`
`Questions and dilemmas related
`immunoglobulin (lV|g) in I'IeUr0l0gII.dI urseases
`Satellite Symposium at the 14”‘ Meeting of the European Neurological Society.
`Barcelona, Spain, June 26—30, 2004
`
`ous
`
`Preface
`
`N. Misra, J. Bayry, A. Ephrem, 5. Dasgupta, S. Delignat,
`J.-P. Duong Van Huyen, F. Prost, S. Lacroix—Desmazes, A. Nicoletti.
`M. D. Kazatchkine, S. V. Kaveri
`Intravenous immunoglobulin in neurological disorders:
`a mechanistic perspective
`E. Nubile-Orazio, F. Terenghi
`M9 in idiopathic autoimmune neuropathies: analysis
`in the light of the latest results
`
`II
`
`1
`
`7
`
`I. Illa
`M9 in myasthenia gravis, Lambert Eaton myasthenic
`syndrome and inflammatory myopathies: current status
`M. C, Dalakas
`The role of M9 in the treatment of patients with stilf person
`syndrome and other neurological diseases associated with
`anti-GAD antibodies
`
`M
`
`19
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`16‘l9-8ODx(20050S)252:5+‘l;‘l—Y
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`STEINKOPFF
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`.*.~.1_.m;
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`Page 1 °f 6
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`® S
`— P
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`g
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`AVa]/0b/e
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`0” /"79
`www. springerlink. com
`
`‘
`
`Online edition in SpringerLink — Medicine Gnlinel
`
`www.springerlink.com
`Indexed in ISI.
`lndexMedicus, and EMBASE
`Abstracted in Core Journals in Clinical Neurology
`252 [Suppl ‘El I/l—|/26 (2005) May
`Printed on acid—free paper
`
`.
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`_
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`Biogen Exhibit 2062
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`Biogen Exhibit 2062
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`Page 2 of 6Page 2 of 6
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`
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`
`
`
`J Neural i2005) 252 [Suppl 2]: W1 —|l/51
`D0] 10.1007/S00415~005-2001-7
`
`Fifteenth Meeting of the
`European Neurological Society
`18-22 June 2005, Vienna, Austria
`
`Symposia and Free Communications
`
`The abstracts have been reviewed by:
`Z. Argov, V. Dietz, M. Donaghy, C. Elgar, F. Fazekas, I. M. Fcrro,
`C. Krarup, M.~H. Marion, I. Milonas, G. Moonen, E. Nobiic-Omzio,
`V. Planté-Bordeneuvc, G. Said, R. Soffictti, A. Stock, E. Tolosa,
`I. Vails-Soié, Y. von Crnmon
`
`Page 4 of 6
`
`
`
`II/2
`
`
`
`Contents
`
`Presidential symposium
`Advances in multiple sclerosis
`
`I1/3
`
`Symposia
`Imaging the human mind II/4
`Cell and gene therapy II/5
`Controversies in neurology II/6
`
`Session 9oo<$\U1>J>wN>—-
`
`FREE COMMUNICATIONS
`Oral Sessions
`Session
`:Cerebrovascular disorders 1
`Session
`:Cerebrovascular disorders 2
`Session
`:Clinical neurophysiology 1
`Session
`: Clinical neurophysiology 2
`Session
`:Epilepsy 1
`II/14
`Session
`:Epilepsy2
`ll/15
`Session
`11/17
`:Motor neuron disease 1
`Session
`: Motor neuron disease 2 H118
`:Multiple sclerosis 1
`11/20
`Session 10:
`Multiple sclerosis 2
`11/22
`Session 11:
`Muscle and neuromuscnlar junction disorders
`Session 12:
`Muscle disorders 2
`11/25
`Session 13:
`Cerebrovascular disease 3
`II/26
`Session 14:
`Cerebrovascular disease 4
`II/28
`Session 15:
`Extrapyramidal disorders 1
`II/29
`Session 16:
`Extrapyramidal disorders 2
`IIl3l
`Session 17:
`Neuro-ophthalmology and vestibular disturbance
`Session 18:
`Infections of the nervous system II/34
`Session 19:
`Neurogenetics 1
`11/35
`Session 20:
`Neurogenetics 2
`11/37
`Session 21:
`Multiple sclerosis 3
`11/38
`Session 22:
`Multiple sclerosis 4
`11/40
`Session 23:
`Higher function disorders 1
`Session 24:
`Higher function disorders 2
`Session 25:
`Multiple sclerosis 5
`11/45
`Session 26:
`Peripheral neuropathy II/47
`Session 27
`:Neuro—oncology
`II/49
`
`II/8
`11/10
`11/11
`III 12
`
`11/41
`11/43
`
`II/23
`
`II/32
`
`Epilepsy II/55
`Generalneurology II/58
`Genetics
`I1/59
`Headache HI60
`I1/62
`Multiple sclerosis
`Neurobiology II/66
`Neuro—onc0logy II/68
