombocytopenia are frequent in the duced in animals treated with ApoE (133–149) peptide. first post-SCI week and correlate with the extent of injury. Transgenic mice treated with peptide also had a reduction of Disruption of neural regulation of the hemopoietic system TNF␣ after injury as well as less A␤ 1–40 deposition. may play important role in the pathobiology of hematologi- CONCLUSIONS: We demonstrate that ApoE (133–149) cal abnormalities after SCI. Study supported by the Krembil significantly reduced Alzheimer’s pathology and improved Foundation. Part of my postdoctoral fellowship salary is sup- behavioral outcome in wild-type, E2, and E3 transgenic ported by the Krembil Fourndation. mice. This therapeutic approach had no palliative effect on the E4 animals, suggesting that endogenous ApoE4 may ex- ert a dominant negative effect. Study supported by Cognosci. 125. Arundic Acid in Acute Ischemic Stroke: Pharmacokinetics and Coagulation Effects L. Creed Pettigrew, Scott E. Kasner, William B. Smith, Tuesday, October 5, 2004 Mark Gorman, Richard P. Atkinson, Ken Ng, Rodney Bell, Jon M. Rogers, and Masahiro Katayama; Lexington, KY; Philadelphia, PA; New Orleans, LA; New Haven, CT; EPILEPSY WALKING TOUR Sacramento, CA; Ocala, FL; and Lawrenceville, NJ 201. Inhibition of Cyclooxygenase-2 Prevents the BACKGROUND: Candidate stroke neuroprotective drugs Epileptogenic Process with Suppression of Inflammation must reach effective blood levels and should not increase and Aberrant Ectopic Granule Cell Formation hemorrhagic risk when used with thrombolytics. Arundic Kon Chu, Keun-Hwa Jung, Soon-Tae Lee, Manho Kim, and acid (AA; ONO-2506; astrocyte modulator) improved neu- Jae-Kyu Roh; Seoul, Seoul, Republic of Korea rological outcome in primate focal cerebral ischemia at plasma levels of 15–56 ␮g/mL. We studied the pharmacoki- Ectopic granule cell formation after prolonged seizure has netics of AA and determined AA effects on coagulation. been known to be a contributing factor in the formation of METHODS: Ninety-two patients received AA (n ϭ 49; epilepsy. The upstream molecular mechanism that is in- 2–12 mg/kg/hr; 8–9/group; daily ϫ7) or placebo (n ϭ 43) volved is currently unknown. Here, we show that inhibition within 24 hr of stroke onset. Pharmacokinetic profiling was of cyclooxygenase-2 (COX-2) exerts neuroprotective effects, conducted on days 1 and 3. Healthy volunteers received 10 blocks inflammation after prolonged seizure (PS), and ame- mg/kg/hr AA (n ϭ 6) or placebo (n ϭ 3). Pre-dose/ liorates the epileptogenic process. PS was induced by immediate/6-hr post-dose hemostasis was evaluated by plate- lithium-pilocarpine injection. Selective COX-2 inhibitor let aggregation, PT/aPTT, and whole blood/Ivy clotting (celecoxib, 20 mg/kg) or PBS was administered orally from 6 times. RESULTS: Dose-dependent increases in systemic ex- hr after PS and daily afterwards for 7 or 28 days. Celecoxib ϩ posure to AA were noted. Doses Ն2 mg/kg/hr in stroke pa- treatment reduced neuronal death and OX-42 microglial tients reached plasma levels that were efficacious in primates. activation in the hilus, CA1, and CA3 at 7 or 28 days after ϩ There was no effect on cellular/humoral coagulation after PS. BrdU cells were decreased at 7 or 28 days after PS. ϩ ϩ ϩ ϩ 1-hr infusion of AA. CONCLUSIONS: The pharmacoki- Also, BrdU NeuN or BrdU Calbindin ectopic granule netic profile of AA was predictable in acute stroke. No dose cells in the hilus were decreased in the celecoxib-treated adjustment was required despite a modest reduction in drug group. Celecoxib treatment also significantly reduced the fre- clearance in elderly subjects. We conclude that AA has po- quency and duration of spontaneous recurring seizure during tential for clinical efficacy, as well as for safe administration video monitoring (from day 28 to day 42). Taken together, when used with or without thrombolytics in stroke. Study we provide evidence that inhibition of COX-2 prevents the supported by the Ono Pharmaceutical Company. Dr. Jon epileptogenic process, which might be due to the neuropro- M. Rogers and Mr. Masahiro Katayama are salaried employ- tective and anti-inflammatory effects. ees of the Ono Pharmaceutical Company.

202. Does Extratemporal Hypometabolism Affect 126. An ApoE-Based Therapeutic Improves Outcome Temporal Lobectomy Prognosis? and Reduces Alzheimer’s Disease Pathology after Head William H. Theodore, Susumu Sato, William D. Gaillard, Injury Patricia Tyer-Reeves, Anto Bagic, Robert Bonwetsch, and John R. Lynch, Haichen Wang, Wen Tang, Michael Vitek, John Heiss; Bethesda, MD and Washington, DC Lori Durham, Patrick Sullivan, David S. Warner, and Patients with complex partial seizures and temporal hypome- Daniel T. Laskowitz; Durham, NC tabolism on fluorodeoxyglucose positron emission tomogra- INTRODUCTION: ApoE-deficient animals have impaired phy may have extratemporal hypometabolism, particularly in outcomes after traumatic insult by regulating the neuroin- frontal regions and thalamus ipsilateral to seizure foci. To flammatory response. We demonstrate that a small peptide assess the effect of extratemporal hypometabolism on tempo- derived from the ApoE receptor binding region improves ral lobectomy outcome, we studied 78 patients with ictal functional and histological outcomes of ApoE2, ApoE3, but video-EEG localized temporal lobe seizure foci, who had had not ApoE4 transgenic mice following closed head injury. at least a 1-year follow-up. Fifty-four patients had MRI find- METHODS: Mice were subjected to closed head injury us- ings suggesting mesial temporal sclerosis (MTS) (increased ing a stereotactically guided pneumatic compression device T-2 signal, hippocampal atrophy), and 24 patients had nor- to produce an acute acceleration/deceleration injury. The 17- mal MRI. We used a standard template to measure asymme- amino-acid peptide was derived from ApoE residues 133– try between glucose metabolic rates ipsilateral and contralat- 149(receptor binding region). Mice were injected via tail eral to patients’ seizure foci. Postoperatively, patients were vein with peptide (4.0 mg/kg of ApoE 133–149) or vehicle classified as seizure-free (they could have non-disabling auras) 30 min following head injury. RESULT: Rotorod latency or not seizure-free. There was no effect of epilepsy duration was improved in E2 and E3 (p Ͻ 0.05) but not in E4 mice or age at surgery. Mesial temporal, but not inferior, mid- or

S42 Annals of Neurology Vol 56 (suppl 8) 2004 superior frontal metabolic asymmetry, was a significant pre- 205. Interictal Extracellular Glutamate Concentrations dictor of surgery outcome. There was a non-significant trend Are Increased in Hippocampal Sclerosis (0.05 Ͻ p Ͻ 0.1) for seizure-free patients to have greater Ognen A. Petroff, Idil Cavus, Jung H. Kim, and preoperative thalamic asymmetry. In logistic regression with Dennis D. Spencer; New Haven, CT metabolic asymmetry and MRI as factors, mesial temporal but not thalamic hypometabolism was a significant predictor Combined depth electrode and microdialysis studies of tem- of surgical outcome. Our study suggests that hypometabo- poral lobe epilepsy show that increased extracellular gluta- lism in frontal or thalamic regions does not affect temporal mate concentrations are characteristic of the epileptogenic lobectomy outcome. Study supported by the NINDS Divi- hippocampus. The observations are surprising in light of the sion of Intramural Research. loss of glutamatergic neurons and proliferation of glia that characterize hippocampal sclerosis (HS). After informed con- sent, interictal extracellular glutamate concentrations were 203. Heart Rate Variability during Sleep in Patients measured by “zero-flow” microdialysis in the hippocampus with Refractory Eepilepsy of 19 patients. Hippocampal glial and neuronal densities and Yajun Li and Peng Xie; Shaanxi, China and Chongqing, tissue glutamate content were measured in 7 patients; the Chongqing, China hippocampus was not epileptogenic in 12 patients, who had PURPOSE: This study was to determine the features of car- neocortical resections (NCs). Patients with HS had above- diac autonomic control during sleep without ictal epilepti- normal interictal, extracellular glutamate concentrations (HS form electroencephalogram (EEG) activity in patients with 13.1 micromolar, se 7.7, n 4 vs. NC 3.2, se 0.7; p Ͻ 0.04) intractable epilepsy. METHOD: Thirty-seven patients (me- despite significant neuron loss (66%, se 7) and gliosis (90% dian age: 33.6 years) with a history of intractable epilepsy for greater glial density, se 30), compared to autopsy controls. 7–31 years (median: 18.6 years) were recruited from our ep- Patients with paradoxical temporal lobe epilepsy (PTLE) had ilepsy center; 35 healthy volunteers (median age: 31.5 years) nearly normal extracellular glutamate (4.0, se 1.3, n 3) and served as controls. All subjects had no evidence of ischeamic heart disease or diabetes and slept in the laboratory for 2 minimal neuron loss (26%, se 9) and gliosis (26%, se 10). Conversely, tissue glutamate content was greater in PTLE consecutive nights. Sleep was polygraphically recorded, in- Ͻ cluding one electrocardiography (ECG) channel, and signals (9.8 mM, 0.6, p 0.01) compared to HS (5.1, se 0.5). Ab- were digitally stored. A series of 5-min ECG epochs were normal extracellular glutamate appears to be associated with chosen from each sleep stage, during periods without evident gliosis, suggesting glial dysfunction. Study supported by NIH ictal epileptiform activity in the EEG. HRV was analyzed in NINDS PO1-NS39092. time and frequncy domains with a computer program. RE- SULT: We found that HRV in both time and frequency domain measures were lower in patients with refractory epi- lepsy than in controls (p Ͻ 0.05) during sleep, especially during rapid eye movement (REM) sleep (p Ͻ 0.01). CON- EPILEPSY CLUSION: There exist autonomic dysregulation in patients with refractory epilepsy during sleep, principally during 206. Ethics Consultation for Epilepsy Surgery REM sleep. These abnormalities in HRV may partly contrib- Candidates: Changes in Patterns ute to SUDEP, which takes place most during sleep. Paul J. Ford, Carol E. Blixen, George G. Agich, William E. Bingaman, and Elaine Wyllie; Cleveland, OH 204. Latency to First Spike in Epileptics Decisions around whether, and when, to offer epilepsy sur- Jaishree T. Narayanan, Neil Schaul, and Douglas R. Labar; geries are particularly complex. Epileptologists at the Cleve- Hyderabad, AP, India; New York, NY; and Queens, NY land Clinic Foundation refer a portion of surgery candidates BACKGROUND: Routine EEGs in individuals with epi- to be evaluated for ethical contraindications to surgery. We lepsy have interictal spikes in 56% of cases. The availability retrospectively reviewed 174 consecutive ethics consultations of prolonged EEG has changed the use of EEG in the as- for epilepsy surgery candidates (January 1988 to July 2003) sessment of epilepsy. OBJECTIVE: To determine the time and examined trends in cautionary recommendations, time to first epileptiform activity on EEG in patients with epi- between consult and surgery, age, and types of surgeries. We lepsy. METHODS: Continuous EEG (for 1–6 days) was an- determined that 61.9% (13 of 21) of cautionary recommen- alyzed in 46 consecutive patients aged 10 years or older to dations occurred during the most recent 3.5 years. Time be- find the first definite epileptiform activity and the latency. tween consultations and surgery decreased from mean 75.1 Individuals with seizures in the prior 24 hr or with acute days (SD 107.4) in 1988–1989 to 36.2 days (SD 58.6) in symptomatic seizures were excluded. RESULTS: Thirty- 2000–2002. The mean age went from 22.8 (SD 12.1) in seven percent of the patients had epileptiform activity in the 1988–1989 down to 13.4 years (SD 12.3) in 2001–2002. first 20 min of the recording; 89% had epileptiform activity The proportion of corpus callosotomy performed in those within 24 hr. The yield drops beyond 24 hr. Eight percent with an ethics consultation went from 46.2% (17 of 47) in of the individuals had no epileptiform activity on their mon- 1988–1993, to 1 in 1997–2002. The proportion of hemi- itoring. CONCLUSIONS: There is a need to consider a change in EEG strategy to assess interictal epileptic activity. spherectomies went from 8.6% (4 of 47) in 1988–1993 to Only 37% of patients had epileptiform activity in 20 min. 31.3% (20 of 64) in 1997–2002. Although this study tracks The greatest probability of capturing an interictal abnormal- epilepsy surgery ethics consultation in a single institution, it ity within 20 min was in individuals with generalized epi- provides the basis for further study of, and reflection on, the lepsy. Rather than multiple “routine” EEGs, a 24-hr study values (ethical) implications of process and selection in epi- after a first negative EEG may be the next step in the elec- lepsy surgery. Study supported by the Cleveland Clinic trographic assessment of individuals with epilepsy. Foundation Research Program Committee.

Program and Abstracts, American Neurological Association S43 207. Temporal Lobe Epilepsy as the Presenting BEHAVIORAL NEUROLOGY Feature of Chorea-Acanthocytosis in Two French- Canadian Families 209. Exercise Lowers Pain Threshold in Chronic An C. Jansen, Aman Badhwar, Abdullah Al-Asmi, Fatigue Syndrome Adrian Danek, Carol Dobson-Stone, Anthony P. Monaco, Abhijit Chaudhuri, Alan Whiteside, Stig Hansen, and Sylvain Chouinard, Chaim Shustik, Suha Mercho, Wilhelmina Behan; Glasgow, Scotland, United Kingdom Francois Dubeau, Frederick Andermann, and Patients with chronic fatigue syndrome (CFS) experience ex- Eva Andermann; Montreal, Quebec, Canada; Al-Khod, cessive pain and fatigue after physical exertion. The mecha- Muscat, Oman; Mu¨nchen, Germany; and Oxford, United Kingdom nism of post-exertional pain in CFS is unknown, but it is an important reason for failure to comply with the graded ex- Chorea-acanthocytosis is a neurodegenerative disorder char- ercise therapy. We compared changes in pain threshold in acterized by chorea, tics, orofaciolingual dyskinesia, areflexia, five CFS patients with five sex- and age-matched controls seizures, dementia, and acanthocytosis. Mutations in the after exercise. All CFS patients fulfilled the Centers for Dis- CHAC gene encoding for chorein on chromosome 9q21 ease Control criteria, were not physically deconditioned, and have been found in both autosomal-dominant and had all analgesic medications withdrawn 48 hr before the autosomal-recessive CHAC families. We ascertained six indi- exercise. After writtent consent, patients and control subjects viduals in two French-Canadian (FC) families. EEG, video completed a standardized exercise protocol consisting of telemetry, magnetic resonance, and volumetric studies were three 5-min treadmill walks, set to a speed of 5 km/hr and performed. All patients presented with seizures. Age at onset with an increasing incline of 5, 10, and 15 degrees at each ranged from 22 to 38 years. EEG showed either no or in- stage. Pain thresholds were measured in the skin web be- frequent epileptiform discharges originating independently tween thumb and index finger using an in-house Algome- from both temporal lobes. Epilepsy was initially well con- ter. Pain threshold after incremental exercise was elevated trolled, but later all patients had periods of increased seizure in the control subjects; however, in the CFS patients, the frequency. Seizures preceded other clinical manifestations of threshold was significantly reduced. Our study provides the CHAC by up to 11 years. Abnormal movements worsened first evidence that increased perception of pain after exer- with carbamazepine and lamotrigine. Phenytoin and pheno- cise in CDC-defined CFS patients has an organic basis and barbital were better tolerated. Acanthocytosis was present in is probably related to exercise-induced changes affecting pe- all patients. Both our families, as well as two other FC fam- ripheral sensory receptor or central anti-nociceptive path- ilies, share the same haplotype in the region of the CHAC ways. Study supported by the David and Frederick Barclay gene and are homozygous for an exon 70–73 deletion, sug- Foundation. gesting a founder effect. Epilepsy in CHAC patients repre- sents a challenge because the seizures may at times be intrac- table and because anti-epileptic drugs may worsen the involuntary movements. 210. Stroke Hospitalization in New York City, 1990 and 2000 Jing Fang, Sun-Hoo Foo, and Michael H. Alderman; Bronx, NY and New York, NY 208. Seizures after Bone Marrow Transplantation: Etiologies and Implications Age-adjusted stroke mortality in the United States has de- James C. Watson and Eelco F.M. Wijdicks; Rochester, MN clined in recent decades. National hospital discharge indi- Although they are poorly studied, seizures are a well-known cates that stroke hospitalization rate increased by 18.6% complication of bone marrow transplantation (BMT). We from 1988 to 1997. To determine the impact of race/eth- retrospectively reviewed 1,210 patients with BMT and iden- nicity on stroke hospitalization, we estimated changes in age- tified 39 (3.2%) with a confirmed seizure after BMT: 46% adjusted annual stroke hospitalization from 1990 to 2000 in had seizures of partial onset; 39% were generalized tonic- NYC, using hospital discharge data for the 1988–1992 and clonic; and 15% were indeterminate or represented other sei- 1998–2002 periods, and using census data from 1990 and zure types. In 72%, the seizure occurred within 8 months of 2000. Race/ethnicity was categorized as whites, blacks, His- the BMT, at a median of 33 days. Seizure recurrence was panics, and Asians. Those of “other” were eliminated from common, occurring in 41% in the first 24 hr. Status epilep- the analysis. Stroke hospitalization rate was highest among ticus occurred in 15%. A structural etiology, identifiable by blacks (790 and 745 per 100,000 population for men and neuroimaging, was implicated in 67% of patients. Of these, women, respectively), followed by whites (679 and 531). 73% had newly identified lesions. Drug toxicity was impli- Asians (363 and 321) had the lowest rate. From 1990 to cated in approximately 30% (in six patients it caused a struc- 2000, overall stroke hospitalization rate declined 12%, and tural abnormality, leukoencephalopathy). CNS infection the decline was largest among Hispanics (25%) and smallest could not be confirmed as the cause of seizure in any case. among Asians (7%). The percentage of hemorrhagic stroke Metabolic abnormalities were common, but were never im- was slightly higher among men than women (15% vs. 12%) plicated, as the primary etiology of a seizure. Seizures follow- and differed by race/ethnicity. It was highest among Asians ing BMT are rare, but when they occur, a structural etiology (23%) and lowest among whites (12%). In summary, in is most commonly implicated. CNS infection or acute met- NYC, stroke hospitalization has fallen recently in race/ethnic abolic derangements are unlikely primary causes of a seizure groups. Although Asians had the lowest stroke hospitaliza- post-BMT. Seizure recurrence is common, particularly in the tion rate comparing with other races/ethnicities, they had the first 24 hr, and justifies the early use of anti-epileptic drugs. highest proportion of hemorrhagic stroke.

S44 Annals of Neurology Vol 56 (suppl 8) 2004 211. Role of the “Visual Word Form Area” in CEREBROVASCULAR DISEASE Reading Argye E. Hillis, Melissa Newhart, Jennifer Heidler, 213. Effect of Intravenous Ascorbate Infusion on Peter Barker, and Mahaveer Degaonkar; Baltimore, MD Normal and Fabry Cerebral Vasculature David F. Moore, Frank Ye, Marie-Luise Brennan, Activation of midfusiform gyrus (“visual word form area” or Surya Gupta, Bruce A. Barshop, Robert D. Steiner, VWFA) while reading words is among the most robust find- William J. Rhead, Roscoe O. Brady, Stanley L. Hazen, and ings in functional imaging. However, studies have also re- Raphael Schiffmann; Winnipeg, MB, Canada; Bethesda, MD; vealed activation of VWFA during naming, repetition, and Cleveland, OH; San Diego, CA; Portland, OR; and Braille reading, indicating that VWFA may be essential for Milwaukee, WI modality-independent lexical processing. To test this alterna- Fabry disease results in systemic accumulation of the glyco- tive hypothesis, we examined effects of damage to VWFA on lipid globotriosylceramide. High concentrations are observed written word comprehension (which requires access to writ- in vascular tissue and may contribute to endothelial dysfunc- ten word forms but not lexical output), oral reading, and tion. We have observed evidence of increased oxidative stress naming. Eighty patients had language testing, diffusion- and cerebral hyperperfusion in Fabry disease. This may be weighted imaging, and perfusion-weighted imaging within related to excess production of endothelium-dependent hy- 24 hr of stroke onset. Associations between damage/dys- perpolarizing factor (EDHF) or reactive oxygen species. In function of each of five regions and impaired language order to test the hypothesis that reactive oxygen species con- functions were evaluated with ␹2 tests. RESULTS: Hypo- tribute to cerebral hyperperfusion in Fabry disease, we exam- perfusion/infarct in VWFA was not associated with im- ined the effect of intravenous ascorbate (1000 mg over 4 paired written word comprehension (p ϭ 0.75), but was min) on cerebral blood flow (CBF) using MR arterial spin- associated with impaired oral reading (p Ͻ 0.03), picture tagging. Nineteen Fabry patients and 15 controls were stud- ied as part of a multi-centered randomized double-blind naming (p ϭ 0.02), and naming with tactile input (p Ͻ placebo-controlled trial of enzyme replacement therapy 0.004). Of 52 patients with hypoperfusion/infarct in (ERT).We confirmed vertebro-basilar hyperperfusion in VWFA, 21 had intact written word comprehension. All pa- Fabry patients. Decreased plasma ascorbate was also observed tients with impaired written word comprehension had hy- in Fabry disease. CBF decreased following ascorbate infusion poperfusion/infarct extending to Wernicke’s area. CON- in both control subjects and ERT-treated patients. The pla- CLUSIONS: VWFA is essential not for accessing written cebo group CBF response to ascorbate was significantly de- word forms, but for modality-independent lexical process- layed, suggesting increased reactive oxygen species. Increased ing for output (or silent reading). Study supported by NIH CBF in Fabry disease may be related to abnormal cerebral RO1 DC05375. vessel EDHF/ROS activity, while low ascorbate levels suggest a redox imbalance. The CBF abnormalities improved with ERT. Oxidative imbalance may contribute to accelerated atherosclerosis in Fabry disease. Study supported by the Intra-Mural Program of the National Institutes of Health. 212. Rate of Cognitive Decline in Alzheimer’s Disease and Spirituality/Religiosity Yakir Kaufman, David Anaki, Malcolm Binns, and 214. Elevated Pulsatility Index by Transcranial Morris Freedman; Toronto, Ontario, Canada Doppler Is associated with Risk of Ischemic Stroke and TIA OBJECTIVE: To assess the effects of spirituality/religiosity Kumar Rajamani, Mohammad F. Sunbulli, on the rate of progression of dementia in Alzheimer’s disease Renee B. Van Stavern, and Bradley S. Jacobs; Detroit, MI (AD) patients. INTRODUCTION: A growing body of data OBJECTIVE: Determine if the pulsatility index (PI) is in- shows that spiritual/religious involvement is associated with dependently associated with risk of ischemic stroke (IS) and better heath outcomes. In this study, we examine the associ- TIA. INTRODUCTION: PI is associated with ischemic ation between religiousity/spirituality and the rate of demen- white matter disease but has not been studied as a risk factor tia progression in AD. METHODS: In this ongoing cross- for IS/TIA. METHODS: We performed a case-control study sectional/retrospective study, we have recruited 85 subjects, of IS/TIA patients referred for TCD and control subjects ages 50 to 80 years, with probable AD. Religiosity and spir- without intracranial disease or stroke. Risk factors, including ituality were measured using several validated scales that as- age, hypertension, diabetes, hypercholesterolemia, and smok- sess organizational and private religious/spiritual practices in- ing, were determined by chart review of cases and question- cluding attendance, private religious activities, and intrinsic naires completed by controls. The mean PI (mPI) of intra- religiosity. We conducted a simultaneous multiple linear re- cranial vessels in each subject was calculated. A t-test gression analysis for factors contributing to cognitive impair- compared means of mPI between cases and controls. Multi- ment. RESULTS: Three variables were found to be signifi- ple logistic regression was used to determine odds ratios cantly associated with progression of cognitive impairment: (ORs) of IS/TIA associated with mPI while adjusting for risk factors. RESULTS: We evaluated 108 cases of IS/TIA (83 religiosity, private religious practices, and intrinsic religiosity IS, 25 TIA) and 88 controls. The mPI of controls was 0.92, accounting for 20% of the total variance [F(5,58) ϭ 2.49, Ͻ Ͻ and the mPI of cases was 1.15 (p 0.0001). After adjusting p 0.05]. Higher levels of religiosity and private religious for risk factors, the OR associated with each 0.1 increase in practices were significantly correlated with slower rates of mPI was 1.42 (95% CI, 1.05–1.94, p Ͻ 0.025). CONCLU- cognitive decline. This relationship was also found in the SION: mPI is elevated among patients with IS/TIA indepen- zero-order correlation. CONCLUSION: Higher levels of re- dent of other risk factors. Prospective studies are needed to ligiosity and private religious practices are associated with confirm this association. Persons with elevated mPI may slower progression of Alzheimer’s disease. need to be targeted for intensive stroke prevention.

Program and Abstracts, American Neurological Association S45 215. In Acute Ischemic Stroke Patients Is White the Department of Rehabilitation, Research, and Develop- Matter Disease a Single Pathophysiologial Entity? ment, Department of Veteran’s Affairs. Mohammad Sajed, Souvik Sen, Michael Rosenberg, Subramanian Hariharan, and Naushiba Aziz; Edison, NJ and Chapel Hill, NC OBJECTIVE: We reviewed acute ischemic stroke patients and compared white matter lesions (WMLs) on brain 217. Emergency Department Laboratory Parameters in FLAIR-MRI with risk factors, as such a relationship is un- Acute Ischemic Stroke as Potential Predictors of 90-Day known. DESIGN/METHODS: The individual parts of the Mortality Fazekas score (periventricular hyperintensities and deep white Latha G. Stead, Wyatt W. Decker, Amy L. Weaver, and matter changes) for WMLs were used, using brain FLAIR- Robert D. Brown, Jr.; Rochester, MN MRI. Patients were assessed for age, race, gender, ESR, fast- OBJECTIVE: To determine whether routine laboratory pa- ing lipids, homocysteine, cholesterol level, alcohol, smoking, rameters are predictors of early mortality after acute ischemic hypercholesterolemia, hypertension, atrial-fibrillation, and stroke (AIS). METHODS: The cohort was 356 consecutive coronary artery disease. RESULTS: Of 141 adults(mean age: patients with AIS presenting to the emergency department 64 years) with ischemic stroke, 92 (56 female, 36 male) had (ED) at a tertiary referral center between 12/2001 and brain FLAIR-MRI. Demographics showed a 55% incidence 6/2003, residing within the surrounding 10 counties. Serum of hypertension; 27%, diabetes; 16%, atrial fibrillation; 28%, laboratory values were obtained for all patients and catego- coronary artery disease; and 25%, hypercholesterolemia. Age rized according to whether the levels were low, normal, or was highly correlated in both periventricular hyperintensities (p Ͻ 0.0009) and deep white matter changes (p Ͻ 0.0009). high. These laboratory results were considered as potential The ordinal-logistic-regression method was used to evaluate predictors of 90-day mortality using Cox proportional haz- hypertension, age, and hypercholesterolemia to predict ards models. The associations were summarized by calculat- FLAIR-MRI changes. Hypertension was significant only to ing risk ratios (RRs) and 95% confidence intervals (CIs). Ͻ RESULTS: The presence of leukocytosis (RR 2.2, 95% CI deep white matter changes (p 0.042) and hypercholester- ϭ olemia to both periventricular hyperintensities (p Ͻ 0.016) 1.3–3.7, p 0.003), low bicarbonate (RR 5.7, 95% CI 3.1– Ͻ and deep white matter changes (p Ͻ 0.024). There was no 10.2, p 0.001), and low calcium (RR 5.0, 95% CI 2.2– correlation with other parameters. CONCLUSIONS: Age 11.6, p Ͻ 0.001) were each univariately associated with and hypercholesterolemia were associated with an increase in higher early mortality. After a multivariate Cox regression both periventicular and deep white matter lesions, whereas model was fitted and a step-wise variable selection model was hypertension was associated only with changes for deep white used, leukocytosis, low bicarbonate, and low calcium were matter. We propose that periventricular and deep white mat- each identified as being jointly associated with early mortal- ter changes have different risk factors, suggesting different ity (p Ͻ 0.05). CONCLUSION: Early leukocytosis, acido- pathophysiological processes. sis, and hypocalcemia in AIS appear to be associated with early mortality. Whether addressing these factors will impact survival remains to be investigated.

216. Improved Prediction of Post-Stroke Aspiration with Measures of Voluntary Cough Carol A. Smith Hammond, Larry B. Goldstein, Ron D. Horner, Linda Gray-Leithe, Leslie Gonzalez-Rothi, 218. Do Early Laboratory Parameters in Acute and Don C. Bolser; Durham, NC and Gainesville, FL Ischemic Stroke Influence Hospital Length of Stay? BACKGROUND: We hypothesized that use of objective Latha G. Stead, Wyatt W. Decker, Amy L. Weaver, and measures of voluntary cough would improve identification of Robert D. Brown, Jr.; Rochester, MN patients with post-stroke aspiration vs. the clinical evaluation OBJECTIVE: To determine whether any emergency depart- alone. METHODS: Clinical swallowing evaluations, aerody- ment (ED) laboratory values are associated with longer hos- namic and sound pressure measures of voluntary cough, and pital length of stay (HLOS). METHODS: This observa- videofluoroscopic or endoscopic instrumental swallowing tional study included 531 consecutive patients with final studies were obtained in 96 consecutive stroke patients. diagnosis of acute ischemic stroke (AIS) who presented to Stroke severity was determined with the Canadian Neurolog- the ED of an academic medical center with an annual ED ical Scale. RESULTS: On the basis of instrumental studies, census of 80,000. Laboratory values were categorized accord- 29% had severe dysphagia with aspiration; 21%, mild dys- ing to whether the levels were normal, low, or high. Com- phagia; and 50%, no dysphagia. Cough expulsive phase rise time (EPRT), impaired speech, and language and stroke se- parisons of the median length of stay between groups of pa- verity on the day of the swallowing evaluation were indepen- tients defined by the laboratory levels were made using dently associated with aspiration (p Ͻ 0.001). EPRT and Wilcoxon rank-sum tests. RESULTS: Among the 531 pa- volume acceleration of cough had sensitivities of 93% (95% tients, 284 (53%) were male, and the mean age was 71.6 CI: 0.77, 0.98) and 96% (95% CI: 0.82, 0.99) and speci- years (range: 21–101). The HLOS ranged 1–61 days with a ficities of 90% (95% CI: 0.78, 0.96) and 92% (95% CI: median of 5 days (mean: 6.0; SD: 5.6). On the basis of uni- ϭ 0.80, 0.97), respectively, for identifying aspirators vs. non- variate analyses, the presence of leukocytosis (p 0.008), dysphagics. Sensitivity and specificity for the clinical evalua- elevated sedimentation rate (ESR) (p ϭ 0.011), or elevated tion were 60.7% (95% CI: 0.42, 0.76) and 81% (95% CI: aspartate aminotransferase (AST) (p ϭ 0.010) each indepen- 0.68, 0.90), respectively. CONCLUSION: Objective mea- dently predicted longer HLOS. CONCLUSION: Early ele- sures of voluntary cough are sensitive and specific indicators vations of white blood cell count, ESR, and AST appear to of dysphagia and aspiration and provide a useful adjunct to be associated with a longer HLOS. The potential association the standard bedside clinical assessment. Study supported by of these factors in impacting stroke severity will be evaluated.

S46 Annals of Neurology Vol 56 (suppl 8) 2004 219. Cerebral Venous Thrombosis in Adults: Multi- 221. Microglia Potentiate Astrocyte Injury: Reversal Center Cohort from the United States by Inducible Heat Shock Protein 70 Mohammad Wasay, Rohit Bakshi, George Bobustuc, Gerardo J. Zambrano, Yanli Qiao, Joyce H. Ma, and Suleman Kojan, Neeraj Dubey, Zubair Sheikh, Alper Dai, Midori A. Yenari; Stanford, CA Zahid Cheema, and Hal D. Unwin; Karachi, Pakistan; We and others previously showed that heat shock protein 70 Boston, MA; Houston, TX; Dallas, TX; Buffalo, NY; Ann (HSP70) reduces ischemic cell death. Although HSP70 is Arbor, MI; Nashville, TN; and Oklahoma City, OK thought to protect by preventing protein aggregation, recent OBJECTIVE: The purpose of our study was to identify clin- work suggests that it may also modulate immune responses. ical presentation, risk factors, and outcome of patients with Here we subjected astrocyte and microglial cultures derived cerebral venous thrombosis (CVT) in the United States. from HSP70 transgenic (HSP70-Tg) mice to aglycemia METHODS: Patients were enrolled at 10 centers in the (GD), serum deprivation (SD), and oxidative stress (HPE). United States. RESULTS: One hundred and eight-two adult HSP70-Tg astrocytes showed less death compared to wild- patients were included in study (age range: 13–82 years; type (Wt) astrocytes following SD (42%, p Ͻ 0.001), GD mean: 38 years). A hypercoagulable state was the most com- (72%, p Ͻ 0.05), and HPE (29%, p Ͻ 0.05). Addition of mon predisposing factor (10%), followed by pregnancy microglia increased injury by more than 2-fold compared to (7%), malignancy (7%), and homocystinuria (5%). Behav- astrocytes cultured alone (p Ͻ 0.05). Astrocyte and microglia ioral symptoms were present in 32 patients (18%). Neuro- HSP70-Tg co-cultures exhibited significantly less cell death logic exam was normal in 69 patients (38%). Sixty-one pa- compared to Wt co-cultures by 67% (SD, p Ͻ 0.001), 84% tients (33%) had evidence of hemorrhage by CT/MRI. (GD, p Ͻ 0.05) and 54% (HPE, p Ͻ 0.05). To determine Twenty-seven patients (15%) were treated with thromboly- the relative contributions of astrocytes and microglia to this sis, 98 (54%) with fractionated heparin, 26 (14%) with low- protection, we compared mixed co-cultures from HSP70-Tg molecular-weight heparin, 7 (4%) with intravenous hydra- and Wt cells. HSP70-Tg astrocytes protected against cell tion and antibiotics alone, and 10 (5%) with hydration death due to Wt microglia (p Ͻ 0.05). Interestingly, alone. Overall mortality was 13% (n ϭ 24). Of these, 26 HSP70-Tg microglia also reduced Wt astrocyte injury com- (27%) were normal, 43 (45%) were ambulatory with assis- pared to Wt microglia, but only against severe HPE (57%, tance, and 27 (28%) were still bedridden. On multivariate p Ͻ 0.001), suggesting that HSP70 overexpression in micro- analysis, the best predictors of a poor outcome were coma at glia may protect by preventing activation. These finding sug- presentation and intracerebral hemorrhage. CONCLUSION: gest a novel anti-inflammatory role for heat shock proteins. Overall clinical presentation and outcome in our patients are Study supported by the NIH NINDS, the American Heart comparable to previously reported series. Coma at presenta- Association, and the Stanford Medical Student Research tion and intracerebral hemorrhage were the best predictors of Scholars Program. poor outcome. Study supported by the Aga Khan Founda- tion.

222. Molecular Mechanism of Ischemic 220. Ipsilateral Hemiparesis to the Affected Preconditioning on Experimental Brain Injury Hemisphere on Recurrent Stroke Patients Hong Zhang and Yuanyuan Hu; Ann Arbor, MI Shiro Yamamoto, Mitsuru Kinoshita, Yoshiomi Shimizu, and Ischemic preconditioning was produced by bilateral carotid Koji Kajiyama; Amagasaki City, Hyogo, Japan artery occlusions and hypotension for 2 min. After various Stroke in one hemisphere causes contralateral hemiparesis be- survival times, the coronal brain sections were used to study cause the corticospinal tract generally crosses at the pyrami- the mRNA expression of HSP70, c-fos, MAP-2, brain- dal decussation. Although the existence of uncrossed cortico- derived neurotrophic factor (BDNF), and nerve growth fac- spinal tracts has long been established, ipsilateral hemiparesis tor (NGF) by in situ hybridization and the expression of to the affected hemisphere has not been reported. We report apoptosis-related proteins Bcl-2, Bcl-xl, and Bax by immu- two cases having the ipsilateral hemiparesis to the affected nohistochemical assay. BDNF and NGF were significantly hemisphere. They had chronic right hemiparesis after pre- upregulated in the hippocampus, and c-fos was detected in vious stroke in left cortical or subcortical hemisphere. the hippocampus, cortex, and striatum. HSP70 mRNA was However, when their right hemiparesis progressed, induced in the cortex, hippocampus, and striatum. MAP-2 diffusion-weighted MRI showed an acute lacunar infarction showed no change in expression. The expression of protein on the right corticospinal tract. Within 2 weeks after their of Bcl-2 and Bcl-xl were increased after sublethal forebrain admission, their right hemiparesis gradually recovered to al- ischemia, and expression of Bax remained unchanged. These most the same level they were before the new infarction. It results indicate that the increased expression of these stress- was considered that the uncrossed corticospinal tract in related, neurotrophic, and immediate-early genes in response these two cases was reorganized as an alternative motor to a mild preconditioning insult may help mediate the pro- pathway after chronic stroke. In addition, the recurrent in- tection of vulnerable neurons to subsequent lethal ischemic farction in the right hemisphere may have inhibited the insults. The expression of Bcl-2 and Bax oncoprotein after reorganized ipsilateral motor pathways. Our findings sug- sublethal ischemic preconditioning might be associated with gest that the reorganized ipsilateral motor pathway after the preconditioning protection against neuronal damage fol- stroke is actually functioning and that its inhibition causes lowing subsequent lethal ischemia. Study supported in part ipsilateral hemiparesis. by the Neuroscience Program in China.

Program and Abstracts, American Neurological Association S47 DEMENTIA AND AGING 225. Association of Sleep Abnormalities and Parkinsonism in Alzheimer’s Disease 223. ␤-Amyloid Burden in Alzheimer’s and Pick’s Margaret Park, Cynthia M. Comella, Sue Leurgans, Disease: What Is the Relationship to ␣-Synuclein Wenqing Fan, Robert S. Wilson, and David A. Bennett; Aggregation? Chicago, IL Carol F. Lippa and Hiroshi Mori; Philadelphia, PA and OBJECTIVE: To associate sleep abnormalities and parkin- Osaka, Japan sonian signs in Alzheimer’s dementia (AD). BACK- Pathologic aggregation of one protein may promote fibrilli- GROUND: Sleep abnormalities and parkinsonian signs are zation of other proteins. We demonstrated that ␣-synuclein common in AD. However, data are lacking regarding their commonly aggregates into secondary Lewy bodies (LBs) in association. DESIGN/METHODS: Cross-sectional analysis, the amygdala, and that tau aggregates (neurofibrillary tangles with the use of data from initial visits of consecutive patients or Pick bodies) increase the likelihood LBs will occur. The evaluated at the Rush Alzheimer’s Center from 03/1999 to current study examines ␤-amyloid burden in Alzheimer’s dis- 07/2003. In this study, 635 subjects met NINCDS/ADRDA ease (AD) and Pick’s disease (PiD) to determine if it is as- criteria for AD. Knowledgeable informants were interviewed sociated with secondary LB formation. We used immunohis- regarding sleep and soporific medications (benzodiazepines, tochemical methods on 6-micron sections from 15 AD (6 amitryptiline, and buspirone). Clinical evaluations included a with LBs) and 5 PiD (3 with LBs) amygdala. Sequential sec- modified version of the motor Unified Parkinson Disease ␤ Rating Scale. Sleepiness presence/absence (Wilcoxon analysis) tions were stained with antibodies to -amyloidϪ40 (H Mori; ␤ and daytime nap frequency (Spearman correlations) were 1:250) and -amyloidϪ42 (H Mori; 1:500) using formic acid ϭ pretreatment. A semi-automated Image-Pro computer pro- correlated to parkinsonian signs. RESULTS: Mean age 56.13. Benzodiazepine use ϭ 26.8%. Amitryptiline or buspi- gram (Media Cybernetics) measured amyloid burden. AD ϭ cases with LBs did not have significantly increased rone 36%. Daytime napping correlated with: bradykinesia ␤ ␤ (r ϭ 0.12/p ϭ 0.004), gait (r ϭ 0.23/p Ͻ 0.001), rigidity -amyloidϪ42 or -amyloidϪ40 burden compared with cases ␤ ϭ ␤ (r ϭ 0.17/p Ͻ 0.001), and resting tremor ( ϭ 0.14/ lacking LBs ( -amyloidϪ42 6.5% and 6.1%; -amy- ϭ pϽ0.001). Parkinsonian signs correlated with fewer soporif- loidϪ40 3.3% vs. 2.5%, respectively). In PiD, amyloid ϭ Ͻ burden was minimal regardless of whether LBs were present ics; only bradykinesia (p 0.008) and gait (p 0.001) ␤ ␤ were significant. Non-significant findings included less diffi- ( -amyloidϪ42 burdens were 0.0 % and 0.7%; -amyloidϪ40 burdens were 0.0% in both groups). These data suggest that culty falling asleep and fewer nocturnal/morning awakenings. CONCLUSIONS: Our study positively correlates sleepiness neither ␤-amyloidϪ or ␤-amyloidϪ plaque burden is the 42 40 and parkinsonian signs in AD. Awakenings were similar in exclusive cause of secondary LB formation. Study supported our subjects, but those with parkinsonian signs had more by the Robert Potamkin Fund. daytime napping. Also, despite increased daytime napping, AD patients with parkinsonian signs needed fewer soporifics for nighttime sleep. This suggests that sleepiness may be in- trinsic to parkinsonism in AD. Study supported by NIH grant P30 AG10161. 224. Learning-Enhancing and Anxiolytic Effects of Memantine in Nontransgenic and Transgenic Mice Over-Expressing APPswe and PS1 226. Memantine Monotherapy Increases Brain Heikki Tanila, Rimante Minkeviciene, and Metabolism and Effectively Treats Mild to Moderate Pradeep K. Banerjee; Kuopio, Finland and Jersey City, NJ Alzheimer’s Disease Memantine, an uncompetitive NMDA receptor antagonist, Steven G. Potkin, Gustavo Alva, Scott McDonald, is approved in the United States for the treatment of mod- Ivan Gergel, David B. Keator, and James H. Fallon; Irvine, erate to severe Alzheimer’s disease. This study sought to de- CA and Jersey City, NJ termine the effects of subchronic dosing of memantine on Memantine is an uncompetitive NMDA receptor antagonist spatial memory and other behaviors in transgenic and non- approved for moderate to severe Alzheimer’s disease (AD). transgenic mice. Eight-month-old male C57BL/6J mice (C), Positron emission tomography (PET) was utilized in this pi- transgenic C57BL/6J mice carrying mutated human APPswe lot study to assess memantine’s effect on regional cerebral and PS1 (A246E) genes (A/P), and their nontransgenic lit- hypometabolism in a subset of mild to moderate AD patients termates (NT) were used. Memantine (10, 30, and 100 mg/ randomized to either memantine or placebo in a 24-week, kg/day to C mice; 30 mg/kg/day to A/P and NT mice) was double-blind, placebo-controlled, Phase III U.S. clinical trial. administered in drinking water for 3 weeks. Spatial memory Outpatients (n ϭ 403) with diagnostic evidence and an MRI was determined in Morris water maze; motor/exploratory ac- or CT scan consistent with probable AD were randomized to tivity was assessed by an automated activity monitor; and memantine or placebo. PET was performed at baseline and social behavior was tested by the intruder-induced aggression at week 24 on five memantine-treated patients and five test. Anxiety was assessed in the elevated plus-maze appara- placebo-treated patients. In the clinical trial, memantine- tus. Memantine improved spatial learning in both A/P and treated patients performed significantly better than placebo- NT mice without affecting the swimming speed or the loco- treated patients on primary outcome measures: ADAS-cog motor activity. In C mice, memantine produced a dose- and CIBIC-Plus. PET revealed metabolic declines in glucose dependent anxiolytic response. These data indicate that me- metabolism in brain regions of placebo-treated patients, in- mantine improves learning in transgenic mice expressing cluding the orbital, cingulate, retrosplenial, and dorsal lateral Alzheimer’s disease-like pathology and also exhibits prefrontal cortices, whereas memantine-treated patients anxiolytic-like activity in nontransgenic mice. Study sup- showed metabolic increases in these areas. These results sug- ported by Forest Laboratories, Heikki Tanila, and Rimante gest that memantine can reverse regionally specific metabolic Minkeviciene. (Forest Laboratories provided grant/research decreases associated with untreated mild to moderate AD. support and employed Pradeep Banerjee.) When combined with the statistically significant primary

S48 Annals of Neurology Vol 56 (suppl 8) 2004 outcome measures, these results demonstrate that memantine cluster. RESULTS: There were 202 families with 783 family is efficacious in providing clinical benefit to patients with members. Adjusting for age, gender, and education, APOEε4 mild to moderate AD. Study supported by Forest Laborato- (OR 1.9; 95% CI 1.3–2.7; p Ͻ 0.001) and history of stroke ries. Steven Potkin received grant/research support and con- (3.1; 1.5–6.5; p Ͻ 0.003) were associated with AD. Repeat sulting fees from Forest Laboratories. Gustavo Alva received analysis showed an interaction between APOEε4 and stroke speakers bureau and consulting fees from Forest Laborato- on AD risk (6.8; 1.2–38.8; p Ͻ 0.032). Risk further in- ries. Scott McDonald and Ivan Gergel were employees of creased restricting the analysis to probable AD (9.6; Forest Laboratories. 1.3–69.4; p ϭ 0.025). Hypertension, diabetes, and myocar- dial infarction were not associated with AD. CONCLU- SIONS: Our study suggests that stroke and APOEε4 interact 227. Memantine Monotherapy Is Effective and Safe to increase risk of familial AD among Caribbean Hispanics. for the Treatment of Mild to Moderate Alzheimer’s Disease: Randomized, Controlled Trial Elaine R. Peskind, Steven G. Potkin, Nunzio Pomara, 229. Plaques, Stops, and Virtual Cops Brian R. Ott, Scott McDonald, Yang Xie, and Ivan Gergel; Matthew Rizzo, Qian Shi, Thomas Pietras, Ida Kellison, and Seattle, WA; Irvine, CA; Orangeburg, NY; Pawtucket, RI; Jeffrey Dawson; Iowa City, IA and Jersey City, NJ PURPOSE: Investigate situation awareness and response to a Memantine, an uncompetitive NMDA receptor antagonist, roadway emergency in drivers with AD. BACKGROUND: is approved in the United States for moderate to severe Alz- Drivers with AD pose increased risk for car crashes because heimer’s disease (AD). Prior to this 24-week, randomized, of perception, attention, memory, and executive dysfunction. double-blind, parallel-arm, placebo-controlled, Phase III METHOD: We tested the performance of 92 licensed older trial, no well-controlled trials addressing memantine mono- drivers by using a high-fidelity interactive driving simulator therapy in patients with mild to moderate AD had been per- with a 150° forward field of view: 41 had mild AD (mean formed in the United States. This study was conducted to age: 73.7 years) and 51 were neurologically normal (mean determine the efficacy and safety of memantine in patients age: 67.0 years). We evaluated driver control over the steer- with mild to moderate AD. Outpatients with probable AD ing, brake pedal, and accelerator pedal in a 55 mph drive were randomized to placebo or memantine. Primary out- that involved reacting to an emergency vehicle (police car) come measures were the ADAS-cog (cognition) and CIBIC- parked by the roadside. RESULTS: Compared to controls, Plus (function). Safety assessment was based on adverse drivers with AD reacted more slowly (p ϭ 0.002), leading to events (AEs), clinical laboratory evaluations, ECGs, and vital more abrupt decelerations, and failed to steer clear of the signs. Of 403 patients, 82.1% of memantine-treated patients police car (p ϭ 0.04). Unsafe reactions were predicted by and 82.7% of placebo-treated patients completed the trial. standard visual and neuropsychological measures. Five drivers Memantine-treated patients performed significantly better (four with AD) stopped in the middle of the road. CON- than placebo-treated patients on primary outcome measures. CLUSION: Cognitive errors leading to unsafe driver behav- Memantine was safe and well tolerated; the incidence of AEs iors can be tested safely in a simulator. Our findings suggest was similar between memantine- and placebo-treated groups. decreased situation awareness or poor executive control over These results demonstrate that memantine is effective and response implementation in drivers with AD, possibly at the safe for patients with mild to moderate AD. Taking previ- level of selecting one of several possible learned evasive motor ously published data into consideration, it appears meman- actions. Study supported by NIA R01 AG17717, NIA R01 tine is efficacious in providing cognitive and global benefit AG15071. for patients at all stages of AD. Study supported by Forest Laboratories. Elaine Peskind received grant/research support and honorarium and consulting fees from Forest Laborato- 230. Robust Response to Memantine Treatment when ries. Steven Potkin, Nunzio Pomara, and Brian Ott received Functional and Behavioral Results Are Combined with grant/research support and consulting fees from Forest Lab- Cognition oratories. Scott McDonald, Yang Xie, and Ivan Gergel were Frederick A. Schmitt, Pierre N. Tariot, Jeffrey L. Cummings, employees of Forest Laboratories. Joanne M. Bell, Daniel Jia, and Jason T. Olin; Lexington, KY; Rochester, NY; Los Angeles, CA; and Jersey City, NJ Memantine, an uncompetitive NMDA receptor antagonist, 228. Interaction between Stroke and Apolipoprotein-E is approved for moderate to severe Alzheimer’s disease (AD). ␧4 and Risk of Familial Alzheimer’s Disease among A 24-week, double-blind, placebo-controlled U.S. trial tested Caribbean Hispanics the efficacy of memantine on global, functional, and cogni- Gregory A. Rippon, Ming-Xin Tang, Joseph H. Lee, tive domains in 404 moderate to severe AD patients receiv- Rafael Lantigua, and Richard Mayeux; New York, NY ing ongoing treatment with the acetylcholinesterase inhibitor BACKGROUND: Apolipoprotein-E ε4 (APOEε4) is donepezil (AChEI). This analysis examines the relationship strongly associated with increased risk of late-onset familial between response rate and criteria for response using mea- Alzheimer’s disease (AD) among Caribbean Hispanics. Vas- sures of cognition augmented by activities of daily living cular risk factors have been shown to influence stroke- (ADLs) or behavior (dual response rate). Robust response associated AD risk. OBJECTIVES: To examine the potential was defined as improvement or no change over the course of relationship between stroke, vascular risk factors, APOE, and evaluation on efficacy measures: SIB, ADCS-ADL19, NPI. AD in a genetically homogenous population. METHODS: For all outcomes, there was greater response under meman- Caribbean Hispanic families in New York City, the Domin- tine/AChEI treatment, with statistically significant treatment ican Republic, and Puerto Rico underwent medical and neu- differences in favor of memantine. Combining positive re- rological examinations, neuropsychometrics, and APOE sponse on the SIB with improvement on the NPI, meman- genotyping. Odds ratios were computed using generalized es- tine/AChEI treatment was 16% better than placebo/AChEI. timating equations in which each family was treated as a Similarly, combining SIB results with stability or improve-