`Neuro-ophthalmology II/70
`Rehabilitation II/72
`
`II/74
`
`Poster session 2
`Cerebrovascular disorders
`Epilepsy II/79
`General neurology I1/82
`Genetics
`II/85
`Infection Il/86
`II/88
`Motor neuron disease
`Multiple sclerosis
`II/90
`Poster session 3
`Cerebrovascular disorders
`Extrapyramidal disorders
`General neurology II/101
`Headache
`II/103
`Higher function disorders
`Multiple sclerosis
`II/ 108
`Neurophysiology II/113
`Poster session 4
`Cerebrovascular disorders
`Extrapyramidal disorders
`General neurology Il/122
`Higher function disorders
`Multiple sclerosis
`II/126
`Muscle disorders
`11/132
`Peripheral neuropathy II/134
`Poster session 5
`Cerebrovascular disorders
`Neurophysiology II/142
`Eirtrapyramidal disorders
`Multiple sclerosis
`II/146
`Muscle disorders
`I1/149
`Pain
`II/153
`Peripheral neuropalhy II/154
`Sleep disorders
`II/158
`
`II/95
`II/98
`
`11/105
`
`III 1 15
`II/119
`
`11/125
`
`II/137
`
`lll144
`
`Abstracts for Foster Sessions
`Poster Session 1
`Child neurology II/S1
`Cerebrova
`scular disorders
`
`II/53
`
`P
`
`age5 of6
`
`Author index
`
`I1/160
`
`Page 5 of 6
`
`
`
`II/148
`
`creased cortisol serum levels at all five time points as compared to MS pa-
`tients in remission. TNFR-1 as well as TNFR-2 levels followed a less marked
`(p < 0.05) descending course over the day in all groups. MS patients with
`Gd-enhancement had again significantly (p < 0.05) elevated levels for
`TNFR-1 but not for TNR-2 as compared to healthy donors. In contrast, IL-
`4—R and TNF-beta serum Concentrations were relatively stable over the day.
`Both MS groups had significantly (p < 0.05) elevated TNF-beta serum lev-
`els at any time point as compared with the control group. Moreover, the
`TNF-beta serum levels were further (p < 0.05) increased in the group Wll'.l1
`active MS patients as compared to patients in remission.
`‘
`_
`Conclusion: Our data show that the diurnal rhythmicity of.immur1o-
`logical markers must be Considered in at least some of the investigated im-
`munological markers. We could not observe a substantial difference in the
`circadian rhythmicity between MS patients and healthy donors. However,
`the increase of cortisol serum levels in MS patients with active disease
`shows that MS disease activity has an at least indirect influence on the cir-
`cadian rhythmicity.
`
`P573
`Glatiramer acetate induces pro-apoptotic mechanisms involving Bcl—2,
`Bax and Cyt-c in peripheral lymphocytes from multiple sclerosis patients
`M. Ruggieri, C. Avolia, S. Scaccu, C. Pica, A. Lia, G. B. Zimatore, S. Papa, P.
`Livrea, M. Trojario
`University of Bari, University of Foggia (Bari, Foggia, I)
`
`Apoptotic deletion of autoreactive T—cells is defective in patients with Mul-
`tiple Sclerosis (MS). Glatlramer Acetate (GA) treatment seems to restore
`apoptosis of detrimental T-cells.We analyzed the mitochondria membrane
`pro- (Bax) and anti-apoptotic (Bcl-2) and cytosolic pro-apoptotic (Cyt-c,
`APAF—1) proteins expression in peripheral lymphocytes from RR MS pa-
`tients during GA treatment. Blood samples from 8 RR MS patients, before
`and every three months during 9 months of GA treatment, and from 8
`healthy controls (HCs) were collected. PBMNC Bcl—2, Bax, Cyt-c and APAF-
`l were quantified by western blot followed by densitometric scanning and
`Bax/Bcl—2, cytosolic Cyt-c/Bcl-2 and APAF—l/Bcl—2 ratios were calculated.
`The percentage of apoptotic cells was assessed by a dye exclusion test. T-
`cells were in vitro tested for oxygen consumption by a respirometric analy-
`sis. Bax/Bcl—2, cytosolic Cyt-c/Bcl-2 and APAF-1/Bcl—2 ratios in untreated
`MS patients were significantly (p < 0.05) lower than in HCs. Bax/Bcl—2 ra-
`tio increased (p = 0.03) and Cyt-cIBcl—2 ratio showed a trend to increase
`during 9 months of GA treatment in MS patients. An increase of85 % in the
`rate of apoptotic PBMNCS was observed during treatment. A reduction by
`58 % in oxygen consumption by T—cells was evident after GA treatment in
`vitro. Our findings suggest that GA exerts a regulatory effect on peripheral
`T lymphocytes through pro—apoptosis mechanisms involving mitochon-
`dria and cytosolic proteins.