Program and Abstracts, American Neurological Association S49 Ͻ ment on the ADCS-ADL19 revealed 16% greater response to number of incorrect turns (p 0.05, Spearman coeffi- memantine/AChEI than placebo/AChEI. The responder cients). Within PD group, at-fault safety errors also corre- rates demonstrate that memantine/AChEI treatment is supe- lated with severity of parkinsonism (p Ͻ 0.05). CONCLU- rior to placebo/AChEI treatment on the basis of combined SIONS: Despite better topographical orientation, drivers multiple outcomes. Memantine/AChEI treatment provides a with PD appear to have a safety risk similar to AD during beneficial impact on cognition, ADLs, and behavior in addi- the RFT that can be due to the additional burden of the tion to the effects seen for AChEI treatment alone. Study RFT on motor planning and implementation. Study sup- supported by Forest Laboratories. Frederick Schmitt and ported by NIA AG 17717, NIA AG 15071, and UI CPH/ Pierre Tariot received grant/research support and honorar- COM New Investigator Research Award (to E.Y.U.). ium and consulting fees from Forest Laboratories. Jeffrey Cummings received honorarium and consulting fees from Forest Laboratories. Joanne Bell, Daniel Jia, and Jason Olin 233. Voxel-Based Parametric Mapping of were employees of Forest Laboratories. Acetylcholinesterase Activity Using [11C]PMP Positron Emission Tomography in Mild Cognitive Impairment Rik R. Vandenberghe, Mathieu Vandenbulcke, 231. What Best Predicts Dementia with Lewy Bodies? Patrick Dupont, Guy Bormans, Alfons Verbruggen, Pietro Tiraboschi, David P. Salmon, Lawrence A. Hansen, Luc Mortelmans, and Koen Van Laere; Leuven, Belgium Hofstetter Richard, Thal J. Leon, and Corey-Bloom Jody; BACKGROUND: Recent studies have cast doubt on the Milano, Italy and La Jolla, CA role of cholinergic depletion early in the course of Alzhei- To determine which clinical feature(s) (among visual hallu- mer’s disease (AD). AIM: To investigate acetylcholinesterase cinations, VHs; extrapyramidal signs, EPSs; and visuospatial (AChE) activity in mild cognitive impairment (MCI) by impairment) at initial presentation best predicted a diagnosis means of quantitative, voxel-based parametric mapping and of DLB at autopsy. First-visit data of 21 pathologically positron emission tomography (PET). METHODS: Seven proven DLB and 94 AD cases were compared. DLB patients MCI patients (mean age: 66.4 years) and eight healthy vol- displayed an increased prevalence of VHs (p ϭ 0.004), but unteers (mean age: 64.6) participated. An extensive neuro- not EPSs (p ϭ 0.4), compared to AD patients. However, psychological protocol confirmed the presence of an isolated only a minority of DLB cases (Ͻ25%) had either VHs or episodic memory deficit (mean FAQ: 2.28; mean CDR: EPSs or both. Visuospatial dysfunction, conversely, was ob- 0.57). Subjects underwent a T1 MPRAGE MRI and dy- served in most of the DLB cases. Among clinical variables, namic PET scanning (HRϩ) combined with arterial sam- presence/recent history of VHs was the most specific (99%) pling and metabolite correction after injection of 300 MBq to DLB, and visuospatial impairment was the most sensitive intravenous N-[11C]methylpiperidin-4-yl-propionate ([11C]- (71%). As a result, VHs represented the best positive predic- PMP), a substrate for AChE. For kinetic modeling, we used tor of DLB (PPV: 80% vs. Ͻ30% for all other variables), a constrained three-compartment model. Parametric images whereas lack of visuospatial impairment was the best negative were subsequently analyzed using a fixed-effects analysis predictor (NPV: 90%). We conclude that the best model for (SPM2). RESULTS: Voxel-based MRI morphometry and differentiating DLB from AD includes early VHs (not EPSs!) PMP influx (K1) were matched between the two groups. as a positive predictor and intact visuospatial function as a AChE activity (k3) was significantly lower for MCI in pos- negative predictor. This suggests that clinical history plus a terior cingulate (0, Ϫ30, 30; Z ϭ 3.24), left anterior para- brief assessment of visuospatial function may be of greater hippocampal gyrus (Ϫ36, Ϫ24, Ϫ26; Z ϭ 3.33), posterior value than clinical examination in correctly identifying DLB orbitofrontal cortex (Ϫ28, 20, Ϫ18; Z ϭ 3.43), and middle during life. Study supported by grants AG05131 and temporal gyrus (Ϫ68, Ϫ34, 10; Z ϭ 3.17). CONCLU- AG12963. SION: In MCI, a cholinergic deficit is present with a neu- roanatomical distribution that matches areas of predilection early in the course of AD. Study supported by Geneeskun- 232. Route-Following in Drivers with Parkinson’s dige Stichting Koningin Elisabeth and Fonds voor Weten- Disease vs. Alzheimer’s Disease schappelijk Onderzoek. Ergun Y. Uc, Matthew Rizzo, Qian Shi, Steven W. Anderson, Robert L. Rodnitzky, and Jeffrey D. Dawson; Iowa City, IA 234. Association among Plasma Lipoprotein Subfractions as Characterized by Analytical OBJECTIVE: Compare impairments of navigation and driv- Isotachophoresis, Apolipoprotein E Phenotype, ing safety, and assess their mechanisms in drivers with Par- Alzheimer’s Disease, and Mild Cognitive Impairment kinson’s disease (PD) and Alzheimer’s disease (AD) during a Tatsuo Yamada, Bo Zang, and Keijiro Saku; Fukuoka, route-following task (RFT). BACKGROUND: Despite dif- Fukuoka, Japan ferent neural systems and cognitive impairment profiles, drivers with PD and AD both commit more navigational We examined the association among plasma lipoprotein sub- and at-fault safety errors compared to controls. DESIGN/ fractions as characterized by capillary isotachophoresis METHODS: Drivers mild PD (n ϭ 24) and AD (n ϭ 32) (cITP), apoE, Alzheimer’s disease (AD), and mild cognitive participated in a battery of visual, cognitive, and motor tests. impairment (MCI), to clarify whether or not lipoprotein Each driver learned a brief set of verbal directions to follow subfractions are involved in the pathogenesis of AD and a route in an instrumented vehicle on a standardized drive transition between MCI and AD. Subjects with MCI (n ϭ under actual road conditions. RESULTS: The drivers with 28), subjects with AD (n ϭ 47), and controls (n ϭ 26) were AD made more “incorrect turns” (p ϭ 0.0236, Wilcoxon included in this study. This study was approved by the Eth- rank-sum test). There was no significant difference in num- ics Committee of Fukuoka University. Lipoprotein subfrac- bers of “times lost” and at-fault “safety errors.” AD drivers tions were quantified by cITP analysis, and apoE phenotype showed worse verbal and visual memory and worse visual was determined by isoelectoric focusing. The results showed perception and attention, deficits that correlated with the that apoE4 isoform is a contributing factor for AD and tran-

S50 Annals of Neurology Vol 56 (suppl 8) 2004 sition between MCI and AD. Serum levels of LDL- average pain severity score. For secondary measures such as cholesterol and apoB were higher in subjects with MCI and the BPI, mean changes showed superiority of duloxetine over AD than those in controls. Increased cITP slow LDL (native placebo, with no significant difference between 60 mg QD LDL) fraction but not fast LDL was associated with MCI and 60 mg BID. Duloxetine showed no notable interference and AD, suggesting that an increased synthesis of cholesterol on diabetic control. Both doses were safely administered and is important in the pathogenesis of AD. Active lipid-lowering well tolerated. This study confirms previous findings that du- may be a therapeutic approach for cognitive impairment. loxetine at 60 mg QD and 60 mg BID is safe and effective Study supported by grants-in-aid from the Ministry of Edu- in treating DNP. Study supported by Eli Lilly and Com- cation, Science, and Culture of Japan and by research grants pany. from the Ministry of Health and Welfare of Japan.

237. Response to Intravenous Immunoglobulins and 235. Aceruloplasminemia Presenting with Dementia: Experimental Evidence for Pathogenic Antibodies in a High Field MR Evidence for Extremely High Levels of Case of Complex Regional Pain Syndrome Brain Iron Andreas Goebel, Michael Stock, Robert Deacon, Earl A. Zimmerman, John F. Schenck, David G. Brooks, Guenter Sprotte, and Angela Vincent; Oxford, Oxford, United Angshuman Saha, and Reeti Tandon; Albany, NY; Kingdom and Wuerzburg, Germany Niskayuna, NY; Philadelphia, PA; and Bangalore, India Some patients with complex regional pain syndrome (CRPS) A 57-year-old man with adult onset brittle diabetes and 6 respond to intravenous immunoglobulins (IVIG; Goebel et years of progressive dementia had markedly decreased signal al., Pain Medicine, 3: 119–127, 2002). We studied a 36- in T2-weighted MRI of the brain and liver consistent with year-old woman with CRPS type 1 of the hand who was unusually heavy iron accumulation. Blood testing showed asked to keep a pain diary. She showed striking responses to ceruloplasmin below the limit of detection and at half- three independent IVIG treatments, with marked pain re- normal levels in father and daughter, diagnostic of the rare duction (p Ͻ 0.0002) and cessation of autonomic signs and recessive genetic disorder, aceruloplasminemia (aCp). Ceru- opioid intake during 6 weeks following each treatment, com- ϩ ϩ loplasmin is a ferroxidase converting Fe2 to Fe3 and is pared with the 6 preceding weeks. We injected two indepen- believed essential for iron efflux from tissues. In aCp, iron dent patient sera (obtained just before treatments), or IgG or accumulates in liver, pancreas, brain, and other organs. Un- non-IgG fractions, or healthy sera or IgG, into a total of 90 treated aCP is associated with progressive deterioration of the C57Bl6 mice. Compared with injection of healthy sera, in- extrapyramidal nuclei and the retina (Miyajima, Neuropathol- jection of patient sera produced abnormal physical behaviors, ogy, 23: 345, 2003). High field MR imaging (to our knowl- clearly evident to blinded observers, and a significant reduc- edge the first of aCP at 3 tesla) showed mean T2 values tion in open-field exploration (rears, p Ͻ 0.0001). Motor more than three standard deviations below the means of age- function and coordination were not affected. Similar differ- matched controls in caudate, putamen, and hippocampus ences were found with the purified IgG (p Ͻ 0.05; 10 con- (p Ͻ 0.0001) and markedly reduced T2 in many other re- trol, 10 test), whereas results with the patient non-IgG frac- gions, including white matter and thalamus. The subject is tion (n ϭ 10) were not different with respect to control. being treated with antioxidants and iron chelation. Lessons These findings support a causative role of serum factors, from aCp may provide insight into possible roles for iron in probably IgG antibodies, in some patients with CRPS. Sup- other neurodegenerative diseases such as Parkinson’s disease port for M.S. was given by ZLB Bioplama, Bern, Switzer- and Alzheimer’s diseases (Zimmerman, Ann. Neurol., 54: land. S68, 2003). Study supported by the Neurosciences Institute of Albany Medical Center and GE Global Research. 238. Withdrawn

HEADACHE AND PAIN 239. Withdrawn 236. Duloxetine in Treatment of Diabetic Neuropathic Pain Joachim F. Wernicke, Yili Lu, Anne Andorn, 240. Epidemiology of Migraine on a Survey of Deborah N. D’Souza, Pierre Tran, and Amy Waninger; Japanese Brain Checkup Indianapolis, IN Ken Ikeda, Hidetoshi Kashihara, Ken-ichi Hosozawa, Kouzo Anan, Masaki Tamura, Yasuo Iwasaki, and Serotonin (5-HT) and norepinephrine (NE) are involved in Fumihiko Sakai; Tokyo, Japan and Sagamihara, Japan pain modulation via descending inhibitory pathways in the brain and spinal cord. This study assessed the efficacy of du- Brain checkup (BC) is a unique brain health system in Ja- loxetine, a potent and balanced inhibitor of 5-HT and NE pan. We show the first epidemiological study of migraine on reuptake, on the reduction of pain severity in patients with a survey of a BC population. A total of 2,127 subjects (1,453 diabetic neuropathic pain (DNP). Patients with DNP (with- men and 647 women) received BC between April 2003 and out co-morbid depression) were randomized to treatment November 2003 in PL Tokyo Health Care Center. Mean with duloxetine 60 mg QD, 60 mg BID, or placebo for 12 age (SD) was 52.8 (11.4) years, 53.1 (11.2) in men and 52.1 weeks. The primary outcome measure was the weekly mean (11.7) in women. BC contained physical check-up, MRI, score of 24-hr average pain severity on the 11-point Likert and MRA (1.5-tesla Hitachi STRATIS II). Migraine with scale. Secondary measures included night and 24-hr worst aura (MA) or without aura (MO) was diagnosed according pain severity and the Brief Pain Inventory (BPI). Duloxetine to the criteria of the IHS. Overall prevalence (%) of migraine 60 mg QD and 60 mg BID demonstrated significant im- was 11.2, 6.6 in men and 21.1 in women. The mean age was provement in the treatment of DNP with rapid onset of ac- 42.9 (8.8) years, 41.4 (8.4) in men and 43.8 (9.0) in tion and separation from placebo at week 1 on the 24-hr women. The prevalence of MO was 10.5, 6.3 in men and

Program and Abstracts, American Neurological Association S51 19.7 in women. That of MA was 0.7, 0.3 in men and 1.3 in 243. Hypothalamus Metabolism Studied in Cluster women. Compared with age- and sex-matched controls (n ϭ Headache Patients by Proton MR Spectroscopy 237), migraineurs (n ϭ238) had a decreased tendency of hy- Raffaele Lodi, Giulia Pierangeli, Caterina Tonon, pertension (p Ͻ 0.07) and diabetes mellitus (p Ͻ 0.09). Sabina Cevoli, Fabiola Magnifico, Stefano Iotti, Prevalence of cerebral lacunas or aneurysms did not differ Pietro Cortelli, Bruno Barbiroli, and Pasquale Montagna; between the two groups. Brain arteriovenous malformation Bologna, Bologna, Italy was discovered in two MO subjects. The most of our mi- The pathophysiology of cluster headache (CH) is still poorly graineurs had no medical consultation. We should pay more understood. Recent PET (May et al., Lancet, 1998) and attention to treatment of migraine. voxel-based morphometric MRI (May et al., Nat. Med., 1999) studies have found altered function and structural changes in the hypothalamus of CH patients. We studied, using in vivo proton MR spectroscopy (1H-MRS), 26 CH 241. Intravenous Valproate Sodium for Status patients in a headache-free state. 1H-MRS studies were per- Migrainosus formed in a 1.5-T General Electric Medical Systems scanner. John Claude Krusz; Dallas, TX Spectra were obtained from the hypothalamus in 26 CH pa- INTRODUCTION: The objective of this study was to look tients (8 patients with the chronic form, 9 with episodic CH at our published clinical data (Krusz et al., 2001) to examine within the cluster period, and 9 with episodic CH outside the effects of intravenous (IV) valproate sodium on patients the cluster period) and 12 sex- and age-matched controls us- whose migraines fit the criteria for status migrainosus; these ing the PRESS single-voxel localization sequence (TE ϭ 144 represent a difficult type of migraine to treat. METHOD: msec; TR ϭ 1500 msec; number of acquisition ϭ 1536). In Patients successfully treated with IV valproate sodium for CH patients, hypothalamic NAA/Cr (1.63 Ϯ 0.21) was sig- migraines were retrospectively reviewed; 23 patients (8 males, nificantly reduced compared to controls (1.94 Ϯ 0.27; p ϭ 15 females) were identified who had status migrainosus. Av- 0.0004). Hypothalamic NAA/Cr was significantly reduced in erage duration of migraine was 82.2 hr. All patients were each CH patients’ subgroup. Reduction in hypothalamic treated in a headache clinic during the status migrainosus NAA content can be related to neuronal loss/dysfunction episode with IV valproate sodium; no other medications and/or changes in the relative content of glial and neural were given. Headaches were rated on a 0-to-10 scale by pa- cells. This alteration may be linked to the pathophysiological tients. Valproate sodium was given at 100 mg every 5 min. mechanism underlying headache attacks in CH. Study sup- RESULTS: Reduction in migraine headache was 84.6%. Mi- ported by MIUR grants ex-60% RFO 2002-3. graines were 8.35/10 prior to treatment and 1.26/10 after. Average dose of valproate sodium was 1,017 mg over 73.5 min. Thirteen out of 23 patients treated (57%) rated their 244. Evidence for Graded and Labeled-Line Pathways migraines as 0/10 after treatment. Only two had less than a in Human Perception of Painful Sensation 50% reduction in severity. CONCLUSIONS: IV valproate Fred A. Lenz, Salil H. Patel, Richard H. Gracely, sodium is highly efficacious and safe as an abortive therapy Patrick M. Dougherty, and Shinji Ohara; Bsltimore, MD; for status migrainosus in the headache clinic. Our results Ann Arbor, MI; and Houston, TX strongly suggest that hospitalization is not needed. Double- The system for pain sensation been previously described as blind studies are definitely warranted. consisting of neurons linked in a pathway to the brain re- sponding exclusively to painful stimuli. It has recently been proposed that the spinothalamic tract (STT) contains a series of analogue labeled lines, each signaling a different aspect of 242. Gamma Knife Radiosurgery Treatment of the internal state of the body, such as visceral/cold/itch sen- Trigeminal Neuralgia in a Suburban Community sations. In this view, pain is the emotion produced by dis- Hospital: Analysis of Demographics and Clinical Result equilibrium of the internal state. We demonstrate that mi- Joseph Landolfi, Steven Zarny, Vinit Mehrotra, and crostimulation of the Vc thalamus receiving the STT, in Shahid Rafiq; Edison, NJ awake humans, produces two different schemes of pain trans- OBJECTIVE: We performed a retrospective review of 68 pa- mission. The first is a labeled line signaling the presence or tients with trigeminal neuralgia treated with Gamma Knife absence of painful stimuli, consistent with an alerting func- radiosurgery. This is the first review of this procedure done tion. The second is analogue: activity is graded with intensity in a community hospital. METHODS: The mean patient of the painful stimulus, consistent with STT neurons encod- age was 65.70 years (range: 26–97), with 24 males and 44 ing properties of external painful stimuli. Both responses to females. Mean duration of facial pain was 6.89 years (range: stimulation were described by the subjects in terms usually 3 months–40 years). Right side was involved in 41 patients applied to external painful stimuli, rather than to emotional (60.29%) and left in 27 (39.71%). After MRI/CT, a single phenomena. This study provides evidence that electrical isocenter, using a 4-mm collimator, was positioned at the stimulation at sites in the human sensory thalamus evokes sensory root of the trigeminal nerve, and 80 Gy to 100% sensations consistent with one of two pathways — one bi- isodose line was administered. RESULTS: Follow-up was nary, the other analog. Study supported by the National In- 1–28 months (mean: 7.26). Sixty-one patients returned for stitutes of Health (grants NS38493 and NS40059 to F.A.L). follow-up. Pain relief was complete in 33 (54.09 %); mod- erate in 15 (24.59 %), and mild in 8 (13.11 %). Five (8.19 245. Migraine Headache in the Postpartum Period %) had no response. Two had recurrence of symptoms, and Tamara Pringsheim, Ralph Kern, Eric Goldszmit, one developed new facial numbness. CONCLUSION: This Kristi Downey, Isabella Devito, and Alison MacArthur; review of clinical outcomes in a community hospital sup- Toronto, Ontario, Canada ports other studies done in major centers that Gamma Knife radiosurgery is a safe and effective method in the treatment Menstruation is a migraine trigger, and is related to the fall in of trigeminal neuralgia. estrogen prior to menses. Pregnancy is often associated with a

S52 Annals of Neurology Vol 56 (suppl 8) 2004 decrease in migraine, and may be due to the absence of cycli- disease (PD). However, recent clinical trials have shown dis- cal fluctuations in estrogen levels. To further understand the appointing motor recovery in patients receiving neural trans- relationship between migraine headache and sex hormones, we plants. We sought to determine if a more comprehensive do- studied postpartum women for the presence of migraine after paminergic grafting strategy may produce better functional delivery. Women delivering a fetus greater than 20 weeks ges- recovery. Embryonic mesencephalic grafts were stereotacti- tation from June 2003 to August 2003 were eligible for this cally placed in the striatum, substantia nigra, subthalamic prospective cohort study. Patients participated in a structured nucleus, and globus pallidus (“multiple graft,” n ϭ 6), or in interview and chart review, and were reassessed at 1 week post- the striatum alone (“single graft,” n ϭ 6), of hemiparkinso- partum. Headaches in this period were diagnosed by an anes- nian rats.Control transplants of spinal cord cells were placed thetist and a neurologist independently and then by consensus, in five other rats (“sham grafts”). Sensorimotor functions using an algorithm based on International Headache Society were tested at baseline, 2 weeks after lesioning of the dopa- criteria. Nine hundred eighty-five women out of 1,606 deliv- minergic nigrostriatal pathway, and 9 weeks after transplants eries participated; 131 (13.3%) had headaches meeting the di- (T9). At T9, “multiple graft” rats had significantly better ad- agnostic criteria for migraine or migranous headache. Peak day justing step test scores compared to “single graft” and “sham of onset for migraine was between day 4 and day 6 postpar- graft” animals; their final score was no different from base- tum. After delivery, serum estrogen levels fall rapidly, and reach line. Both “multiple graft” and “single graft” animals had their lowest values by day 7 postpartum. Migraine headaches complete recovery in amphetamine-induced rotational testing occur in week 1 postpartum, peak between days 4 to 6, and compared to “sham graft” animals. None of the animals im- parallel the rapid decline of estrogen levels in this time period. proved in tests of skilled forelimb use. Better grafting tech- niques may improve motor outcomes in cell-restorative ther- apies for PD. Study supported by a Canadian Stem Cell 246. Migraine with Aura Is Associated with the Network scholarship to A.C.R. Methylenetetrahydrofolate Reductase 677C3T Polymorphism in a Population-Based Sample Ann I. Scher, Monique W.M.M. Verschuren, 248. When the Best Strategy Is Wrong: Optimal Gisela M. Terwindt, Henk J. Blom, Michel D. Ferrari, and Allocation of Cortical Area Can Cause Focal Dystonia Lenore J. Launer; Bethesda, MD; Bethesda, MD; Leiden, in the Context of Overuse Netherlands; Bilthoven, Netherlands; and Nijmegen, Terence D. Sanger; Stanford, CA Netherlands Although it is well known that the area in sensory cortex OBJECTIVE: To determine if the methylenetetrahydrofolate devoted to a particular part of the body may expand or con- reductase (MTHFR) 677C3T mutation is associated with tract depending on the recent history of activity of that body migraine with aura (MA) or without aura (MO) in the pop- part, the reason and mechanism for this change in area is not ulation. BACKGROUND: Migraine, particularly with aura, is understood. I propose that information theory and the the- associated with early-onset ischemic stroke and subclinical in- ory of optimal coding can be used to find an optimal solu- farcts (Kruit, 2004). A common mutation (677C3T) of the tion for allocation of cortical area. I provide the first com- MTHFR enzyme is associated with increased plasma homo- putational algorithm to adjust cortical area allocation cysteine, particularly in the presence of low dietary folate (de- optimally. However, the optimal solution may lead to un- Bree, 2001). This mutation has been associated with MA in wanted results. If one region of the body is stimulated sig- selected clinical samples. METHODS: Participants are 18– nificantly more than other regions, its cortical area may grow 65-year-old adults (52% male) from the Netherlands, classified (and other areas may shrink) to the point that some regions as non-migraine controls (n ϭ 1,212), MO cases (n ϭ 78), and of the body have no sensory representation at all. Here I MA cases (n ϭ 47). Serum homocysteine, folate, and vitamin show that dystonic symptoms including loss of independent B12 were measured. Participants were classified as heterozygotes control and poor sensory discrimination could be caused by (CT) or homozygotes (TT) for the MTHFR 677C3T muta- shrinkage of neighboring cortical regions and abnormal re- tion. RESULTS: After adjustments were made for demographic ceptive fields. Therefore, this model of cortical area alloca- factors, alcohol, smoking, homocysteine, folate, and vitamin tion is consistent with theories of focal dystonia due to de- B12, MA was associated with CT (OR ϭ 1.86; 0.9–3.7) and differentiation of sensory representations. Study supported by TT (OR ϭ 2.9; 1.1–7.5). The MA-TT subgroup had the high- NS41243. est age and gender-adjusted plasma homocysteine and lowest fo- late and B12 levels. CONCLUSIONS: This suggests a specific genetic contribution to MA (not MO) in the populaion. The 249. Effect of Rotigotine on Motor Activity and MTHFR677C3T genotype, possibly via elevated homocys- Disability Scores in MPTP-Treated Common teine, may contribute to the increased risk for cerebral lesions Marmosets seen in MA. Study supported by the Ministry of Health, Wel- Dieter K. Scheller, Lance Smith, Alexander Breidenbach, fare, and Sport of the Netherlands and the National Institute of Michael Jackson, Sarah Rose, and Peter Jenner; Monheim, Public Health and the Environment. Germany and London, United Kingdom Rotigotine is a novel, non-ergolinic dopamine agonist formu- MOVEMENT DISORDERS lated in a patch for antiparkinsonian therapy. This pilot in- vestigation determined drug plasma levels and antiparkinso- 247. Cell Restorative Therapy in the Rat Model of nian activity in MPTP-treated marmosets. Four female Parkinson’s Disease: Employing a Multiple-Target common marmosets (Callithrix jacchus; weight: 325–389 g; Strategy to Improve Motor Outcomes age: 5–8 years) were treated with MPTP (2.0 mg/kg subcu- Arun C. Ramachandran, Mark B. Purdy, and taneously daily for 5 consecutive days).When animals Ivar M. Mendez; Halifax, Nova Scotia, Canada showed stable motor deficits, rotigotine was applied once Emerging cellular restorative treatments may provide mean- daily subcutaneously at doses of 0.019, 0.038, 0.075, 0.15, ingful symptom relief in patients with advanced Parkinson’s and 0.3 mg/kg. Locomotor activity was recorded in activity

Program and Abstracts, American Neurological Association S53 units, and disability was scored according to Smith et al., in culture from 6-hydroxydopamine (6-OHDA)-induced ap- Mov. Disord., 11: 125–135, 1996. Rotigotine produced a optosis (p Ͻ 0.008). TEMPOL/PNA is more effective (at dose-dependent increase in locomotor activity and a corre- equivalent TEMPOL dose) than TEMPOL alone (p Ͻ sponding reduction in disability scores. Even at the lowest 0.01) in this regard. Translocation of NF-␬B to the nucleus dose, motor deficits were completely eliminated. The dura- accompanies protection by TEMPOL with or without PNA. tion of the increase in locomotor activity was dose- In vivo, PNA prolongs the half-life of TEMPOL 5-fold (p Ͻ dependent. The movements of treated animals appeared well 0.001). Intraperitoneal TEMPOL and TEMPOL/PNA pro- coordinated with no signs of stereotyped behavior, suggesting tect mice from intrastriatal 6-OHDA-induced cell loss in the a “normalization” of performance. Maximum locomotor ac- substantia nigra and dopamine metabolite (DOPAC, p Ͻ tivity corresponded to peak plasma levels of rotigotine. 0.005); HVA, p Ͻ 0.05) loss in the striatum. Ongoing stud- Rotigotine produced an apparent complete normalization of ies are assessing extrapyramidal tract function in mice treated the behavior across the dose range, including the lowest dose with intrastriatal 6-OHDA with and without pretreatment of 0.019 mg/kg. On the basis of these data, a subsequent with TEMPOL or TEMPOL/PNA. Study supported by the study will evaluate the potential benefit of continuous dopa- National Institutes of Neurological Disease and Stroke. minergic stimulation. Study supported by Schwarz Bio- Sciences. D.K. Scheller and A. Breitenbach were employees of Schwarz BioSciences. 252. Subjective Patient-Report Versus Objective Performance-Based Measurement of Activities of Daily Living in Parkinson’s Disease 250. Neuroprotection by Rotigotine: Investigations in Lisa M. Shulman, Rashida Stevenson, Karen E. Anderson, MPTP-Lesioned Mice under Continuous Dopaminergic Christopher G. Vaughan, Ann Gruber-Baldini, Stimulation Stephen G. Reich, and William J. Weiner; Baltimore, MD Dieter K. Scheller; Monheim, Germany OBJECTIVE: To compare subjective with objective ratings Rotigotine is a novel, non-ergolinic dopamine agonist ad- of ADLs and instrumental ADLs (IADLs) based on perfor- ministered transdermally to parkinsonian patients to provide mance testing in PD. BACKGROUND: Little is known continuous dopaminergic stimulation. Administration of the about PD patients’ assessment of their abilities to perform compound, including the lowest dose, reduced PD symp- ADLs and IADLs compared to objective performance test- toms in an MPTP monkey model. This present study was ing. METHODS: Eighty PD patients completed the Older designed to evaluate potential neuroprotective properties of Americans Resources and Services scale (OARS) assessing rotigotine. The subcutaneous injection that was used mim- ADLs and IADLs. Structured performance tests of walking, icked the release profile from a patch. MPTP-treated mice eating, dressing, and money and medicine management were were treated in two different ways by doses of 0.3, 1, and 3 administered. Patient performance was rated on a 5-point mg/kg: (A) Mice were acutely co-treated with rotigotine and scale ranging from 1 ϭ independent to 5 ϭ unable to per- MPTP, and the degenerating neurons of the mesencephalon form. RESULTS: Significant differences were found between were quantified after FluoroJade staining. (B) Mice were patients’ and clinicians’ ratings on all tasks except walking. treated subchronically with rotigotine for 7 days after MPTP On the other four tasks, paired groups’ t-tests showed that application, and striatal synaptic density was quantified using patients reported better function compared with the clinician radioligand labeling of the dopamine transporter. Under rating of medication management (1.32 vs. 2.82, p Ͻ acute co-treatment A, rotigotine significantly reduced the 0.001), eating (1.54 vs. 1.79, p ϭ 0.014), dressing (1.64 vs. number of degenerating neurons at 3 mg/kg. Under pro- 1.85, p ϭ 0.021 ), and managing money (1.42 vs. 2.08, p Ͻ longed post-treatment B, rotigotine dose-dependently pre- 0.001). CONCLUSIONS: A discrepancy was found between vented degeneration of striatal terminals; even the lowest patients’ subjective reporting of ADL and IADL function dose provided significant protection. Rotigotine prevented and objective ratings. Patients overestimated their function the degeneration of neurons in the mouse model of PD: on four out of five tasks. These results suggest that subjective Acute co-treatment as well as subchronic post-treatment reports of function in PD are often inaccurate. Study sup- showed clear neuroprotective efficacy. The lowest dose was ported by the Rosalyn Newman Foundation. active, a result that is attributed to the continuous dopami- nergic stimulation. Study supported by Schwarz BioSciences. D.K. Scheller was an employee of Schwarz BioSciences. 253. The Safety of Deep Brain Stimulation in Patients with Parkinson’s Disease, Essential Tremor, and Other Movement Disorders 251. TEMPOL/PNA: Recycling Antioxidant in Yavuz S. Silay, Joseph Jankovic, Kevin D. Vuong, Dopaminergic Mesencephalic Systems Michael Almaguer, William Ondo, Ron Tintner, and Qinghua Liang, Stephen Pan, Karen D. Nylander, Richard K. Simpson; Houston, TX Amanda D. Smith, Terri G. Hastings, and Nina F. Schor; OBJECTIVE: To evaluate short and long-term safety of Pittsburgh, PA VIM and STN deep brain stimulation (DBS) in patients Reactive oxygen species (ROS) have long been implicated in with Parkinson’s disease, essential tremor, and other move- the pathogenesis of Parkinson’s disease (PD). Antioxidants ment disorders. BACKGROUND: At Baylor College of have been proposed as both preventive and symptomatic Medicine and the Methodist Hospital, we have been provid- therapy for PD. Conventional antioxidants are rapidly con- ing DBS as a treatment strategy for movement disorders sumed in the process of detoxifying ROS generated from do- since 1993. METHOD: All patients are assessed at baseline pamine. In contrast, recycling antioxidants hold the promise and at 6-month intervals with rating scales and videos during of perpetual detoxification of ROS. The nitroxyl antioxidant, off-and-on medication state; all adverse events are captured TEMPOL, can be recycled by co-administration with poly- and categorized. RESULTS: Of 266 patients implanted with nitroxylated albumin (PNA). Both TEMPOL and TEM- DBS in our center over the past 10 years, we have adequate POL/PNA protect MN9D dopaminergic mesencephalic cells follow-up data on 254. The targets include STN (n ϭ 106),

S54 Annals of Neurology Vol 56 (suppl 8) 2004 VIM (n ϭ 143), and VIM/STN (n ϭ 5).The following ad- msec interval. The activation was always followed by an in- verse events were encountered: 1. intraoperative: headache hibitory period lasting 118.3 Ϯ 23.4 msec. Sixteen neurons (n ϭ 3) and intracranial hemorrhage (n ϭ 1); 2. immediately (23%) did not show any response of MC to TMS. CON- post-operative: hallucination (n ϭ 5); 3.stimulation related: CLUSION: This is the first report of TMS-induced modu- impaired coordination (n ϭ 8), paresthesia (n ϭ 10), and lation of STN neuronal activity in humans. These findings dysarthria (n ϭ 14); 4. DBS device related: neck pain (n ϭ open up new avenues for in vivo studies of cortico- 6), tremor (n ϭ 2), and skin erosion by subcutaneous lead subthalamic interactions in PD. (n ϭ 4). CONCLUSION: The short- and long-term follow-up of patients with DBS provides evidence that the procedure and the DBS device are well tolerated over a pe- 256. Long Term Effects of Bilateral Subthalamotomy riod of several years. Study supported by Medtronic. for Advanced Parkinson’s Disease Philip C. Su, Ham-min Tseng, Hon-man Liu, Horng-Huei Liou, and Ruoh-Fang Yen; Taipei, 254. Teasing out Mechanisms of Safinamide’s Taiwan, Taiwan Antiparkinson Activity PURPOSE: Unilateral lesioning of the subthalamic nucleus Fabrizio Stocchi, Laura Vacca, Paola Grassini, (STN) did not significantly benefit gait or axial motor 18 Giuseppe Battaglia, Stefano Ruggeri, Carlo Cattaneo, and months following surgery (Su et al., 2002). We studied long- Ruggero G. Fariello; Pozzilli, Italy and Bresso, Milan, Italy term effects of bilateral subthalalmotomy for advanced Par- In a previous placebo-controlled study, doses of SAF provid- kinson’s disease (PD). METHODS: Ten patients underwent ing maximal MAO-B inhibition (40 mg/day) showed an ef- stereotaxic thermal coagulation in the STN bilaterally in ficacy trend. Supramaximal doses (70 mg) reached signifi- stage. Patients have been followed a median duration of 31 cance. Given the excellent tolerability, a study was designed months (range: 3–48 months) with Unified Parkinson’s Dis- to explore efficay and tolerability of higher doses. In an open ease Rating Scale (UPDRS) before and after surgery. RE- design, 24 parkinsonian patients taking either levodopa (n ϭ SULTS: At 30 months in the OFF-period, bradykinesia im- 11) or one dopamine agonist (n ϭ 13) received 100, 150, proved 32%; rigidity, 44%; tremor, 57%; axial motor, 32%; and 200 mg oral SAF in 2-week incremental steps. At base- gait, 30%; UPDRS Part II, 39%; and UPDRS Part III, line and every 2 weeks, motor performance was assessed by 40%. The ON-period parkinsonian features also improved UPDRS-II-III-IV. Also platelets’ MAO B activity and SAF significantly. Levodopa equivalent was reduced from 1166 Ϯ serum levels were measured. Levodopa, dopamine, and me- 461 mg per day to 775 Ϯ 403 mg. Total duration of OFF- tabolites were measured at baseline and at fixed times after period fell from 2.4 Ϯ 0.79 preoperatively to 1.5 Ϯ 1.29. levodopa intake. MAO-B activity was fully inhibited at all Dyskinesia (7.0 Ϯ 3.9) became relatively free (0.5 Ϯ 0.6). doses. Significant incremental improvement of UPDRS-III Five patients who completed neuropsychological tests was seen, which was greater in dopamine-agonist-treated pa- showed no significant changes. Hemichoreic occurred in 2 tients, whereas improvement of UPDRS-IV was greater in out of 20 procedures that resolved completely. Speech was levodopa-treated patients. Significant progressive augmenta- not affected with bilateral procedures. CONCLUSIONS: tion of both levodopa’s and dopamine’s peaks and AUC was Staged bilateral subthalamotomy appears safe and effective seen. Despite the flaw of an open design, these data suggest for advanced PD with gait and axial involvement. The effi- a minor role for MAO-B inhibition in symptom relief and cacy persists 30 months following the procedures. call for other mechanisms of action. The role of glutamate release and dopamine uptake versus COMT inhibitions is discussed. Study supported by Newron Pharmaceuticals. F.S. 257. CURE, a French Epidemiological Study on the has received consultation fees from Newron Pharmaceuticals. Use of Ropinirole in Patients with Parkinson’s Disease: C.C. and R.G.F. have been full-time employees of Newron Usefulness of “Handipark,” a New, Brief Questionnaire Pharmaceuticals. Francois Tison, Marie Vidailhet, Alain Destee, Olivier Rascol, and Anne-Francoise Gaudin; Pessac, France; Paris, France; Lille, France; Toulouse, France; and Marly-le-Roi, France 255. Effects of Transcranial Magnetic Stimulation of OBJECTIVE: In this post-marketing analysis of the use of the Human Motor Cortex on Subthalamic Neuronal ropinirole by French neurologists in patients with Parkin- Activity son’s disease (PD), we studied the usefulness of a new hand- Antonio P. Strafella, Ysbrand Vanderwerf, and icap questionnaire, the Handipark. DESIGN/METHODS: Abbas Sadikot; Montreal, Quebec, Canada Baseline assessments included the standard questionnaires BACKGROUND: Animal research suggests that the cerebral (UPDRS, PDQ-39, and CGI) and the Handipark question- cortex plays an important role in regulating the activity of naire. In this 10-level questionnaire, level 1 corresponds to STN. Cortical innervation of STN originates from motor ar- no or minimal functional impairment, and level 10 to total eas through a direct and an indirect multisynaptic circuit. dependency. RESULTS: This study included 341 patients. METHODS: Five PD patients undergoing stereotactic sur- The mean age was 65.2 years (SD: 9.6 years). The mean gery for bilateral implantation of deep-brain stimulators were duration of the disease was 2.1 years (SD: 3.7). The mean investigated with TMS. Single-pulse TMS of the motor cor- Hoehn and Yahr grade was 1.8 (SD: 0.8). The mean level of tex (MC) was performed during intraoperative single-unit re- Handipark was 3.6 (SD: 1.6): this level increased signifi- cordings from STN. The effect of MC stimulation was in- cantly with age and with the duration of disease (p Ͻ vestigated on the ipsilateral STN neuronal activity. 0.0001), and was strongly correlated to the levels of the stan- RESULTS: The effect of MC stimulation was investigated dard questionnaires (p Ͻ 0.0001 for all). CONCLUSIONS: on 56 STN neurons. In 61% of these cells, a cellular activa- This large cohort of PD patients is characterized by a disease tion was observed at 18.7 Ϯ 2.5 msec following ipsilateral of moderate severity. The questionnaire Handipark is well stimulation of the MC. In a smaller proportion (16 %), the correlated with the standard questionnaires and with the se- activation consisted of a double response separated by 2–3- verity of the disease. Further validation will be provided by

Program and Abstracts, American Neurological Association S55 the 1-year follow-up data. Study supported by GlaxoSmith- 260. Facial Motor Evoked Potentials during Kline, France. Consulting fees were provided by Glaxo- Microvascular Decompression for Hemifacial Spasm SmithKline. (HFS): New Evidence for a Hyperexcitable VII Nucleus Marshall F. Wilkinson, and Anthony M. Kaufmann; Winnipeg, MB, Canada 258. Prospective Characterization of Movement BACKGROUND: We investigated facial motor evoked po- Disorders in an HIV-Positive Population tentials and lateral spread (LS) during microvascular decom- Winona Tse, Lydia Estanislao, Susan Morgello, pression (MVD) surgery for hemifacial spasm (HFS). Daniel Polowetzky, and William Koller; New York, NY METHODS: We monitored LS and bilateral fMEP in eight consecutive patients during MVD for HFS. Latency, ampli- BACKGROUND: Despite known extensive basal ganglia in- tude, and duration of fMEP were compared between the volvement in patients with HIV infection, minimal data ex- spasm side, the non-symptomatic side, and seven control pa- ists regarding characterization of movement disorders in this tients undergoing MVD for trigeminal neuralgia (TN). population, which have been previously reported in 2–3% of FINDINGS: Baseline fMEP had significantly elevated dura- such patients. METHODS: A movement disorder specialist tion and amplitude versus the non-spasm side. MVD re- specifically examined a group of patients participating in the sulted in significant decreases in fMEP duration and ampli- Manhattan HIV Brain Bank project for the presence of a tude (p Ͻ 0.03). These changes were consequent to the movement disorder. RESULTS: Thirty-seven patients (12 fe- elimination of LS in seven of eight patients and 50% reduc- males, 25 males; mean age: 48 Ϯ 7 years) were evaluated. tion in one. fMEPs from the asymptomatic side did not The mean motor UPDRS score was 3.78 Ϯ 8.29. Move- change significantly during the MVD procedure. The fMEP ment disorders were seen in 11/37 (29.7%) patients. Nine latencies were similar and stable, bilaterally during MVD for patients (24.3%) had tremor (postural and action related). HFS and TN. All patients were alleviated of the HFS post- Etiologies identified included HIV-related cerebellar degen- operatively. CONCLUSION: Hyper-excitability of the facial eration diagnosed by biopsy (n ϭ 1), metabolic abnormali- motor system was demonstrated with both LS and fMEP ties (n ϭ 2) and drug-induced (n ϭ 2). Etiology was un- monitoring and was successfully reversed and correlated with known in four cases. In two of these cases, there was a family MVD surgery. This study is the first to report the utility of history of tremor, suggesting the possibility of essential fMEP monitoring during MVD for HFS. tremor. Two patients (5.4%) had chorea: the first had PML diagnosed by brain biopsy, and the second had multiple ce- rebral lesions consistent with toxoplasmosis on CT scan. No dystonia nor myoclonus was identified. CONCLUSION: When specifically evaluated, movement disorders are com- NEUROIMMUNOLOGY AND MULTIPLE monly present in HIV-positive individuals. Study supported SCLEROSIS in part by R24MH 59724 (the Manhattan HIV Brain Bank). 261. Unexpected Demographic Profile in Pediatric MS Lauren B. Krupp, William S. MacAllister, Maria Milazzo, Anita L. Belman, Christopher Christodoulou, 259. Respiratory Center in a Patient with Perry Patricia Melville, William Scherl, and Syndrome Pediatric MS Study Group; Stony Brook, NY Yoshio Tsuboi, Dennis W. Dickson, Eduardo E. Benarroch, Migration and epidemiologic studies suggest that the devel- Zbigniew K. Wszolek, and Tatsuo Yamada; Fukuoka, Japan; opment of MS involves an interaction between age of expo- Jacksonville, FL; and Rochester, MN sure, environmental triggers, and genetics. We have exam- Since the original description in 1975, an additional six fam- ined and compared the demographic characteristics of ilies with Perry syndrome have been described throughout pediatric MS cases and non-MS controls, as well as com- the world. Perry syndrome is characterized by autosomal- pared pediatric cases, referred to adult MS patients. Sixty- dominant, hereditary parkinsonism associated with depres- nine pediatric patients were referred. Thirty-eight (55%) sion, weight loss, and central hypoventilation. Previous neu- were diagnosed with MS, 11 (17%) had acute disseminated ropathological reports in Perry syndrome demonstrated encephalomyelitis, and 13 (19%) had another disorder. neuronal loss in the substantia nigra without Lewy bodies. Seven experienced a clinically isolated syndrome. The MS Neurons in ventrolateral medulla play an essential role for cases had significantly more minority patients (19/38, 50%) respiratory control, but their functions in Perry syndrome than the non-MS group (4/31; 13%) (␹2 ϭ 10.57; p Ͻ have not yet been addressed. We conducted the clinical and 0.01). Nearly all Hispanic patients were first-generation neuropathological assessments including immunohistochem- Americans whose parents immigrated to the United States, istry of a newly diagnosed Japanese family with Perry syn- and the lineage of seven of these children was from the Is- drome. The proband died at age 46 with 5-year history of land of Hispaniola. The pediatric MS group also had signif- parkinsonism, weight loss, depression, and central hypoven- icantly more minorities when compared to the adult MS tilation. His two siblings and father were also affected. In group (5/75; 6%), (␹2 ϭ 19.64; p Ͻ 0.001). There were no this patient, neurokinin-1 receptor-like (NK-1R-L1) and ty- apparent differences in referral patterns between groups that rosin hydroxylase (TH)-immunoreactive neurons were signif- could account for these demographic findings. These prelim- icantly reduced in the ventrolateral medulla compared to inary observations highlight the importance of more defini- controls. These findings may explain the presence of central tive epidemiological studies of pediatric MS in the United hypoventilation seen in Perry syndrome. In addition, severe States. Study supported by the National Pediatric MS Cen- neuronal loss in the substantia nigra without ␣-synuclein or ter. Grant support was provided by NMSS, Biogen, Serono, tau pathology but with loss of NK-1R-L1 and TH-positive Berlex, and Teva Neurosciences over the past 3 years. Dr. neurons in the medulla may be a pathologic hallmark of this Lauren Krupp has received honoria for speaking from Berlex, syndrome. Teva Neurosciences, and Serono.

S56 Annals of Neurology Vol 56 (suppl 8) 2004 262. Frequency of MBP- and PLP- but Not MOG- 264. Clinical Implications of Benign Multiple Specific T Cells Is Reduced in Multiple Sclerosis Sclerosis: 20-Year, Population-Based Follow-up Study Patients Treated with Intramuscular Inteferon-␤1a: Sean J. Pittock, Robyn L. McClellan, William T. Mayr, Correlation with Changes in Th1 and Th2 Cytokine Neal W. Jorgensen, Brian G. Weinshenker, Expression John H. Noseworthy, and Moses Rodriguez; Rochester, MN Brett T. Lund, Huy Q. Ta, Nazely Ashikian, and A common scenario for the neurologist is the patient with Norman J. Kachuck; Los Angeles, CA established multiple sclerosis (MS) for years with no or min- The clinical course of multiple sclerosis, an autoimmune dis- imal disability for whom the question of whether to start ease of the central nervous system, most typically follows an immunomodulatory medications is unclear. We reported the initial relapsing-remitting pattern (RRMS) in which immu- functional status of a 1991 MS prevalence-cohort in Olm- nosuppressive therapies such as intramuscular interferon-␤1a sted County of whom 49 were considered to be doing well (IFN-im) have been shown to slow disease progression. after a minimum duration of 10 years (expanded disability Ͼ IFN-im has also been shown to have both in vivo and in status scale (EDSS) score: 0–4; duration 10 years). We vitro effects on both antigen-specific proliferative responses reassessed each patient a decade later. Patients with EDSS of Ͻ and cytokine production by T cells. In this study, we exam- 0–2 and 2.5–4 for 5 years had a 29% chance and a 25% Ͼ ined the effect of continuous IFN-im therapy in RRMS pa- chance, respectively, of having EDSS 4, 10 years later. tients; specifically on the in vitro MBP-, PLP-, and MOG- The risk of developing disability once disease duration was Ͼ Յ specific T cell frequencies, and the Th1/Th2 phenotype of 5 years was much less for those with EDSS 2 compared with patients with EDSS 2.5–4 (p Ͻ 0.05). Of 28 patients these antigen-specific cells. The frequency of MBP- and Յ Ͼ PLP-specific T cells was reduced in 80% of patients after 12 with EDSS 2 for 10 years in 1991, 25 remained ambu- latory (EDSS Յ3) a decade later. In contrast, of 21 patients months of continuous therapy, in contrast to less than 50% Ͼ of patients after only 6 months of therapy. No changes in with EDSS 2.5–4 in 1991, 12 had EDSS 4 in 2001; 6 MOG-specific T cell frequencies were seen at any time. The required unilateral or bilateral assistance to walk, and 6 de- frequency of control antigen-specific T cells remained con- veloped a secondary progressive course. This data will assist stant throughout the study. Reductions in T cell frequency physicians in conjunction with clinical/radiological findings correlated with significantly increased production of Th2 cy- to counsel patients in the shared therapeutic decision-making tokines and significantly lower levels of Th1 cytokines. Study process. This work is supported by grant P01-NS38468 from the National Institutes of Health. supported by Biogen.

265. Paraneoplastic Autoantibodies Commonly Coexist 263. Human Antibody That Promotes Remyelination as Complementary Predictors of Cancer Enters the Central Nervous System and Decreases Sean J. Pittock, Thomas J. Kryzer, and Vanda A. Lennon; Lesion Load as Detected by T2-Weighted Spinal Cord Rochester, MN Magnetic Resonance Imaging in a Virus-Induced Murine Model of Multiple Sclerosis In the past 4 years, we have identified, by immunofluores- Istvan Pirko, Allan J. Bieber, Jeff Gamez, cence screening, one of seven defined neuronal nuclear or Slobodan I. Macura, Bogoljub Ciric, and Moses Rodriguez; neuronal cytoplasmic IgGs in serum of 553 patients amongst Cincinnati, OH and Rochester, MN 60,000 with a suspected paraneoplastic neurological disorder (0.9%). The antibody frequencies were: ANNA-1 (anti-Hu), The human monoclonal antibody rHIgM22 enhances remy- 217 (0.4%); CRMP-5-IgG, 208 (0.4%); PCA-1 (anti-Yo), elination following spinal cord demyelination in Theiler’s 101 (0.2%); PCA-2, 43 (0.06%); amphiphysin-IgG, 26 murine encephalitis virus (TMEV)-induced murine models (0.04%); ANNA-2 (anti-Ri), 17 (0.02%); and ANNA-3, 10 of multiple sclerosis. Using high field strength 3D, T2- (0.01%). One or more of these autoantibodies coexisted with weighted, in vivo spinal cord MRI, we have assessed the ex- PCA-2 (50%), amphiphysin-IgG (31%), ANNA-3 (30%), tent of spinal cord demyelination in chronically TMEV- ANNA-2 (29%), CRMP-5-IgG (28%), or ANNA-1 (19%), infected SJL/J mice, before and after 5 weeks of treatment but none coexisted with PCA-1.We additionally detected in with rHIgM22, to determine whether antibody-enhanced re- 25% of instances a coexisting cation channel autoantibody myelination can be detected by MRI. A significant decrease (muscle or ganglionic acetylcholine receptor, neuronal cal- Ͻ (p 0.0001) was seen in high signal T2-weighted lesion cium channel, or potassium channel) or striational antibody. volume following antibody treatment. Histologic examina- In summary, one or more autoantibodies coexisted with tion of the spinal cord tissue reveals that this decrease in PCA-2 (63%), CRMP-5-IgG (57%), ANNA-1 (43%), lesion volume correlates with antibody-promoted remyelina- ANNA-3 (40%), amphiphysin-IgG (38%), ANNA-2 (35%), tion. We also determined that rHIgM22 enters the spinal and PCA-1 (9%). These serological observations suggest that cord and co-localizes with demyelinating lesions by using ul- targeting of multiple autoantigens contributes to the multi- trasmall superparamagnetic iron oxide particle (USPIO)- focal neurological manifestations encountered in individual labeled remyelinating antibodies as MR contrast agents. This patients with paraneoplastic disorders. Evaluation of para- supports the hypothesis that rHIgM22 promotes remyelina- neoplastic autoimmunity by broadly screening for immuno- tion by binding to CNS cells. The reduction in high signal globulins reactive with antigens in neuronal and muscle T2-weighted lesion volume may be an important outcome plasma membrane and cytoplasm, or neuronal nucleus, op- measure in future clinical trials of remyelinating antibodies timizes the yield of autoantibody profiles predictive of can- in humans. cer. Study supported by the Mayo Clinic Cancer Center.

Program and Abstracts, American Neurological Association S57 266. Sustained Clinical Effectiveness of Interferon-␤- 268. Mitoxantrone (Novantrone) for Treatment of 1b in Multiple Sclerosis Patients Relapsing Neuromyelitis Optica Amita V. Shimpi, Beverly Layton, and Khurram Bashir; Bianca Weinstock-Guttman, Joan Feichter, Norah Lincoff, Birmingham, AL and Rohit Bakshi; Buffalo, NY and Boston, MA A retrospective study was performed to evaluate the long- Relapsing neuromyelitis optica (R-NMO) is a severe demy- term effectiveness of IFN-␤-1b among 83 definite relapsing- elinating disease involving the optic nerves and the spinal remitting multiple sclerosis (MS) patients treated for greater cord, having primarily a B cell-induced pathogenesis. Mitox- than 7 years (treatment started between December 1993 and antrone (MITO), which has the trade name Novantrone, December 1996). Eighteen (21.7%) of these patients was shown to suppress humoral response. We conducted a prospective 2-year study to evaluate the benefit of MITO in switched to a secondary progressive course during a mean R-NMO. The treatment protocol consisted of intravenous treatment duration of 8.8 Ϯ 0.9 years. Natural history data 2 MITO 12 mg/m monthly for 6 months followed by addi- (Weinshenker et al., Brain, 1991) was used as the control. tional three treatments every 3 months. Neurological assess- Fory-nine percent of the patients worsened by Յ1 EDSS Ͻ ment (EDSS) was performed every 3 months and during re- step, compared to 85% expected (p 0.0001). The annual lapses. Brain and spinal cord MRIs were performed at Ϯ rate of mean EDSS progression was 0.09 0.19 compared baseline and at 3, 6, 12, 18, and 24 months. Visual evoked to historical control rate of 0.5 (p Ͻ0.0001). The annual potentials and ophthalmologic evaluations were performed at relapserateof0.26Ϯ 0.26 while on therapy was signifi- baseline and annually. RESULTS: Five patients (three fe- cantly lower than that in the two years prior to treatment males and 2 males; age range: 22–51 years; disease duration: (1.07 Ϯ 0.82) in the same cohort (p Ͻ0.0001). Another 4 months to 19 years; EDSS: 2.5 to 6, mean: 4.07) were 43 patients, started on IFN-␤-1b during the same period, included in this study. During 2 years of treatment, two pa- were either lost to follow-up (n Ϯ 22) or discontinued tients relapsed once within the initial 3 months of treatment treatment (n Ϯ 21) for a variety of reasons. While not pla- (one severe and one moderate). Significant clinical (mean cebo controlled, this report suggests a striking stabilization EDSS: 1.88) and MRI improvement were seen in four pa- of disease course (relapses and disability) in MS patients tients. Patients tolerated the treatment well, although one treated with IFN-␤-1b compared to natural history con- had a reversible decrease in ejection fraction measured by trols. Study supported by an unrestricted educational grant MUGA. CONCLUSION: Our results suggest a beneficial from Berlex. effect of MITO for R-NMO. Study supported by a grant from Immunex/Serono Corporation. The principal author received consulting honoraria from Immunex Corporation.

267. Adaptive Cortical Reorganization in Acute Optic Neuritis: Longitudinal Functional Magnetic Resonance 269. Dynamics of Interferon-␤-Modulated Biomarkers Imaging Study in Multiple Sclerosis Patients with Persistent Anti- Ahmed T. Toosy, Simon J. Hickman, Gordon T. Plant, Interferon-␤-Neutralizing Antibodies Daniel Altmann, Gareth J. Barker, David H. Miller, and Bianca Weinstock-Guttman, Roseane Santos, Alan J. Thompson; London, United Kingdom Frederick Munschauer, Theresa Justinger, Kara Patrick, Cortical reorganization associated with neurological recovery Richard Rudick, and Murali Ramanathan; Buffalo, NY and may be adaptive (contribute to clinical function) or non- Cleveland, OH adaptive. Distinguishing between these is important because OBJECTIVES:To evaluate multiple interferon (IFN)-specific adaptive plasticity may be more amenable to future therapeu- markers in multiple sclerosis (MS) patients with anti-IFN-␤- tic strategies. We investigated cortical plasticity by using vi- neutralizing antibodies (NAB) using a pharmacodynamic de- sual fMRI and optic nerve MRI to study 20 acute optic neu- sign. All patients participated in an earlier open label trial of ritis patients at baseline, 1, 3, 6, and 12 months. We IFN-␤-1a immunogenicity during which NAB titers were performed correlation analyses to investigate the relationships obtained every 3 months for 5-year trial duration. Five MS between fMRI activity, clinical function, and optic nerve patients with persistent IFN-␤-NAB positive titers (NAB ti- structure. Coexisting correlations between structure and clin- ters Ͼ 20) and five sex- and age-matched MS patients with ␤ ical function may confound inferences about the adaptive na- negative -NAB titers were enrolled. Blood samples were ture of cortical reorganization, an issue not previously ad- drawn at pretreatment and at 4-, 8-, 24-, 48-, 120-, and 168-hr time points following the intramuscular dose of IFN- dressed in studies of cortical plasticity. We dealt with this by ␤ using a novel technique that modeled the fMRI response and -1a. Total RNA was obtained from peripheral blood cells, processed to cDNA, and analyzed using quantitative real- optic nerve structure together with clinical function. This time polymerase chain reaction. The results showed that helped to determine the contribution fMRI made to clinical early assessment (at 4 hr after IFN-␤ injection) of specific function after accounting for the relationship between optic biomarkers STAT1, Mx1, and TRAIL was more sensitive nerve structure and clinical function. We found significant than the later measurements. Furthermore, the antibody- effects at baseline, bilaterally in the lateral occipital com- positive persistent patient did not show any gene expression plexes, which are normally involved in higher order visual response. The four patients who were previously NAB- processing. These results strongly suggest a genuine adaptive positive and converted to negative had average responses role for cortical reorganization early after optic neuritis. lower than the persistent NAB-negative patients on several Study supported by the Multiple Sclerosis Society of Great genes, notably STAT1 and TRAIL and, to a lesser extent, Britain and Northern Ireland and by the Barnwood House Mx1. Study supported by Biogen and IDEC grants and hon- Trust. oraria for speaking for Biogen.

S58 Annals of Neurology Vol 56 (suppl 8) 2004 270. Regulation of Differentiation and Functional fluenced by MRI pulse sequence and segmentation algorithm Properties of Monocytes and Monocyte-Derived (SA) in patients with multiple sclerosis (MS) and in normal Dendritic Cells by Interferon-␤ in Multiple Sclerosis controls (NCs). GM- and WM-FVs were obtained in 25 pa- Ying C.Q. Zang, Sheri M. Skinner, Victor Rivera, tients with MS (mean disease duration: 8.1 years; mean age: George Hutton, and Jingwu Z. Zhang; Houston, TX 42.5 years; and mean EDSS: 3) and in 17 age- and sex- matched NCs. Brain MRI segmentation was performed from Interferon-␤ has complex immune-regulatory properties that 3D SPGR T1-weighted images (WI) and 2D-T1-WI. The contribute to its treatment effect on multiple sclerosis. We GMFV was significantly lower in the MS group vs. NCs investigated the role of IFN-␤ in differentiation and func- when measured from 3D SPGR T1-WI with Hybrid tional properties of monocytes and monocyte-derived den- SIENAX (p ϭ 0.013) and SPM99 (p ϭ 0.019). On the dritic cells that are critical to the inflammatory process in same pulse sequence, the SIENAX algorithm revealed a trend MS. The results revealed that IFN-␤ inhibited intracellular (p ϭ 0.068). There was no statistically significant difference production of IL-1b in monocytes exposed to in vitro treat- between MS patients and NCs for the WMFV, measured ment of IFN-␤, and in monocytes analyzed ex vivo from MS from both pulse sequences with all three SAs. When the treated with IFN-␤. IFN-␤ was shown to modulate differ- GM- and WM-FVs were compared on the same pulse se- entiation of monocytes into dendritic cells in the presence of quences using the various SAs, we found a significant differ- IL-4 and GM-CSF, which resulted in a delayed differentia- ence for both sequences (p Ͻ 0.002 after Bonferroni correc- tion process. Furthermore, it characteristically altered the tion for multiple comparisons). MRI estimates of GM- and phenotypic features of differentiated dendritic cells by inhib- WM-FVs are dependent on both the type of pulse sequence iting the expressing CD1a, CD11b, CD11c, CD123, and and the SA. CD209 while upregulating co-stimulatory molecules, such as CD86. The selective regulatory properties of IFN-␤ ap- peared to render the function of differentiated dendritic cells 273. Quantitative Evaluation of Accuracy with to produce an increased amount IL-10 whereas their ability Different Brain Atrophy Techniques to secrete pro-inflammatory IL-12 and TGF-␤ was signifi- Michael J. Dwyer, Kelly L. Watts, Francesca Bagnato, cantly reduced. The observed effects of IFN-␤ seemed to Laura Locatelli, Cosimo Maggiore, Attilio Grop, correlate with Th2 immune deviation. The study has pro- Enrico Millefiorini, Marino Zorzon, and Robert Zivadinov; vided new insights into the regulatory mechanisms of IFN-␤ Buffalo, NY; Rome, Italy; and Trieste, Italy in the treatment of MS. Study supported by Biogen IDEC. The aim of this study was to test the accuracy of various segmentation steps obtained with different brain atrophy 271. High Prevalence of Di-46, Tetra-48, and Di- techniques in patients with multiple sclerosis (MS). Brain ␣ Tetra-48 Nucleotide Microsatellite of TNF Increases fractional volume (BFV) was quantified on spin-echo, 3-mm, Susceptibility to Multiple Sclerosis non-gapped, 2D-T1-weighted axial sequences. BFV was cal- Robert Zivadinov, Michael Chan, Michel H. Rickert, culated by two semiautomated (Buffalo and Trieste) and four Norman Glenister, Priya Shastri, Cornelia Mihai, automated (SIENAX, Buffalo, SPM99, and Hybrid Margaret Planter, and Steven Greenberg; Buffalo, NY and SIENAX) software algorithms. Accurate masks were created Syracuse, NY in 21 MS patients and subtracted from the output files of six The aim of this study was to determine whether different different algorithms to obtain the misclassified extra and patterns of tumor necrosis factor ␣ (TNF␣) microsatellite are missing axial brain volumes. There was a significant differ- associated with multiple sclerosis (MS) susceptibility. In 100 ence among the six algorithms for misclassified extra and MS patients with sporadic and familial MS (ratio 1:1), 101 missing axial percentage brain volumes, even after Bonferroni age- and sex- matched healthy normal controls (NCs), 50 correction for multiple comparisons. The mean error of mis- patients with other neurologic diseases (OND), and 60 un- classified extra axial brain volume was 0.76% for SIENAX , affected familial MS members, the di-, tetra-, and di-tetra- 0.34% for Trieste, 0.29% for SPM99, 0.27% for Buffalo nucleotide microsatellite of TNF␣ has been determined. Af- automated, 0.21% for Hybrid Sienax, and 0.2% for Buffalo ϭ ter the Bonferroni correction was applied, a p value of p Ͻ semiautomated (pcorr 0.01). The figures for missing axial 0.01 was considered significant. Patients with MS and unaf- brain volume were the following: 4.2% for SIENAX, 2.1% fected familial MS members had significantly higher preva- for Hybrid SIENAX, 2.1% for Trieste, 1.3% for Buffalo au- lence of di-46-nucleotide microsatellite than healthy NCs tomated, 1.26% for SPM99, and 0.7% for Buffalo semiau- ϭ (p Ͻ 0.003) or patients with OND (p Ͻ 0.02). Prevalence tomated (pcorr 0.01). of tetra-48- and di-tetra-48-nucleotide microsatellite was higher in MS patients than in other control groups (OR 2.5, 95% CI 1.3–5.1, p ϭ 0.0008). Multiple regression analysis NEUROMUSCULAR DISEASE showed that the only variable that independently predicted the presence of tetra-48- (R ϭ 0.36, p ϭ 0.001) and di-tetra- 274. Significance of Visibility versus EMG 48-nucleotide microsatellite (R ϭ 0.38, p ϭ 0.0009) in MS Documentation of Fasciculation patients was younger age at disease onset. Nicolas Nammour, Dennis R. Mosier, and David B. Rosenfield; Houston, TX We hypothesize that visibility and electrodiagnostic docu- 272. Measurement of Cerebral Grey and White Matter mentation of fasciculation are independent variables, with Atrophy in Patients with Multiple Sclerosis different physiological and clinical significance. We are con- Kelly L. Watts, Michael G. Dwyer, ducting a prospective study in our tertiary referral center for Bhooma Srinivasaraghavan, and Robert Zivadinov; motor neuron disease (MND) patients. Currently, we have Buffalo, NY 25 patients with visible fasciculation or electrodiagnostic To determine whether the measurement of grey matter documentation of fasciculation or both. Electrodiagnostic (GM) and white matter (WM) fractional volume (FV) is in- testing was conducted on a Neuromax 1002 Xltek machine

Program and Abstracts, American Neurological Association S59 (notch filter 60 Hz, LFF 30 Hz, HFF 3KHz). Thirteen have QST evaluating CDT and VDT on the foot in two separate both visible and EMG evidence of fasciculation, eight have sessions, session 1 (S1) and session 2 (S2), at least 1 day EMG evidence without clinical evidence of fasciculation, and apart, three trials at each session. Standard normal deviates four have visible fasciculation without EMG documentation. were used to calculate intraclass correlation coefficients All 21 patients with fasciculation on EMG have MND, of (ICC). RESULTS: For CDT: ICC between S1 and S2 using whom 18 had active denervation (fibrillations, positive the first trial was 0.9. Using the mean of multiple trials did waves, high amplitude polyphasia, decreased recruitment). not significantly improve reproducibility (ICC: 0.93). Repro- The four patients with visible fasciculation but without ducibility results were similar for VDT, although lower than EMG documentation (direct needle recordings from fascicu- CDT (ICC: 0.84). CONCLUSIONS: There is high repro- lating domain, relaxed muscle, 2 min or more) did not have ducibility of quantitative sensory testing, making QST a MND (benign familial tremor, conversion disorder, polyneu- good choice for multicenter clinical trials of subjects with ropathy). Our study suggests that absence of EMG correlates small fiber neuropathy. A single measure was as reproducible of visible fasciculations suggests diagnoses other than MND. as multiple measures. In this setting, CDT was a highly re- This observation may result from different density, size, producible endpoint measure. Study supported by the Na- and/or correlated firing of abnormal motor units. Study sup- tional Institutes of Health, the General Clinical Research ported by the M.R. Bauer Foundation and the Lowin Med- Center, and the University of Michigan. ical Research Foundation.

277. Case Presentations and Pathology of CIDP 275. Anti-Hu Antibodies and Sensorimotor Presenting as Neoplastic Neurofibromas Polyneuropathy Associated with Carcinoid Tumorlet of David W. Polston, P. James B. Dyck, Robert J. Spinner, Lung Kimberly K. Amrami, Brian P. O’Neill, and Phillip A. Low; Mamatha Pasnoor, April L. McVey, Laura L. Herbelin, Rochester, MN James L. Fishback, Richard J. Barohn, and BACKGROUND: Neurofibromas occur focally, multifo- David S. Saperstein; Kansas City, KS cally, and diffusely in nerve. CIDP typically presents sym- Anti-Hu antibody is an antineuronal autoantibody associated metrically, but focal and multifocal forms are reported. with paraneoplastic neurological disease. It is often associated These clinical entities could theoretically be confused. We with small cell carcinoma of lung, but may be seen with present two such cases. METHODS: Two patients, with other malignancies. We report a patient with sensorimotor asymmetric and superficially visible or palpable nerve en- neuropathy, anti-Hu antibodies, and carcinoid tumorlet of largements of the neck and arms, were evaluated. Weaknesses lung. A 62-year-old woman presented with numbness and and sensory deficits were notable in multifocal fashion of weakness in her arms and legs that began 3 years earlier. moderate severity. Their neuropathic symptoms were chronic Sensory and motor symptoms began in one arm and, over (10 years or more) and progressive. Both carried the diagno- several weeks, spread to the other arm and then to both legs. sis of neurofibromatosis, but no systemic features were Examination revealed a cachectic-appearing woman with present, that is, cafe-au-lait, etc. RESULTS: MR imaging quadriparesis, limb atrophy, areflexia, decreased pinprick sen- and/or surgical exploration of affected nerves revealed diffuse sation up to knees/elbows, decreased vibration, and normal fusiform enlargements consistent with neurofibromas. Both proprioception. EMG/NCS revealed sensorimotor polyneu- had CSF protein elevation. Electrophysiologic studies sug- ropathy. Laboratory testing was positive for anti-Hu antibod- gested a mixed axonal and demyelinating process in each ies. Chest CT showed lymphadenopathy, but cytology and case. Directed nerve biopsies were performed in each case. biopsy specimens from bronchoscopy were normal. She died Each specimen had prominent onion bulb formation and in- because of other medical complications. Autopsy revealed flammatory changes most consistent with CIDP. Aggressive carcinoid tumorlet in lung. This case demonstrates that pa- immunotherapy resulted in modest improvement in one case tients with carcinoid tumorlet of lung may develop a para- and clinical follow-up is pending in the other. CONCLU- neoplastic neurological disease associated with anti-Hu anti- SION: Chronic focal or diffuse enlargements of nerve need bodies. Such an association has not previously been not represent neoplastic processes. Directed biopsy can be described. Carcinoid tumorlet of lung should be considered helpful in differentiating CIDP from neoplasms, thereby pre- as a diagnostic possibility in patients presenting with progres- venting potential delays in treatment. Study received indi- sive neurological syndromes and anti-Hu antibody positivity. rectly from the Mayo Fundation and the National Institutes of Health (grant NS 36797).

276. Reproducibility of Quantitative Sensory Testing in the Clinical Trial Setting 278. Gene Expression Profile in Desmin-Myopathy: Amanda C. Peltier, J. Robinson Singleton, Absence of Upregulation of Genes Associated with Jonathan Goldstein, James R. Howard, A. Gordon Smith, Protein Accumulation Raghavanpillai Raju and Marinos C. Eva L. Feldman, and James W. Russell; Ann Arbor, MI; Salt Dalakas; Bethesda, MD Lake City, UT; and New Haven, CT To assess whether the accumulation of myofibrillar proteins INTRODUCTION: Quantitative sensory testing utilizing in desmin-myopathy (DesMy) is related to upregulation of the CASE IV (QST) has been used in small fiber neuropathy their respective genes, we used oligonucleotide microarrays to research as a secondary endpoint. However, there is little study the gene expression profile in the muscles of four pa- data on reproducibility of QST in a multicenter study. OB- tients with DesMy. As controls, we used muscles from two JECTIVES: To determine the reproducibility of QST utiliz- normal controls and four patients with hIBM, a vacuolar ing cold detection thresholds (CDT) and vibration detection myopathy without protein accumulations caused by GNE thresholds (VDT) with the forced choice algorithm at our mutations. RNA isolated from muscle was hybridized to Af- institution. METHODS: Twelve patients with small fiber fymetrix U133A gene chips and analyzed by specific soft- neuropathy and impaired glucose tolerance were studied with ware. Among the proteins accumulated in DesMy (Myotilin,

S60 Annals of Neurology Vol 56 (suppl 8) 2004 desmin, plectin, aBC, dystrophin, NCAM, CDC2 kinase, peaks) pattern. In contrast, in the muscle, not only a lesser Gelsolin, titin, bAPP, prion, ␣1-antichymotrypsin, and ac- number of V␤ families was expressed, but *20.5% (p Ͻ tin), the genes for only three of them (plectin, gelsolin, and 0.05) of them had a monoclonal and **67% (p Ͻ 0.01) a actin) showed Ͼ1.5-fold upregulation. However, these genes restricted pattern. Among seven V␤ families common in all were similarly or more upregulated in hIBM. Several of the biopsies (families 2, 4, 5, 6, 7, 14, and 21), three (families 4, genes that were altered Ͼ4-fold in hIBM were not affected 7, and 21) had the most restrictive pattern. Minimal concor- in DesMy. In DesMy, protein accumulation results from dis- dance was noted between PBL and muscle in reference to the assembly of intermediate filaments and disruption of myofi- highest peaks. Immunohistochemistry is in progress to iden- brillar integrity in degenerating fibers, rather than gene up- tify whether these restricted V␤ families belong to autoinva- regulation. The term “protein-surplus” myopathy is not sive T cells. The results indicate that in sporadic inclusion appropriate. The disparate modulation of genes in hIBM body myositis, the endomysial T cells are specifically re- confirms their different pathogenetic mechanisms. cruited to the muscle and expand in situ in an antigen-driven pattern.

279. Greater Occipital Nerve Involvement in Hereditary Neuropathy with Liability to Pressure Palsy 281. Diagnostic Role of Deep Tendon Reflex in (HNPP) Peripheral Neuropathy Chitharanjan V. Rao, Alan L. Diamond, and Khema Ram Sharma, Daniela Saadia, Alicia G. Facca, and Florian P. Thomas; Saint Louis, MO Ram D. Ayyar; Miami, FL Patients with occipital neuralgia have variable local paresthe- OBJECTIVE: Value of deep tendon reflex (DTR) testing in siae, rarely hypesthesia. Compression/entrapment of greater diagnosis of peripheral neuropathy in patients with preserved occipital nerve (GON) passing through/between neck mus- DTR. METHODS: We prospectively investigated 28 pa- cles, especially when penetrating the semispinalis and trape- tients with chronic or acute inflammatory demyelinating zius (or its aponeurosis), may cause occipital neuralgia, cer- polyneuropathy (CIDP/AIDP; mean age: 61 Ϯ 6 years), 36 vicogenic headache, and post-whiplash occipital pain. GON patients with chronic axonal neuropathy (CAN), and 38 involvement may result from head pressure against the back height- and age-matched controls. All the patients had elec- of a chair, when it emerges from the trapezius/aponeurosis. tromyographic reflexes — a right biceps brachii reflex (BR), Other causes include damage from falls or blows from sharp/ a patellar reflex (PR), and a reflex for both ankles (AR) — hard objects and C2 dorsal ramus neurofibroma. GON in- that were elicited by means of a manually operated reflex volvement has never been described in hereditary neuropathy hammer. RESULTS: On clinical testing, DTRs were normal with liability to pressure palsy (HNPP). We present three or increased in 5 of 28 patients with demyelinating neurop- members of a four-generation family with clinically, electro- athy and 23 of 36 patients with CAN. In comparision with physiologically, and genetically confirmed PMP22 deletion controls, in patients with CIDP/AIDP, the mean latencies in HNPP, who presented with posterior scalp numbness in milliseconds were determined for BR (8.8 Ϯ 1.9 vs. 15.3 Ϯ GON distribution, on prolonged lying on the occiput. Two 3.4, p Ͻ 0.01), PR (17.4 Ϯ 2.4 vs. 28.4 Ϯ 6.3, p Ͻ 0.01), patients had unilateral sensory impairment over the GON and AR (30.0 Ϯ 2.4 vs. 41.0 Ϯ 3.6, p Ͻ 0.01). Similarly, in territory 4–12 months after the precipitating event. The patients with CAN, the latencies were determined for BR other reported intermittent right or left posterior scalp (9.8 Ϯ 8, p Ͻ 0.05), PR (20.3 Ϯ 4.1, p Ͻ 0.01), and AR numbness after lying on the occiput, but had no objective (33.5 Ϯ 4.3, p Ͻ 0.01). Mean latency indicative of demy- sensory loss in GON distribution. GON involvement ex- elination was seen in 60.7% of patients with demyelinatng tends the spectrum of nerve entrapment in HNPP. Its oc- neuropathy compared with 13.9% in patients with CAN currence is not surprising because it is vulnerable to entrap- (p Ͻ 0.01). CONCLUSIONS: DTR latencies were abnor- ment. Although perhaps under-recognized, an unusual mal in the majority of patients with demyelinating and ax- anatomical course of GON in our patients might render it onal neuropathy and were useful for distinguishing between more vulnerable. axonal and demyelinating neuropathy.

280. Spectratyping of the T Cell Receptor ␤-Chain- 282. Respiratory Involvement in DM2/PROMM Variable Region in the Peripheral Blood Lymphocyte Christen L. Shoesmith, Bradley V. Watson, and and Muscle of Patients with Sporadic Inclusion Body Michael W. Nicolle; London, Ontario, Canada Myositis: Evidence of Local Expansion of T Cell Clones INTRODUCTION: Myotonic dystrophy type 2 (DM2), or Mohammad Salajegheh, Goran Rakocevic, Alexey Shatunov, proximal myotonic myopathy (PROMM), is a myotonic dis- Raghavanpillai Raju, Lev G. Goldfarb, and order with proximal muscle weakness, stiffness, and myalgia. Marinos C. Dalakas; Bethesda, MD Respiratory insufficiency, which is associated with myotonic ϩ To characterize the antigen-specificity of CD8 cytotoxic T dystrophy type 1, has not been demonstrated in DM2. cells in patients with sporadic inclusion body myositis, we CASE REPORT: A 48-year-old man with genetically con- used spectratyping to examine the complimentarity- firmed DM2 was assessed for a hypercapnic coma induced determining region (CDR3) of all T cell receptor (TCR) by supplementary oxygen. He described grip myotonia, my- ␤-chain-variable region (V␤) families in simultaneously ob- algia, muscle fatigue, and cramping, which responded par- tained peripheral blood lymphocyte (PBL) and muscle biop- tially to treatment with carbamazepine. He also described a sies from five patients. Spectratyping is sensitive to identify 2-year history of dyspnea which subjectively worsened with clonal T cell expansions and demonstrate whether the en- cold exposure and progressive orthopnea. On examination, domysial T cells are antigen driven. Most of the 24 TCR-V␤ there was mild proximal weakness of neck flexion, arms, and families present in PBL had a polyclonal or Gaussian distri- legs, and there was impaired diaphragmatic excursion. Pul- bution; however, only *4.86% of them expressed a monoclo- monary function testing revealed a restrictive pattern. Motor nal (one-peak), and **16.78% expressed a restricted (Ͻ3 nerve conduction studies showed reduced phrenic ampli-

Program and Abstracts, American Neurological Association S61 tudes, and needle EMG demonstrated myotonic discharges muscle 8 cm inferior to the recording electrode. Amplitude and complex repetitive discharges in serratus anterior, inter- values in normal subjects range from 8 to 48 microvolts costal muscles, and diaphragm. Motor units were generally while the distal latency falls between 1.4 and 2.4 msec. The small and highly polyphasic. Investigations showed no other anatomy, nerve conduction study technique, normal value pulmonary, cardiac, or cord lesion to explain his respiratory data set, and illustrative abnormal cases will be presented. difficulties. Nocturnal BiPAP ventilation improved his dys- pnea. CONCLUSION: We believe this patient’s dyspnea was directly related to DM2, and a consequence of myotonia involving the respiratory muscles. 285. Familial Amyotrophic Lateral Sclerosis Due to a Gly41Ser Mutation in the SOD 1 Gene: Confirmation 283. Impaired Glucose Tolerance Causes Neuropathy of Severe Phenotype (IGTN) Study: Baseline Characteristics and First-Year S.H. Subramony, V.V. Vedanarayanan, Teepu Siddique, Follow-up Erdong Liu, Wu-Yen Hung, and Lisa Dellafave; Jackson, MS A. Gordon Smith, James R. Howard, Eva L. Feldman, and Chicago, IL Amanda Peltier, James Russell, Jonathan Goldstein, and To our knowledge, a Gly41Ser has been reported in three Rob Singleton; Salt Lake City, UT; Ann Arbor, MI; and unrelated pedigrees with familial amyotrophic lateral sclerosis New Haven, CT (FALS). One family (8 affected members) had a lower motor Impaired glucose tolerance (IGT) is identified in 30–40% of neuron presentation and a mean time to death of 11.6 idiopathic neuropathy patients. The Impaired Glucose Tol- month. We confirm the lower motor neuron phenotype and erance Causes Neuropathy (IGTN) study is an NIH-funded rapid course in an African-American family with a Gly41Ser multi-center project prospectively evaluating the clinical fea- mutation. Among 19 persons from this family, 4 (2 males, 2 tures and rate of progression of neuropathy associated with females) were diagnosed with ALS and evaluated by means of IGT. Endpoint measures focused on small fiber injury are periodic follow-up examinations through to their death. One being developed. A diet and exercise regimen modeled on the patient had a Gly41 Ser mutation in the SOD 1 gene estab- Diabetes Prevention Program is being employed. To date, 45 lished.Age at onset was from 38 to 61 years. All developed patients are enrolled, with a mean follow-up of 8 months. rapid diffuse lower motor neuron signs with diminished re- Each has had two abnormal oral glucose tolerance tests ful- flexes confirmed by EMG, with no bulbar weakness or spas- filling the ADA diagnostic criteria for IGT. Nerve conduc- ticity. The time from onset to death for the four patients was tion studies, QST, QSART, skin biopsy, laser doppler flow- 12, 9, 15, and 9 months. To our knowledge, this family with metry, the Michigan Diabetic Neuropathy Score, the Utah FALS related to a glycine-to-serine shift at position 41 of the Early Neuropathy Score, retinal photography, and 24-hr SOD 1 gene is only the second family to have detailed phe- urine albumin measurement are performed yearly. Baseline notype ascertained and confirms the predominantly lower data indicate a painful neuropathy with prominent epidermal motor neuron presentation and rapid course of the disease. denervation and sudomotor dysfunction. Abnormal micro- Study supported by the Luckyday Foundation (S.H.S.). vascular function correlates with neuropathy severity. Reti- nopathy and nephropathy were observed in one subject each. These data suggest peripheral nerve is more susceptible to hyperglycemic injury than kidney or retina, and that micro- vascular dysfunction may play an important pathogenic role. 286. High Muscle Blood Flow in Mitochondrial One-year data regarding neuropathy progression will be pre- Myopathy: Evidence from Forearm Exercise sented. Study supported by R01 NS 5058 and M01 Tanja Taivassalo, John N. Gaffke, Benjamin D. Levine, and RR00064 (NIH/NCRR). Ronald G. Haller; Dallas, TX In mitochondrial myopathies (MMs), exercise cardiac output is high relative to O utilization and inversely proportional 284. Proximal Spinal Sensory Neurophysiological 2 to the severity of oxidative impairment (Taivassalo, Brain, Assessment: Greater Auricular Nerve Conduction Study 2003); exercise limb blood flow is unstudied. We measured Benn E. Smith and P. James B. Dyck; Scottsdale, AZ and brachial artery flow (Doppler ultrasound) and O extraction Rochester, MN 2 (antecubital venous O2sat) during rhythmic forearm exercise Nerve conduction studies predominantly assess distal limb in five MM patients and five controls. All resting values were sensory nerves such as the sural, plantar, superficial fibular similar in both groups. In controls, exercise blood flow was (peroneal), median, ulnar, radial, and antebrachial cutaneous linearly related to contractile force (r2 ϭ 0.78) with a mean nerves. Sensory nerve conduction studies in proximal seg- flow of 23.0 Ϯ 4.4 mL/min/kg force (range: 17–28). In MM ments are limited to trigeminal “blink” reflexes and a few patients, exercise blood flow was exaggerated (mean: 61.7 Ϯ difficult-to-perform and less-than-reliable techniques to study 43; range: 30–148 mL/min/kg force; p Ͻ 0.01). Corre- such nerves as the saphenous, lateral femoral cutaneous, and sponding %O2sat increased from rest to exercise in MM pa- posterior femoral cutaneous sensory nerves. The great auric- tients (mean rest: 66.5 Ϯ 9.2%; exercise: 73.1 Ϯ 14%) in ular nerve (C2,3) is a readily investigated proximal spinal contrast to a decrease from rest (69.3 Ϯ 12.0%) to exercise sensory nerve that can be learned quickly, performed reliably, (43.8 Ϯ 5.0%) in controls. High exercise forearm flow cor- and studied in individuals suspected of having peripheral related closely with the level of exaggerated cardiac output processes affecting proximal segments, ventral rami of the during cycle exercise (r2 ϭ 0.99). These results suggest that cervical plexus, or local disorders affecting the great auricular high muscle blood flow is a direct consequence of impaired nerve in isolation. The recording electrode is placed directly oxidative metabolism and underlies the exaggerated exercise behind the earlobe while the reference electrode is placed 2 cardiac output in MM. Study supported by the Muscular cm away posterior to the helix. The stimulating electrode is Dystrophy Association, the United Mitochondrial Disease placed on the posterior border of the sternocleidomastoid Foundation, and the VA Merit Review.

S62 Annals of Neurology Vol 56 (suppl 8) 2004 287. Familial Oculopharyngeal Myopathy without 289. Effect of Immunotherapy on Expression of PABPN1 Mutation and Intranuclear Inclusions Cytokines and Chemokines in Relation to ␤-Amyloid Eiichiro Uyama, Hirotake Hino, Makoto Uchino, and and Ubiquitin in the Muscle of Patients with Sporadic Fernando M. S. Tome´; Kumamoto, Japan and Paris, France Inclusion Body Myositis Jens Schmidt, Joachim G. Voss, Raghavanpillai Raju, and We report a Japanese family comprising two affected elderly Marinos C. Dalakas; Bethesda, MD siblings presenting as OPMD-like features despite disclosing no PABPN1 mutations and no intranuclear inclusions. To To investigate effects of high-dose prednisone (PRED) and elucidate the nature of this particular disorder, we performed intravenous immunoglobulin (IVIG) on chemokines, cyto- clinicopathologic and genetic studies. The proband, a 76- kines, and ␤-amyloid-associated-proteins, crucial for sporadic year-old man, noted eyelid drooping since the age of 45. Ten inclusion body myositis (sIBM) pathogenesis. IVIG and years later, he developed nasal voice and dysphagia. On ex- PRED are ineffective in sIBM, although proven beneficial in amination at age 68, he showed severe bilateral ptosis, nasal other inflammatory muscle disorders. mRNA was extracted voice, and dysphagia. He also had mild weakness of proximal from 10 sIBM muscle biopsies before and 4 months after limb muscles. Serum CK and lactic acid levels were normal. treatment with IVIG ϩ PRED or PRED. cDNA was ana- Muscle biopsy disclosed mild myogenic changes mixed with lyzed by quantitative (real-time) PCR in relation to GAPDH scattered small fibers. No inflammatory changes, ragged-red expression, using primers for chemokine-ligand CXCL9, fibers, or rimmed vacuoles were observed. Immunostaining CCL3, CCL4, interferon-␥ (IFN-␥), tumor necrosis factor-␣ using anti-PABPN1 rabbit antiserum, specific for OPMD in- (TNF-␣), interleukin-1␤ (IL-1␤), IL-6, IL-10, transforming clusion, was negative in muscle nuclei. EM examination did growth factor-␤ (TGF-␤), inducible costimulator (ICOS), not reveal inclusions of OPMD or IBM types in any nuclei. inducible-costimulator ligand (ICOS-L), perforin, amyloid Genotyping of PABPN1 was normal. By age of 73, moderate precursor protein (APP), and ubiquitin. After IVIG ϩ ophthalmoplegia became evident. His 73-year-old sister PRED or PRED, we observed a 3–12-fold downregulated shared similar disturbances, which began at the age of 63. mRNA-expression: The strongest decrease was noted for Although the father died at age 32, family history indicates CXCL9, CCL3, and CCL4, followed by IFN-␥, TGF-␤, autosomal-recessive inheritance. Our results suggest that this and IL-10. In most patients, IL-1␤, APP, and ubiquitin were family is affected by a novel form of myopathy. Study sup- clearly diminished. TNF-␣, IL-6, ICOS, ICOS-L, and per- ported by grants-in-aid to E.U. from the Ministry of Educa- forin were modestly reduced. Immunohistochemical gray- tion, Science, Culture, and Sports of Japan. scale analysis confirmed downregulation at the protein level. In sIBM, IVIG ϩ PRED or PRED drastically reduced ex- pression of proinflammatory chemokines, cytokines, APP, and ubiquitin. Our results suggest that a stronger downregu- lation of these molecules may be necessary to achieve clinical 288. Multicenter Study of Clinical, Geographical, and efficacy, or that other factors are more relevant for the Ethnic Features of MuSK-Antibody-Associated immunological-degenerative interplay in sIBM pathogenesis. Myasthenia Gravis Study supported by a grant to J.S. from the Deutsche For- Angela Vincent, Donald B. Sanders, Daniel B. Drachman, schungsgemeinschaft (DFG, Schm 1669/1-1) and by an Maria Elena Farrugia, John Newsom-Davis, award from the NINDS. J.G.V. was supported by a K-22 Masakatsu Motomura, Yuko Nemoto, Satoshi Kuwabara, and career transition award from the NINR. the International Seronegative Myasthenia Gravis Study Group; Oxford, United Kingdom; Durham, NC; Baltimore, MD; Nagasaki, Japan; and Chiba, Japan 290. Altered ␣1-Syntrophin Expression of the Myofibers in Human Muscular Dystrophies Myasthenia gravis (MG) is found worldwide, but little is Yoshihiro Wakayama, Masahiko Inoue, Hiroko Kojima, known about the prevalence of the new MuSK antibody- Takahiro Jimi, Sumimasa Yamashita, Toshiyuki Kumagai, associated form of AChR antibody-negative MG. We present Seiji Shibuya, and Hajime Hara; Yokohama, Kanagawa, the preliminary data from a multinational (17 centers) study Japan and Kasugai, Aichi, Japan of patients with MuSK antibodies. There was variability in the proportion of MuSK-antibody-positive sera (MuSK pos- ␣1-Syntrophin, an adaptor and modular protein, is one of itivity). MuSK positivity (0–46%) correlated negatively with the cytoplasmic components of dystrophin-associated glyco- distance from the equator in North America and Europe (12 protein. This study was undertaken to investigate immuno- centers, p ϭ 0.04), but correlated positively in the East (0– histochemically the expression of ␣1-syntrophin in Duch- 25% in Phillipines, Taiwan, Japan, and Korea; p ϭ 0.04). In enne and Fukuyama muscular dystrophies (DMD and the two USA centers, MuSK positivity was more common in FMD). The biopsied muscles of five DMD, five FMD, five black MG patients than in white MG patients (12/21 com- normal controls, and five disease controls (three myotonic pared with 9/48, p ϭ 0.004). As previously reported, most and two facioscapulohumeral dystrophies) were analyzed. MuSK-antibody-positive patients were female, the onset was The serial sections of biopsied muscles were immunostained usually below 40 years, and bulbar symptoms were common. by affinity-purified rabbit anti ␣1-syntrophin and rabbit However, MuSK positivity was not uncommon among older anti-muscle-specific ␤-spectrin antibodies. The immunoreac- patients in the United States and Japan. These preliminary tive patterns of sarcolemma were classified into (1) normal results indicate intriguing relationships between MuSK anti- continuous pattern, (2) partially immunostaining pattern, (3) bodies and MG in different countries, and suggest that ge- negative immunostaining pattern, and (4) faintly but contin- netic or environmental factors, or both, are important in the uously positive immunostaining pattern. The group mean etiology of this form of MG. Study supported by the Myas- percentages of ␣1-syntrophin and ␤-spectrin immunonega- thenia Gravis Association/Muscular Dystrophy Campaign of tive myofibers were 39.3% and 10.8%, respectively, in the Great Britain and the Association Francaise contre les My- DMD group; those of the FMD group were 45.5% and opathies. Angela Vincent’s department receives royalties for 10.4%, respectively. These values were statistically signifi- the MuSK antibody assays. cantly numerous as compared with those of disease control

Program and Abstracts, American Neurological Association S63 and normal control muscles. Thus we found that the NEUROONCOLOGY dystrophin-deficient DMD muscles contained the significant number of ␣1-syntrophin-positive fibers, and the significant 293. Nonconvulsive Status Epilepticus in Metastatic number of ␣1-syntrophin-negative fibers were present in the Central Nervous System Disease dystrophin-positive muscles of severe muscular dystrophy Svetlana Blitshteyn and Kurt A. Jaeckle; Jacksonville, FL such as FMD. Study supported by the Research Grant for Nervous and Mental Disorders (14B-4) from the Ministry of OBJECTIVE: Although nonconvulsive status epilepticus Health, Labor, and Welfare, Japan. (NCSE) has been described in primary brain tumors, it has not been reported in patients with metastatic central nervous system (CNS) disease. We describe the clinical and diagnos- tic characteristics of four patients with metastatic CNS dis- ease presenting in de novo NCSE and report treatment out- 291. BiPAP and Early Guillan Barre´ Syndrome Eelco F. M. Wijdicks and Tuhin K. Roy; Rochester, MN comes. METHODS: Four patients with acute mental status change, abnormal EEG, known metastatic CNS disease, and BACKGROUND: BiPAP has been introduced in acute neu- no history of seizures were evaluated. Melanoma, breast can- romuscular respiratory disease. OBJECTIVE: To report the cer, small cell lung cancer, and chronic myelogenous leuke- first use of BiPAP in Guillain–Barre´ syndrome. RESULTS: mia were the primary malignancies. EEG and MRI were A 52-year-old man with progressive weakness, areflexia, and Ϫ each obtained at least once. Treatment with Fosphenytoin respiratory discomfort. His PI max was 62 mmHg; Pe- was initiated in all patients. RESULTS: All patients pre- MAX was 60 cm Hg; vital capacity was 800 mL. He was sented with acute mental status change and EEG findings started on IPAP of 14 and EPAP of 8 with 5 L oxygen per compatible with NCSE. MRI of the brain demonstrated pro- minute with immediate improvement and tidal volumes gression of metastatic CNS disease in all patients. Adminis- around 700 mL. He suddenly deteriorated after 5 hr with an acute hypoxemia and cyanosis.Vital capacity was 500 mL, tration of Fosphenytoin resulted in marked improvement in and PiMAX and PeMAX after intubation were, respectively, mental status with parallel resolution of abnormal patterns Ϫ10 and 15 mmHg. A 79-year-old woman was admitted on EEG in two patients and brief improvement followed by after onset of diplopia, imbalance and respiratory failure. a relapse in two patients. CONCLUSION: De novo NCSE PiMAX was Ϫ24 mmHg with a vital capacity of 1 L. For 10 should be considered in the differential diagnosis of acute hr she was comfortable with IPAP of 8 and EPAP of 4 on mental status change in patients with metastatic CNS disease room air. She deteriorated with marked hypoxemia. After in- and without history of seizures. Administration of Fospheny- tubation, a PiMAX of 5 and a PeMAX of 5 cmHg with a toin may result in clinical improvement. vital capacity 700 mL were recorded. CONCLUSIONS: The first attempt to use BiPAP in two consecutive patients with Guillain–Barre´ syndrome and early neuromuscular respira- tory failure were unsuccessful. We strongly warn against its use in early Guillain–Barre´ syndrome. 294. The IGF System Regulates Osteoprotogerin in Human Neuroblastoma Cells Tracy S. Schwab, Cynthia M. van Golen, Kevin Fung, Kenneth L. van Golen, and Eva L. Feldman; Ann Arbor, MI 292. Inflammation in Muscle Biopsy in Acute Neuroblastoma (NBL), the second most common pediatric Myasthenia Gravis Mimicking “Inflammatory extracranial tumor, produces metastases in bone. NBL pa- Myopathy” in the Acute Phase of the Experimental tients with secondary tumors in bone have a survival rate of Autoimmune Myasthenia Gravis less than 7%. Therefore, understanding how bony metastases Angela M. Young Achong, Gwendolyn C. Claussen, and form is critical for improving patient survival. Our laboratory Shin J. Oh; Birmingham, AL has shown that the Type I insulin-like growth factor receptor Inflammatory myopathy is described in the acute phase of (IGF-IR) regulates NBL cell proliferation, motility, invasion, the experimental autoimmune myasthenia gravis (EAMG). and survival. Given the large amount of IGF-I produced in There are few reports on the inflammatory cells in the mus- bone, we addressed the potential role for the IGF system in cles from biopsy or autopsy specimens in human myasthenia NBL metastasis to bone. High-IGF-IR-expressing NBL cells gravis (MG). Similar lesions have been reported in MG pa- adhere more strongly to human bone stromal cells, and in- tients with polymyositis. In these cases, CPK is elevated, and tratibial injection of these NBL cells leads to tumor forma- a thymoma is often present. We report a case of a 75-year- tion and osteolytic lesions. Osteolytic lesions form when os- old female with acute MG crisis who died in a month even teoclasts become activated in response to tumor cells. with plasma exchange. Neurological examination showed Receptor of nuclear factor kappa b ligand (RANKL), its true ptosis, weakness in the lateral recti, facial, neck, and proxi- receptor RANK, and the decoy receptor osteoprotegerin mal muscles with absent ankle jerks. This patient had a pos- itive tensilon test, a 19–47% decrement in the RNS test, (OPG) are important mediators of osteoclast activity. NBL positive AChR antibody, an active myopathy pattern in the cells expressing high IGF-IR levels have decreased OPG EMG, and an inflammatory myopathy in muscle biopsy in RNA and protein expression, while RANKL and RANK lev- the absence of elevated CPK and thymoma. Contrary to els remain stable. When these NBL cells are co-cultured with what is expected in polymyositis, this patient did not im- human bone cells, OPG levels decrease. Finally, OPG pro- prove with steroids. The disparity of “inflammatory myop- tein expression decreases within bone in vivo when high- athy” between the human MG and the acute EAMG has IGF-IR-expressing NBL cells are present. Study supported by been a matter of controversy for the last 100 years. This pa- the National Institutes of Health (RO1 NS36778) and the tient’s unusual findings certainly mimic “inflammatory my- Program for Understanding Neurological Diseases opathy” in the acute phase of the EAMG. (PFUND).

S64 Annals of Neurology Vol 56 (suppl 8) 2004 295. Diffusion-Weighted MRI Correlates of Subacute 297. Ventriculoperitoneal Shunt in Patients with Chemotherapy-Related Leukoencephalopathy Leptomeningeal Metastasis Marti Haykin, Mark J. Gorman, Robert K. Fulbright, and Antonio M.P. Omuro, Enrico C. Lallana, Mark H. Bilsky, Joachim M. Baehring; New Haven, CT and Lisa M. DeAngelis; New York, NY BACKGROUND: A subacute leukoencephalopathy has been BACKGROUND: Leptomeningeal metastasis (LM) is fre- most commonly observed in recipients of intrathecal metho- quently complicated by hydrocephalus and intracranial hy- trexate for childhood leukemia. Although conventional mag- pertension (ICH). Because of the poor prognosis, the deci- netic resonance imaging (MRI) correlates have been de- sion to insert a ventriculoperitoneal (VP) shunt is sometimes scribed, diffusion-weighted MRI (DWI) data are unavailable. difficult. METHODS: We reviewed charts of all patients METHODS: We present a retrospective analysis of five pa- with LM treated with VP shunt in our institution (1995– 2003). Possible prognostic factors, complications of the pro- tients who suffered a subacute neurological syndrome after ϭ cedure, and survival were assessed. RESULTS: Thirty-seven intrathecal (methotrexate for acute leukemia; n 4) or sys- patients (seven men) underwent VP shunt. The median age temic chemotherapy (capecitabine for breast cancer). A stan- was 53 (31–80). Primary cancer was breast in 23 patients, dardized MRI protocol was employed within 48 hr of symp- lung in 6, melanoma in 3, other in 5. All patients presented tom onset and included isotropic DWI with generation of with symptoms of ICH and had some clinical improvement apparent diffusion coefficient (ADC) maps. RESULTS: after the procedure. Nine patients had normal ventricular DWI of all patients revealed well-demarcated hyperintense size. Complications included subdural hematoma in one pa- lesions within the subcortical white matter of the cerebral tient, but none died as a result of VP shunt. Three patients hemispheres and the corpus callosum corresponding to areas underwent one or more shunt revisions. Median overall sur- of restricted proton diffusion on ADC maps. Lesions ex- vival was 8 weeks from the time of shunt placement, but five ceeded the confines of adjacent vascular territories. Complete patients survived more than 6 months. CONCLUSIONS: resolution of symptoms within 1–4 days was accompanied VP shunt improved symptoms of increased intracranial pres- by disappearance of DWI abnormalities. One patient suf- sure even if ventricular size was normal. Overall prognosis fered recurrence of neurological symptoms and DWI abnor- remained poor, but the procedure was safe and particularly malities upon re-exposure to chemotherapy. CONCLU- beneficial for a subgroup of long-term survivors. A better un- SIONS: Several pathophysiological models of subacute derstanding of prognostic factors in LM is necessary to es- leukoencephalopathy after exposure to intrathecal or systemic tablish clear indications for VP shunt. chemotherapy have been proposed. DWI findings in this co- hort seem to reflect cytotoxic edema and lend support to a NEUROPHARMACOLOGY reversible metabolic derangement as the basis for this syn- drome. 298. Effect of Humanin on ATP Production: Therapeutic Candidate for Mitochondrial Disorders Shingo Kariya, Makito Hirano, Yoshiko Furiya, and Satoshi Ueno; Kashihara, Nara, Japan 296. Quantitative Sensory Testing in the Assessment Humanin (HN) is a peptide that suppresses apoptosis in- of Oxaliplatin-Induced Neuropathy duced by mutant Alzheimer’s disease genes. We have recently found the potential of HN to increase ATP levels of lym- Susanne Koeppen, Zaza Katsarava, and Ildiko Halmai; phocytes from patients with mitochondrial disorders (MDs). Essen, Germany To gain further insights into the ATP-producing effect of PURPOSE: To identify the most sensitive neurophysiologi- this peptide, we analyzed rhabdomyosarcoma TE671 cells cal and/or clinical parameter indicating the onset of neuro- treated with HN. The ATP/ADP ratio was elevated along toxicity associated with oxaliplatin-based chemotherapy. PA- with the ATP increase, proposing that HN activates either TIENTS AND METHODS: Twelve patients receiving glycolysis or oxidative phosphorylation (OXPHOS). No in- oxaliplatin at a dose of 85 mg/m2 as an intravenous 2-hr crease in byproducts of glycolysis (pyruvate and lactate) in- infusion every 2 weeks for advanced metastatic colorectal dicated that the elevated ATP was derived from OXPHOS. cancer had a baseline examination and follow-up studies be- Our confocal microscopic study revealed that HN permeated fore each treatment cycle. All patients underwent a thorough cytoplasmic membranes and reached mitochondria. All these findings indicated that HN promotes ATP production by neurological evaluation. Neuropathic symptoms were scored directly acting on mitochondrial OXPHOS. In MDs, im- on a 10-point scale. Quantitative sensory testing was per- paired OXPHOS causes ATP deficiency and excessive ROS formed by assessment of vibration and thermal threshold in formation, and these abnormalities lead to further impair- the upper and lower extremities. RESULTS: Statistical anal- ment of this energy-generating system. The OXPHOS acti- ysis of our data showed a significant increase of both the vation is therefore a rational therapy to break this vicious vibratory and warm perception thresholds in the lower ex- circle, and thus HN may be a new therapeutic candidate for tremities after 6 weeks (p ϭ 0.003 and p ϭ 0.001, respec- MDs. This study was supported by the Grant-in-Aid for Sci- tively) as the earliest changes during the treatment course. entific Research from the Ministry of Education, Culture, No significant changes in clinical scores were observed Sports, Science, and Technology of Japan. within this period. DISCUSSION: Because neurotoxicity represents the dose-limiting side effect of oxaliplatin, early recognition of peripheral nerve damage is of high clinical rel- 299. Lack of Neurotoxicity with Sirolimus evance. Predictability of oxaliplatin-related peripheral neu- Boby V. Maramattom and Eelco F. M. Wijdicks; ropathy allows an adequate timing of prophylactic treatment. Rochester, MN Moreover, a nerve-fiber-selective diagnostic approach may INTRODUCTION: Sirolimus (SRL) is structurally similar improve neuroprotective strategies. to tacrolimus and new in organ transplantation. No detailed

Program and Abstracts, American Neurological Association S65 studies of SRL neurotoxicity have been reported. MATERI- ical constraints on a neural system. The most important of ALS AND METHODS: We reviewed the medical records of these is the energy available in a neural system. The tech- 203 consecutive patients who received SRL therapy after kid- nique begins with observable behaviors that allow character- ney (n ϭ 151) and liver transplantation(n ϭ 52) during the ization of the system into a limited number of structurally years 2001–2004. RESULTS: The dose of sirolimus (SRL) stable states. These states form a manifold whose topology is ranged from 1 to 10 mg/day. Serum levels of SRL were related to a set of potential energy equations. These equa- maintained at 8–15 ng/mL. The mean duration of SRL tions are able to be mechanistically parameterized by synaptic therapy was 18 months (15 days–4 years). Sixty-one patients strength, number, and decay constants. This parameteriza- (30%) switched to SRL alone after initial therapy with cy- tion provides a rigorous method that can be evaluated espe- closporine A (CsA) or tacrolimus. SRL was the initial immu- cially with functional MRI and psychophysiological dynam- nosuppresant along with with mycophenolate mofetil ical measurements. Two predictions that test the validity of (MMF) and prednisolone in 82 renal transplant patients the technique are (1) that ambiguous perception causes (40%). Sixty patients (30%) received it concurrently with higher energy consumption than perception of stable figures low-dose CsA or tacrolimus. No neurotoxicity or nephrotox- and (2) that cortical energy consumption as reflected in icity was documented with administration of SRL. Severe blood flow to the amydgdala can be accurately mapped onto side-effects of SRL, which included recurrent infections and a dynamical manifold for cases such as emotional content in buccal ulceration, were observed in 8% of patients. DIS- faces. Test cases using fMRI data have supported the validity CUSSION: Unlike calcineurin inhibitors, sirolimus was not of the intelligence modeling equations. These findings sug- associated with neurotoxicity. This finding is of major im- gest that this technique can be useful in determining the portance for consulting neurologists. Sirolimus could become mechanisms of complex neural behaviors. a preferred replacement drug when neurotoxicity occurs with other immunosuppressive agents. 302. Differential Regulation of Insulin Receptor Substrate-1 Degradation during Apoptosis 300. Neuroanatomical Correlates of Apathy associated Bhumsoo Kim, SangSu Oh, Cynthia M. van Golen, and with Alzheimer’s Disease by Means of Statistical Eva L. Feldman; Ann Arbor, MI Parametric Mapping Shehnaz Moosa, Krista L. Lanctoˆt, Nathan Herrmann, Insulin receptor substrate (IRS) proteins are major docking Usoa E. Busto, Farrell S. Leibovitch, and Sandra E. Black; molecules for the type I insulin-like growth factor receptor Toronto, Ontario, Canada (IGF-IR) and mediate their effects on downstream signaling molecules. In this report, we investigated IRS-1 regulation INTRODUCTION: Previous studies examining brain- during apoptosis in human neuroblastoma SH-EP cells. behavior relationships for apathy associated with Alzheimer’s Treatment of SH-EP cells with mannitol or okadaic acid disease (AD) were confounded by the presence of depression. (OA) induces apoptosis with the typical characteristics of This study was undertaken to explore the relationship be- anoikis. Mannitol treatment results in IRS-1 degradation tween regional brain perfusion and apathy in nondepressed with concomitant appearance of smaller fragments, likely AD patients. METHODS: Nondepressed outpatients with representing caspase cleavage products. In contrast OA- probable AD (NINCDS-ADRDA criteria), a mean (ϮSD) induced IRS-1 degradation is accompanied by a mobility age of 76.4 Ϯ 8.8 years, and a mean (ϮSD) Mini-Mental shift in IRS-1, suggesting IRS-1 serine/threonine phosphor- State Examination score of 22.2 Ϯ 5.1 were categorized as ylation. Mannitol-induced, but not OA-induced, degradation apathetic (n ϭ 23) or non-apathetic (n ϭ 29). Neuroana- is blocked by IGF-I. Pretreatment of the cells with caspase or tomical correlates of apathy were determined from 99mTc- proteasome inhibitors also partially blocks mannitol-induced ECD SPECT scans by means of statistical parametric map- IRS-1 degradation. These results suggest two independent ping (SPM99) software. RESULTS: SPM99 determined that pathways are involved in IRS-1 degradation; one pathway is hypoperfusion in the orbitofrontal gyri (Brodmann areas 11 dependent on caspase activation and is blocked by IGF-I, and 47) significantly correlated to Neuropsychiatric Inven- whereas a second pathway is caspase-independent and IGF- tory (NPI) apathy subscore (p-corrected Ͻ 0.001, bilateral). I-insensitive. Study supported by the Institutes of Health In apathetic patients, the right cingulate gyrus (p- (NS38849 and NS36778), the Juvenile Diabetes Research uncorrected ϭ 0.026), the right middle temporal gyrus (p- Foundation Center for the Study of Complications in Dia- uncorrected ϭ 0.016) and the right precuneus (p- betes, and the Program for Understanding Neurological Dis- uncorrected ϭ 0.003) exhibited a greater degree of cerebral eases (PFUND). hypoperfusion with increasing severity of apathy, though un- corrected p values were nonsignificant. CONCLUSIONS: In this relatively large sample of outpatients, the presence of ap- 303. IGF-I Protects Hyperglycemic Neurons from athy was significantly correlated with orbitofrontal hypoper- Apoptosis via Akt Activation and Caspase Inhibition fusion. Increased severity of apathy may be related to de- Gina M. Leinninger, Carey Backus, Michael D. Uhler, creased cerebral blood perfusion in the right cingulate gyrus, Stephen I. Lentz, and Eva L. Feldman; Ann Arbor, MI middle temporal gyrus, and precuneus. The database was partially supported by a CIHR grant to S.E.B. We study insulin-like growth factor-I (IGF-I)-mediated neu- roprotection in diabetic neuropathy. We treated embryonic dorsal root ganglia (DRG) with 20 mM glucose to investi- NEUROSCIENCE gate the mechanisms of glucose-induced caspase activation and IGF-I protection. This serves as an in vitro model of 301. Experimental Validation of a Dynamical Systems neurons subjected to high glucose in poorly controlled dia- Model of Neural Behavior betes. High glucose treatment decreases proform caspase-9 Peter R. Bergethon; Boston, MA but does not increase caspase-8 cleavage. IGF-I inhibits the Intelligence modeling is a dynamical modeling technique loss of proform caspase-9 and decreases caspase-3 cleavage, that incorporates neuroanatomical, chemical, and physiolog- suggesting that IGF-I inhibits apoptosis by suppressing the

S66 Annals of Neurology Vol 56 (suppl 8) 2004 caspase-9 cascade. We next investigated the effects of IGF-I cells were separated by a filter membrane. Our data suggest on the Akt and ERK pathways, both implicated in neuro- that supplying normal cells for the ALDm by HCT corrects protection. IGF-I treatment phosphorylates Akt but not metabolic abnormalities in ALD tissues through a cell- ERK. IGF-I treatment also causes phosphorylation of mediated process. The correction requires direct cell-to-cell GSK-3␤ and the transcription factors CREB and FKHR; contact for recovering the normal cell function. Study sup- this is prevented by addition of the Akt pathway inhibitor ported in part by a grant from the Ministry of Health, La- LY294002. Our results suggests the following: (1) High glu- bor, and Welfare of Japan and a grant-in-aid for scientific cose induces apoptosis in neurons via caspase-9 and research from the Japan Society for the Promotion of Sci- caspase-3. (2) IGF-I protects at the cytoplasmic and nuclear ence. level via the Akt pathway. This research is supported by the NINDS (F31 NS043023-02) and the JDRF. 306. Granulocyte Colony-Stimulating Factor Protects Human Cortical Neurons from in Vitro Ischemia 304. Difference in Nigral Iron between Parkinson’s Keun-Hwa Jung, Kon Chu, Soon-Tae Lee, Manho Kim, and Disease and Control Is in the Iron Binding Not in Jae-Kyu Roh; Seoul, Republic of Korea Amount Granulocyte colony-stimulating factor (G-CSF) has neuro- Andrzej Friedman, Jolanta Galazka-Friedman, protective effects against experimental focal cerebral isch- Dariusz Koziorowski, and Erika R. Bauminger; Warsaw, emia. In this study, we attempted to determine whether Poland and Jerusalem, Israel G-CSF can protect the human cerebral neurons from in vitro Iron-mediated oxidative stress is one of the mechanisms of ischemia. Human cortical neurons (A1G11) were exposed to nigral cell death in Parkinson’s disease (PD). Many studies hypoxia with glucose deprivation (6 hr). Human recombi- showed an increase in the total amount of iron in parkinso- nant G-CSF (0, 5, 25, 50, or 100 ng/mL) was used, and nian substantia nigra (SN); others did not find any. AIM: To cells used in this experiment expressed G-CSF receptor. Cell compare the concentrations of iron, iron bindings, and con- viability or cytotoxicity was determined by MTT or LDH centrations of H and L ferritins in SN in PD and control assay. Flow cytometry by annexin-V and propidium iodide brains. MATERIALS AND METHODS: Nine PD and 21 (PI) and immunocytochemistry by active caspase-3 antibody control brains were assessed by Mo¨ssbauer spectroscopy, and were performed to detect apoptotic or viable cells. A decrease 6 PD and 11 controls were measured with ELISA. RE- in cell viability was observed following 6 hr of ischemia. SULTS: No difference between the total iron in SN in PD G-CSF promoted cell survival (42% vs. 32%) and decreased and control was found (about 165 Ϯ 15 ␮g/g). At least 85% cytotoxicity (9% vs. 18%) at a maximally effective concen- of iron is ferritin-bound. Mo¨ssbauer spectra showed an asym- tration of 25 ng/mL, which was associated with upregulation metry more pronounced in PD samples. ELISA demon- of STAT3. From flow cytometric analysis, G-CSF reduced ϩ Ϫ strated a decrease in the concentration of L ferritin in par- early apoptotic (annexin-V /PI ) and late apoptotic (an- Ϫ Ϫ kinsonian SN vs. control (47 Ϯ 8 vs. 105 Ϯ 21 ng/mg). nexin-V /PI ) cells. A decrease in immunoreactivity against CONCLUSIONS: The asymmetry may reflect the presence activated caspase-3 in the G-CSF-treated group was corre- of a small amount of non-ferritin iron, higher in PD. To- lated with the neuronal protection. Our results provide evi- gether with the decrease of L ferritin, it shows that iron may dence that G-CSF can protect human cerebral neurons from be involved in the pathogenesis of PD not by an increase of apoptotic cell death after an ischemic insult. Study supported the total amount but by an increase of non-ferritin iron. by the 21st Century Frontier Research Fund of the Ministry Study partially supported by a grant from the Committee for of Science and Technology (M102KL010001-02K1201- Scientific Research in Poland (project 4 P05A 096 19). 01310), Republic of Korea.

305. Therapeutic Effects of Normal Cells on ABCD1- 307. Novel Endogenous Neuroprotective Pathway Deficient Cells in Vitro and Hematopoietic Cell Comprising Nitric Oxide-Induced Erythropoietin Transplantation on the X-ALD Mouse Model Production Hirokazu Furuya, Takeshi Yamada, Nobue Shinnoh, Sanjay C. Keswani, Angela Fischer, Nicole Reed, and Hitoshi Kikuchi, and Jun-ichi Kira; Fukuoka, Fukuoka, Ahmet Hoke; Baltimore, MD Japan; Chikugo, Fukuoka, Japan; and Iizuka, Nitric oxide (NO) has been implicated in both neurotoxicity Fukuoka, Japan and neuroprotection. Examples of NO-mediated neuropro- To clarify the mechanisms of hematopoietic cell transplanta- tection include the pivotal role played by NO in ischemic tion (HCT) for adrenoleukodystrophy (ALD), we examined preconditioning, and the fact that nNOS-knockout mice the effects of HCT in ABCD1 knockout mice (ALDm) and have increased peripheral nerve degeneration following sciatic co-culture of ALD patient fibroblasts with normal cells. We nerve transection compared to wild-type animals. We have treated ALDm with HCT using lacZ-transgenic mice as the recently demonstrated that erythropoietin (EPO) production donors. We also examined the effects of co-culturing normal is increased by Schwann cells that are in close proximity to microglia cell line with ALD fibroblasts. The injured primary sensory neurons. We show that this endog- ␤-galactosidase(␤-GAL) activity was higher in the spleen, enous EPO prevents axonal degeneration and neuronal lung, and kidneys than in the liver, brain, and spinal cord of death. By using dissociated primary DRG cultures from em- the recipient ALDm. HCT reduced the accumulation of very bryonic rats, we show that NO staining is increased in sen- long chain fatty acid (VLCFA) in those tissues. The reduc- sory neurons in a variety of neurotoxic paradigms, including tion of the VLCFA ratio was significant in the spleen and NGF-deprivation and acrylamide exposure. When TFPI, a lung, tissues with higher ␤-GAL activity. ABCD1 was de- specific nNOS inhibitor, is co-administered, the neurotoxic- tectable in the spleen in HCT mice. Co-culture of ALD fi- ity of the conditions mentioned earlier is markedly increased, broblasts with normal fibroblasts reduced VLCFA accumula- in contrast to 1400W, an iNOS inhibitor, which has no ef- tion in the ALD cells. This effect was not observed when the fect. We show that NO donors increase EPO mRNA by RT-

Program and Abstracts, American Neurological Association S67 PCR in pure Schwann cell cultures and result in EPO release use the BCAB. Study supported by the Medical Research into the supernatants of these cultures. Our data suggest that Council, South Africa Allied Health Professionals Scholar- NO produced by injured neurons stimulates surrounding ship. Two years of support of the master’s project was pro- glial cells to produce EPO, which via EPOR binding on neu- vided the form of a salary. rons, mediates an endogenous neuroprotective pathway. Study supported by RO1 NS047972-01 (awarded to S.C.K.).

OTHER 308. Immortalized Human Bone Marrow Mesenchymal Stem Cell Lines with Neurogenic 310. Subthalamic Stimulation Alleviates Pain in Potentials Parkinson’s Disease Seung U. Kim, Atsushi Nagai, Woo K. Kim, Seok H. Hong, Boulos-Paul W. Bejjani, Mazen G. Jabre, Kwang S. Kim, In H. Park, and Jung H. Bang; Vancouver, Asmahane Al-Shubaily, Katia G. Habib, and George Nohra; British Columbia, Canada and Suwon, Korea Byblos, Lebanon and Kuwait, Kuwait Bone marrow mesenchymal stem cells (MSCs) have multi- BACKGROUND: Pain is a disabling sensory non-motor lineage differentiation capacity potential to become various fluctuation present in a group of patients with advanced Par- cell types, including bone, cartilage, fat, muscle, and neu- kinson’s disease (PD). OBJECTIVE: To assess the effective- rons. MSCs have been engrafted and survived in animal ness of subthalamic stimulation (STN DBS) on PD-related brains, raising the possibility of therapeutic potential for pa- pain in 3 of our 42 patients. METHODS: Before surgery, tients with neurological disorders. Human fetal bone marrow patients presented with a severe refractory intermittent non- MSCs were transfected with a retroviral vector carrying dystonic pain mostly affecting the abdomen, chest, neck, and v-myc, and twelve clones of human bone marrow MSC cell limbs, accompanied by headache, and of unknown etiology. lines have been generated. B10, one of the cell lines, carries Evaluation of pain was mainly based on a subjectively rated normal human karyotype of 46XX and expresses cell-type- (0–10) pain scale, before and after STN DBS. RESULTS: specific markers for human MSCs including CD13, CD29, After surgery and until a mean of 8.3 months, patients re- CD44, CD49b, CD90, and CD166. When B10 cells were ported 78.6% and 85% improvement on the pain severity grown in differentiation media, better than 80% of cells dif- scale and incidence, respectively, when compared to the pre- ferentiated into osteocytes, chondrocytes, and adipocytes, operative OFF-condition. Likewise, motor function, dyskine- and 40% of cells expressed neuron-specific cell-type markers, sias, and motor fluctuations scores improved by 88%, 87%, ␤-tubulin III and NeuN. After intraventricular transplanta- and 100%, respectively, when compared to pre-operative tion in neonatal mice, engrafted cells were found to migrate OFF-drug findings. Levodopa was stopped in all patients. extensively and differentiate into neurons in hippocampus, Anti-dopaminergic treatment daily doses were decreased by neocortex, and striatum. These results indicate that the im- 89%, as patients were maintained on pergolide monotherpy mortlized human MSCs should serve as a powerful tool for (mean dose: 2 mg/day). CONCLUSION: Subthalamic DBS research into development of stem-cell-based therapy for hu- was markedly effective in alleviating PD-related pain and im- man neurological disorders. Study supported by the Cana- proving motor and non-motor features in our group of pa- dian Myelin Research Initiative and the Korean Science tients. Subthalamic nucleus seems to play a pivotal role with Foundation/BDRC Ajou University. the pathology of non-motor symptoms in general, and with pain in particular.

309. Validation of a Rating Scale for Bedside Cognitive Assessment Annerine Roos and Frans J. Hugo; Cape Town, South Africa 311. Sleep in the Cuttlefish Neuropsychological tests are very useful, but have some lim- S.P. Duntley and M.J. Morrissey; Saint Louis, MO itations. Administration of the tests is limited to a psychol- ogist, can be very time-consuming, and often needs special- Our laboratory has demonstrated that the cuttlefish sepia ized equipment. At the other end of the continuum are very pharaonis exhibits features of behavioral sleep. These features brief screening tests. Although useful, the short tests provide include a rapidly reversible species-specific resting posture, a limited information. An intermediate test streamlining the circadian pattern of consolidated rest periods, an elevated assessment process is therefore introduced by this study. The arousal threshold during rest, and homeostatic regulation. In Bedside Cognitive Assessment Battery (BCAB) was devel- addition, there appeared to be two distinct types of sleep: a oped in 1995 at Tygerberg Hospital’s Memory Clinic, Cape quiescent state with stable skin and color pattern (QS), and Town, South Africa. The test comprehensively assesses atten- a state characterized by stereotypic chromatophore activity tion and concentration, speech, memory, motor functioning, (CAS) with minor tentacle movements. It was hypothesized perceptual functioning, and executive functioning. The aims that this latter state may be analogous to mammalian REM of this study were to validate the BCAB for people aged 18 sleep. This study was an attempt to further characterize that years and older, and to provide normative values. In this CAS is a distinct sleep stage in the cuttlefish sepia pharaonis, study, 160 Afrikaans and English participants and 14 Xhosa and that it has some similarities to mammalian REM sleep. participants were assessed. Results were evaluated for the ef- Both QS and CAS are under homeostatic control, with a fects of the variables’ language, gender, age, and education. more prominent rebound in CAS than QS during the first Gender did not affect results as dramatically as age or (espe- recovery day. As in mammalian REM sleep, eye movements cially) education. These significant effects on the aforemen- occur during CAS. Although CAS was not obtained during tioned variables have been described in previous reports. The the acute EEG telemetry recording, this data demonstrates BCAB is thus relevant and useful as a detector of mild to the feasibility of such recording. Chronic implantation and moderate impairment. Medical and non-medical staff can long-term recording is currently being performed.

S68 Annals of Neurology Vol 56 (suppl 8) 2004 312. Neurology in Pharaonic Era tion are less common. Patients diagnosed with this disorder Mohamed E. El-Gengaihy and Ahmed E. El-Gengaihy; are reported the British Neurological Surveillance Unit, and Zagazig, Sharkia Governorate, Egypt and Cairo, Egypt the clinical details and investigation results are ascertained. Patients are then contacted at yearly intervals with a postal The Egyptian physician (SWNW) was an advanced medical questionnaire, and further details are requested from the re- practitioner for his time. Medical institutes (peri-ankh) were ferring neurologist. Over 5 years, 41 cases have been re- started since the first dynasty (3150–2925 BC). Specialties viewed; 22 are female, and the age range is 14–72 years. were pushed to their extremes, and the concept of neurolog- Twenty-one cases involved inflammatory lesions within the ical diseases in ancient Egypt was little different from that brain, and 10 of these case involved lesions in the brain current in the 18th century. Dissecting and bandaging mum- stem. Six had cord lesions, and one each involved peripheral mies for thousands of years and managing traumatic brain nerves and muscle. Optic neuropathy arose in one case, and and spinal cord injuries gave ancient Egyptians extensive ex- recurrent meningitis occurred in three. Vascular complica- perience in identifying pathological lesions. In 1600 BC, the tions arose in eight cases. To date, the majority have had anatomy of human brain, its blood supply, and ischemic only one attack, but eight patients have had recurrent (2–9) brain lesion were described for the first time. Brain was re- attacks, of whom two have undergone a progressive disease moved from the nose through the cribriform plate, and men- course. This study will continue over the next 10 years. tal changes and consciousness were examined. Vascular and traumatic causes of aphasia were identified and were related to the temple. Hemiplegia due to unilateral brain lesion and 315. Parkinson’s Disease and Diplopia quadriplegia due to cervical cord lesion were described. An- Frederick E. Lepore; New Brunswick, NJ cient Egyptians studied different neurological disorders and designed for them appropriate drug prescriptions. Physiother- The spectrum of ocular dysconjugacy is not well described in apy heliotherapy and hydrotherapy were practiced in special Parkinson’s disease (PD), and 44 consecutive PD patients sanatoria. In this paper we selected available Egyptian med- with diplopia (and 9 controls) were examined for diplopia ical papyri — mainly Edwin Smith Papyrus (1600 BC), Ebers including convergence insufficiency (CI) (defined as distance Papyrus (1550 BC), and Hearst, Kahun, Berlin, and Rames- fusional amplitude Ͻ19 prism diopters base out or near seum Papyri — to illuminate the practice of neurology in the point of convergence Ͼ10 cm from interocular baseline). pharaonic era. Forty-two patients had CI with or without diplopia (two could not be tested). Fifteen out of 44 patients also had dis- tance diplopia (hypertropia, 9; exotropia, 4; variable horizon- 313. The Incidence of Idiopathic Intracranial tal heterotropia, 1; esotropia, 1) of diverse etiologies. Nine Hypertension in Mississippi control PD patients of similar age without diplopia and with ϭ Jennifer H. Garrett, James J. Corbett, Ronald A. Braswell, shorter disease duration (p 0.05) had CI with significantly Ͻ and Maria Santiago; Jackson, MS greater (p 0.0001) convergence fusional amplitudes than PD patients with diplopia. No patients were receiving anti- BACKGROUND: Idiopathic Intracranial Hypertension cholinergic medications. Prior studies underestimate the fre- (IIH) can rapidly cause blindness in young, obese females. quency of CI in PD patients with visual complaints. In this Statistics from the CDC report that Mississippi carries the series, 100% of tested patients with diplopia had CI. Com- highest rate of obesity at 25.9%. OBJECTIVE: To investi- parison of PD patients with and without diplopia demon- gate the incidence of IIH in Mississippi compared to the strates that convergence fusional amplitudes decrease as dis- incidence from the 1988 Iowa and Louisiana studies. ease duration increases. CI is a common accompaniment of METHODS: All ophthalmologists, neurologists, and neuro- PD, the most frequent cause of diplopia, and may reflect surgeons in Mississippi were surveyed monthly from April extranigral pathology. 2003 to April 2004 to report newly diagnosed cases of IIH. Included are each patient’s initials, age, sex, height, weight, pregnancy status, visual acuity, and county of residence. RE- 316. Chronic Exposure to 1-Bromopropane associated SULTS: Calculated incidences are based on 11 months of with Spastic Paraparesis and Distal Neuropathy: Report data applied to the annual statistics. Fifty-one patients are of Six Foam-Cushion Gluers currently included with a female-to-male ratio of 16:1. The Jennifer J. Majersik, John D. Steffens, and mean age is 29, and the mean BMI is 38.5. The incidence of E. Martin Caravati; Salt Lake City, UT IIH in the general population in Mississippi is 1.8/100,000, twice that of the Iowa study. The incidence for women ages 1-Bromopropane (1-BP) is being substituted for traditional 15–44 is 6.3/100,000, almost twice that of the Iowa study ozone-depleting solvents in the industrial setting. We de- (3.5/100,000). CONCLUSIONS: The prevalence of obesity scribe six cases of 1-BP neurotoxicity in foam-cushion gluers in Mississippi directly correlates to the incidence of IIH. As exposed to 1-BP vapors from spray adhesives over several the rates of obesity continue to increase, patients with symp- months. All patients complained of subacute onset of lower toms of IIH should be promptly screened for the disease. extremity pain or paresthesias, and five of six complained of difficulty walking. On exam, five patients had bilateral lower extremity spastic paraparesis, distal sensory loss, and hyper- reflexia. Serum bromide concentrations ranged from 44 to 314. United Kingdom Study of the Natural History of 170 mg/dL (reference: 0–40 mg/dL). Factitious hyperchlor- Neurological Complications of Behc¸et’s Syndrome emia was present with serum chloride concentrations of 105 Desmond P. Kidd; London, United Kingdom to 139 mmol/L (reference: 98–107 mmol/L). Air samples Behc¸et’s syndrome affects the nervous system in some 5% of taken at the workplace 1 day after gluing operations ceased cases. An inflammatory infiltration of the central nervous revealed a 1-BP mean air concentration of 130 ppm (range: system and, less often, the peripheral nerves and muscle, 91–176 ppm), well above the EPA-recommended 25 ppm. arises in 75% of cases, whereas vascular complications due to Fifteen months later, the two most severely affected patients venous sinus thrombosis and, rarely, arteial aneurysm forma- had regained only minimal function and still required assis-

Program and Abstracts, American Neurological Association S69 tance to walk; three patients continued to experience chronic Canadian Myelin Research Initiative, and the Korea Science neuropathic pain. Chronic exposure to high vapor concen- Foundation/BDRC Ajou University. trations of 1-BP in the workplace was associated with a dis- tinct and incapacitating neurotoxic syndrome. NEUROVIROLOGY

319. West Nile Encephalitis Presenting as Opsoclonus- 317. Granulomatous Amebic Encephalitis in a Myoclonus-Cerebellar Ataxia Transplant Patient: Case Report Jaswinder Khosla, Martin J. Edelman, Nancy Kennedy, and Oscar Mendez, Marta Couce, Emanuel Kanal, Stephen G. Reich; Baltimore, MD Kareem Abu-Elmagd, and Sasa Zivkovic; Pittsburgh, PA OBJECTIVE: To report West Nile virus (WNV) presenting A 40-year-old man with multivisceral allograft presented as opsoclonus-myoclonus-cerebellar ataxia. BACKGROUND: with a 1-day history of mild headache and right-sided numb- WNV appeared in North America in 1999, causing an out- ness (face, arm, and leg). On examination, he had decreased break of meningoencephalitis in the New York region. The sensation for light touch and pinprick over the right hemi- neurological manifestations range from typical meningoen- body. Tacrolimus level was normal. Cranial MRI revealed a cephalitis to flaccid paralysis, movement disorders, cranial neu- weakly ring-enhancing left parietal lesion. CSF analysis ropathies, optic neuritis, and seizures. There have been no re- showed normal cell count and glucose level, mildly elevated ported cases of WNV causing opsoclonus-myoclonus- protein content (65 mg/dL). and negative Gram stain and cerebellar ataxia. RESULTS: A 62-year-old man with stage IV cultures. Four days later, he became confused with right- non-small cell lung cancer presented with a 1-week history of sided weakness. Stereotactic brain biopsy was suggestive of a low-grade fever, rash, weakness, and lethargy. On examina- post-transplant lymphoproliferative disorder. Gradually, the tion, he was febrile and encephalopathic, and he had a stiff patient became stuporous and died 13 days after the onset of neck. MRI of the brain was normal. CSF demonstrated 112 symptoms. Autopsy demonstrated Achantamoeba cysts in the WBCs, protein 157 mg/dL, and glucose 62 mg/dL. Within 1 brain, as confirmed by immunofluorescence. Amebic CNS week, he developed opsoclonus-myoclonus-cerebellar ataxia. infections are rare despite their ubiquity. Risk factors include Serum and CSF IgM antibodies for WNV were positive. freshwater swimming, chronic illness, and immunosupres- Anti-Hu and anti-Yo antibodies were negative. He improved sion. Granulomatous amebic encephalitis (GAE) has an in- with supportive care. Two months later, mental status was sidious onset that may present with focal symptoms. Patients near normal, the opsoclonus and myoclonus had resolved, and usually follow a subacute to chronic course leading to death the ataxia had improved. CONCLUSION: We report a case within weeks to months. Our case highlights diagnostic dif- of WNV presenting as opsoclonus-myoclonus-cerebellar ficulties encountered with investigations of GAE and sug- ataxia. This adds to the widening clinical spectrum of WNV gests that we should also consider amebic encephalitis in the and emphasizes the need to consider WNV in the differential differential diagnosis of opportunistic CNS infections in diagnosis of opsoclonus or an acute cerebellar syndrome. transplant patients.

320. Interaction of HIV Tat and Matrix 318. Generation of Stable Immortalized Human Metalloproteinase: New Host Defense Mechanism Neural Stem Cell Lines via Tetracycline-Responsive Jeffrey A. Rumbaugh, David Galey, Oncogene Activation for Cell Therapy in Neurological Jadwiga Turchan-Cholewo, Katherine Conant, Disorders Coryse St. Hillaire, Carol Anderson, Robert Slevin, and Seung U. Kim, Kwang S. Kim, Woo K. Kim, Seok H. Hong, Avindra Nath; Baltimore, MD and In H. Park; Vancouver, British Columbia, Canada and HIV infection causes dementia, the pathogenesis of which Suwon, Korea remains poorly understood. Tat protein and matrix metallo- Human neural stem cells with self-renewal and multilineage proteinase (MMPs) have been implicated. MMP-1 levels differentiation properties that provide a renewable resource were significantly elevated (p Ͻ 0.05) in brain extracts, and of human neurons would substantially facilitate development strong immunoreactivity was noted for MMP-2 in brain sec- of stem-cell-based cell therapy for human neurological disor- tions from HIV dementia patients. Thus, to determine if ders including Parkinson’s disease, Huntington disease, ALS, MMPs can modulate Tat-mediated neurotoxicity, recombi- stroke, and spinal cord injury. We have isolated clonal hu- nant Tat and MMP-1 were co-incubated in human neuronal man neural stem cell lines that have been immortalized via a cultures. Surprisingly, this produced significant (p Ͻ 0.05), tetracycline-responsive v-myc oncogene; addition of tetracy- dose-dependent attenuation of neurotoxicity, measured by cline in the medium activated oncoprotein, allowing the mitochondrial matrix potential, compared to the effect of stem cells to proliferate rapidly. One of the cell lines, each protein independently. Similarly, MMP-2 attenuated HB2.G2, shows a normal human karyotype of 46XX, a dou- the reactive oxygen species produced in neuronal cultures by bling time of 46 hr, and expresses nestin and ABCG2, cell- Tat alone, measured by dihydrorhodamine flourescence. type-specific markers for neural stem cells. In the absence of When Tat and MMP-1 were co-incubated and analyzed by tetracycline, Ͼ70% of G2 cells differentiate into neurons, as Western blot, we found that MMP-1 can degrade Tat. This shown by the expression of neuron specific markers, includ- degradation was blocked by MMP inhibitors, suggesting the ing ␤-tubulin III, MAP2, neurofilament (NF)-L, NF-M, decrease in Tat-induced neurotoxicity is due to Tat’s enzy- NF-H, and NeuN. After intraventricular transplantation in matic cleavage by MMP. For the first time, the direct inter- neonatal mice, engrafted cells were found to migrate exten- action of human MMPs with viral proteins has now been sively and differentiate into neurons in various brain sites. demonstrated, with resultant modulation of neurotoxicity. These results indicate that the immortalized human neural Surprisingly, results suggest that MMP-1 can cleave Tat and stem cells have great potential in clinical utility for cell ther- neutralize its toxicity. This study demonstrates a unique apy in human neurological disorders. Study supported by the viral-host interaction that may serve as an adaptive host de-

S70 Annals of Neurology Vol 56 (suppl 8) 2004 fense mechanism. Study supported by the National Institutes 323. Antiretroviral Exposure Is a Risk Factor for HIV- of Health, which awarded grants to Dr. A. Nath. Associated Sensory Neuropathies Justin C. McArthur, Jason Creighton, Richard Skolasky, Luxmi Lal, Richard Moore, Steven Wesselingh, and Katherine Cherry; Baltimore, MD and Melbourne, Victoria, Australia 321. Herpes Simplex Virus Type 1 Neurotropism BACKGROUND: Specific reverse transcriptase inhibitors Studies in Organotypic Brain Slices may provoke HIV-associated sensory neuropathies (SNs). Israel Steiner, Efrat Braun, and Amos Panet; Jerusalem, Israel METHODS: One hundred fifty-six HIVϩ adults under- HSV-1 is an important neurotropic pathogen. The cellular went standardized clinical/physiological assessments. PGP9.5 and molecular mechanisms responsible for HSV-1 dissemi- immunostaining quantified epidermal innervation. Antiretro- nation and infection throughout the nervous system are still viral exposure was assessed with multivariate analysis. RE- unclear. We have used organotypic cultures of mice brain SULTS: At JHU, 86% were black, 35% had a history of sections infected with HSV-1 to study HSV-1 neurotropism. IDU, and 71% were HepCϩ. At MU, 95% were white, Two HSV-1 mutants containing the LacZ gene under con- 92% had a history of MSM, and 11% were HepCϩ. trol of different exogenous promoters were used. No infec- HgbA1C levels were Ͼ5.8% in 23% at JHU and 12% at tion of brain parenchyma in 1-month-old mice was noted, MU (p ϭ 0.101). Thirty-three percent were neuropathy- and reporter gene expression was limited to cells underlining free, 18% had asymptomatic SNs, and 49% symptomatic the ventricular system and to peri-ventricular and ependymal SNs. The likelihood of having symptomatic SNs was strongly associated with use of ddI (OR ϭ 2.6, p ϭ 0.024) cell layers. Using the same viral mutants, we demonstrated ϭ ϭ very widespread expression of the reporter gene in the 1-day- or d4T (OR 5.1, p 0.002). Thermal and vibration old brain tissue. Brain slices from 1-week-old mice showed thresholds were measured with the Case IV device, and vi- intermediate permissiveness for HSV-1 infection. This pat- bratory QST was relatively insensitive to symptomatic SNs. tern differed from the one observed with adeno and vaccinia More morphological abnormalities on skin biopsy were viruses. Increasing the amount of HSV-1 used for infection noted in SN subjects, but 23% of neuropathy-free subjects enabled a more widespread infection. These findings suggest had abnormalities. CONCLUSIONS: The frequency of SNs that HSV-1 infects selectively only certain cell types in an was high and correlated strongly with exposure at anytime to age-dependent manner. Because HSV-1 encephalitis is ddI or d4T. Hepatitis C serostatus did not modify the prev- mainly a disorder of the mature brain, studies are underway alence of SNs at baseline. Morphological abnormalities were to delineate the parameters that render the adult brain sus- noted in a high proportion of neuropathy-free subjects. ceptible for HSV-1 infection. Study supported by the Chief Quantitative sensory testing had a low diagnostic efficiency in this cohort. Study supported by NS44807. Scientist, Ministry of Health and the Women’s Health Grants of the Hadassah Medical Organization. Dr. Efrat Braun is an ICRF fellow.

REHABILITATION, REGENERATION, AND RECOVERY

322. Propagation of Archetype JC Virus in Primary 324. Effect of Testosterone on Functional Recovery in Cultures of Non-Neural Cells the Castrate Male Rat Stroke Model Frank J. O’Neill, John E. Greenlee, and Larry W. Kraiss; Yi Pan, Haibo Zhang, Aninda B. Acharya, Ping H. Patrick, Salt Lake City, UT and John E. Morley; Saint Louis, MO JC virus, the agent causing PML, exists in two forms. Arche- Both decreased and increased testosterone levels have been type JCV, the virus that is transmitted in nature and persists reported to correlate with poor outcome after acute ischemic in kidneys, is characterized by an unrearranged regulatory re- stroke. The present study focused on testosterone in the re- gion. In contrast, virtually all PML-associated strains of JCV covery of neurological deficits in a rat focal ischemia model. are variant strains, having regulatory region duplications or Fourteen castrate male rats were subjected to behavioral tests alterations and often having coding region changes. We have after 90-min middle cerebral artery occlusion (MCAO). On recently demonstrated that archetype JCV can be grown in day 7 post-MCAO, neurological-deficit-matched rats were primary culture of human fetal brain (HFB) cells (J. Neuro- implanted with two subcutaneous testosterone pellets (and virol., 9: 567–576, 2003). In the current study, we deter- assigned to the testosterone group, n ϭ 7) or implanted with mined whether the archetype could also be grown in cells of two sham pellets (and assigned to the control group, n ϭ 7). systemic origin. Primary cultures of human fetal kidney Total mean testosterone was 122.29 Ϯ 25.92 ng/dL in the (HFK) cells and umbilical vein endothelial cells were trans- treatment group, but not detectable in the control group by fected with the JCV archetype and evaluated for cytopathic radioimmunoassay. After 4 weeks post-MCAO, rats showed effect and for cells expressing early or late JCV antigens. In- significant improvement in neurological deficits, shortening fected HFK and endothelial cultures both contained increas- the latency of adhesive tape removal, and walking on parallel ing numbers of cells positive for JCV antigens, and lysates of bars in the testosterone group, but not in the control group both cultures caused productive infection when passaged into (per non-parametric Wilcoxon signed-rank test). The average HFB cells, proving viral replication. The ability to grow the infarct volume involved 9.84% of the right hemisphere in JCV archetype in both neural and non-neural cultures sys- the testosterone group and 10.51% of that in the control tems should allow studies of pathogenic mechanisms leading group (no statistical difference). In conclusion, replacement to development of variant JCV strains and to onset of PML. of testosterone post-MCAO showed significantly early func- Study supported by the United States Department of Veter- tional recovery in castrate rats, suggesting a potential thera- ans Affairs. peutic role for testosterone replacement in stroke recovery.

Program and Abstracts, American Neurological Association S71 325. Predictors of a Successful Driver Evaluation after cle in spastic hemiplegia. METHODS: As part of a con- Discharge in a Stroke Patient trolled trial comparing three injection techniques of BTX-A Laureen Smith-Arena, Steven Lee, Dawn Geoghegan, in spasticity, we used the Modified Frenchay Scale to assess Tosun Hilal, and Meheroz H. Rabadi; White Plains, NY 20 hemiplegic patients before and 1 month after an injection One of the most common concerns of a stroke patient is the of 160 units of BTX-A (Botox) into spastic biceps brachii. ability to drive. We aimed to determine which variables on Subjects were videotaped performing four unimanual and six an acute rehabilitation admission evaluation predict the like- bimanual upper limb activities (picking up a cup, using a lihood of a successful driver evaluation after discharge. Forty- comb, etc.). A blinded reviewer rated the performances on a five stroke patients undertook a driver evaluation at our in- visual analog scale from 1 to 10. RESULTS: Functional per- stitution. The male/female ratio was 29/10. The mean formance was significantly enhanced by a mean of 5% (p ϭ (ϮSD) age was 71.0 Ϯ 9.8 years, the Mini-Mental State 0.015; paired t-test). Mean improvement was 9% on uni- Examination (MMSE) score was 22.7 Ϯ 8.1, the upper ex- manual tasks (p ϭ 0.06) and 2% on bimanual tasks (NS). tremity and lower extremity motoricity index (MI) scores Individual task analysis showed significant improvement in were 63.7 Ϯ 34.8 and 71.8 Ϯ 24.3, the Limb placement three tasks (p Ͻ 0.05), two of which were unimanual reach- Task (LPT) was 4.6 Ϯ 3.6 inches, and the admission Total ing movements. CONCLUSION: A single injection of Functional Independence Measure (TFIM) was 68.5 Ϯ 18. BTX-A into biceps brachii was associated with upper limb The admission variables differed between those who failed functional improvements in hemiparetic patients, particularly (n ϭ 10) versus those who passed the in-clinic driver evalu- ϭ Ϯ Ϯ in unimanual reaching activities. Functional scales using ation (n 29): MMSE scores: 17.5 9.7 SD vs. 24.6 blinded video assessments may be useful for detecting 6.7 (p ϭ 0.004); upper extremity MI scores: 82 Ϯ 23.7 SD Ϯ ϭ changes after intervention in hemiplegia. Study supported by vs. 57.4 36.1 (p 0.05); and lower extremity MI scores: Allergan. Jean-Michel Gracies received a research grant and 87.6 Ϯ 11.8 SD vs. 66.4 Ϯ 25.2 (p ϭ 0.01). Twenty-nine speaking honoraria from Allergan. David M. Simpson re- patients passed the in-clinic (75%) driver evaluation. Patients who undertook the driver evaluation had a mild stroke on ceived a research grant and speaking honoraria from Aller- admission. Those who passed in-clinic driver evaluation had gan. a higher admission MMSE score.

326. Impact of Falls Prevention Strategies in Stroke Patients Admitted to an Acute Rehabilitation Unit 328. Aligned Nanofibers Support Neuronal Growth Meheroz Hoshang Rabadi, Hilal Tosun, and and Directionally Guide Neurites Margaret Peterson; White Plains, NY and New York, NY Joseph M. Corey, David S. Lin, David C. Martin, and In this study, the objective was to determine the incidence of Eva L. Feldman; Ann Arbor, MI falls in stroke patients who were admitted to an acute reha- Surgical repair of transected nerves is dependent on au- bilitation unit that used current falls risk screening and pre- tografts that produce morbidity and are often insufficient in ventive strategies. Of 754 patients, 361 were males and 393 number or size. Contemporary nerve guides possess growth were females. The mean age (SD) was 70 (13) years. There factors and extracellular matrix, but lack topography to im- were 159 fall incident reports in 117 patients reported (0.21 part directional cues. We hypothesized that biodegradable fi- falls per patient). The falls incidence rate was 8.2/patient bers with diameters on the cell-length-scale will not only days. The most frequent fall location was the patient’s own provide structure for regenerating neurons, but will also exert room (n ϭ 111, 72%), followed by the bathroom/toilet ϭ directional influence on neurite growth. Scaffolds of aligned (n 24, 15%). No injury was observed in 139 of 159 fall fibers with diameters of 200–1500 nm were fabricated by cases (87%). In 13 cases (8%), there were only minor inju- electrospinning poly-L-lactide (PLA) on a rotating target. ries (bruises, soft tissue tenderness, or minor wounds requir- ing no sutures). Three falls (2%) resulted in serious injuries SH-EP neuroblastoma cells were plated on PLA scaffolds or needing acute hospital transfer. Most of the falls (n ϭ 67, glass, fixed, and stained for actin. Primary dorsal root ganglia 42%) occurred during the patient’s first week of hospital (DRG) explants were cultured on scaffolds or glass coated stay. Current falls risk prevention strategies on a stroke reha- with collagen I, fixed, and stained for neurofilament. SH-EP bilitation unit were associated with 8.2 falls per patient days, cells grown on scaffolds exhibited aligned stress fibers and and 10% sustained minor and major injuries. Most falls oc- elongated cell bodies, whereas cells on glass had randomly curred in the first week, and in the patient’s own room. oriented stress fibers and were well spread. On glass, DRG neurites radiated from the explants in all directions, but those on scaffolds turned from their initial orientation to fol- 327. Functional Changes in the Hemiplegic Upper low PLA fibers. Neurites also grew farther on PLA fibers Limb after Botulinum Toxin Type A Injection into One than on glass. These experiments demonstrate that nanofi- Elbow Flexor: Single-Blind Study bers can effectively guide neurites and align neuronal cells. Jerry Y. Chao, Steve Flanagan, David M. Simpson, and Study supported by NIH T32 NSO7222, NIH NINDS- Jean-Michel Gracies; New York, NY N01-NS-1-2338, and NSF DMR-0084304. OBJECTIVE: Evaluate functional changes after botulinum toxin type-A (BTX-A) injections in a single upper limb mus- DOI: 10.1002/ana.20255

S72 Annals of Neurology Vol 56 (suppl 8) 2004