`
`P574
`
`A randomised, placebo-controlled phase II trial of a novel oral single-
`agent fumarate therapy, BG00012, in patients with relapsing—remitting
`multiple sclerosis
`L.’Ku‘ppas, D. Miller, R. Gold,
`O Aleill, R. Conughurt
`University Hospitals Basle, Institute of Neurology, University of Goettin-
`gen, Ceneral Teaching Hospital Prague, VU Medical Centre, University
`Hospital Essen, Biogen Idec (Basle, Cl-I; London, UK; Goettingen, D;
`Prague, CZ; Amsterdam, NL; Essen, D; Cambridge, USA)
`
`Havrdova, C. Polmmi, I/I Limmroth, G.
`
`Objective: To determine the efficacy and safety of a novel single-agent oral
`fumarate therapy, BG00012, in patients with relapsing-remitting multiple
`sclerosis (RRMS).
`Background: An open-label pilot study demonstrated that a product
`containing a mixture of fumaric acid esters significantly reduced the num-
`ber and volume of gadolinium-enliancing (Gd+) lesions in patients with
`RRMS. BG00012 is being investigated for the treatment of psoriasis and
`other autoimmune diseases, including MS. This phase II study was de-
`signed to evaluate the efficacy of three doses of BG00012 on brain lesion
`activity as measured by magnetic resonance imaging (MRI) in patients
`with RRMS.
`Designt This is a randomized, double-blind, placebo-controlled, phase
`II study being conducted at 45 clinical centers in Europe. Patients were in-
`cluded in the study if they were between 18 and 55 years of age, had a def-
`inite diagnosis of RRMS, and an Expanded Disability Status Scale (EDSS)
`score between 0.0 and
`In addition, patients must have either experi_
`enced at least.1 relapse within 12 months prior to randomization with le-
`iififis on cranial lVl.Rl.C01'lSlStEnt with MS, or hag Gd+ 15510115 on a cranial
`performed within 6 weeks of randomization. Eligible patients were
`
`randomized to receive BG00012 120 mg PO once daily (120 mg/day),
`120mg PO three times daily (360 mg/day), 240mg PO three times daily
`(720 mg/day), or placebo. The study consists of 2 phases: a 24-week dou-
`ble-blind treatment phase followed by a 24-week, blinded, safety-extension
`phase in which all patients will receive some level ofBG00012. The primary
`endpoint is the total number of Gd+ lesions over four MRI scans at weeks
`12, 16, 20, and 24 (calculated as the sum of these four MRI scans). Sec-
`ondaryMRl endpoints include the cumulative number of new Gd+ lesions
`and the number of new or newly enlarging T2-hyperintense lesions at week
`24 compared with baseline. Additional endpoints include: the number of
`new Tl-hypointense lesions at week 24 compared to baseline, safety and
`tolerability, disability progression as measured by EDSS, relapse rate, and
`proportion of relapse-free patients.
`.
`Results: This paper will present details of the study design, as well as
`the baseline demographic and clinical characteristics of enrolled patients.
`Conclusions: This dose-ranging study will determine the efficacy of
`BG00012 on brain lesion activity in patients with RRMS.
`
`P575
`A helper dependent adenovirus efficiently delivers bioactive FGF-II to the
`CNS
`E. Butti, C. Porcheri, A. Bergami, E. Brambilla, A. Catralirii, A. Recchiu, A.
`Stornauiolo, F. Mavilio, G. Martino, R. Furlan
`San Raffaele Scientific Institute (Milan, 1)
`
`We tested a FGF-II-expressing HD-Ad vector called STK120—GFP-FGFII in
`naive mice focusing on the ability of FGF-II to induce stem cells prolifera-
`tion and migration. We injected naive C57BL/6 mice in the cisterna magna
`with 10/\8 transducing unit (t. u.) of STKl20-GFP—FGFII; control mice re-
`ceived the “empty” STKI 20-GFP vector. Mice were sacrificed at 7, 14, 21 and
`28 days post injection. We administered BrdU to the mice to mark all pro-
`liferating cells. Preliminary analysis showed ventricular enlargement in
`STK120-GFP—FGF-II-injected mice; this was evident one week post injec-
`tion and persisted 4 weeks thereafter. We then performed BrdU staining by
`imniunochemistry and counted BrdU positive cells near the lateral ventri-
`cles. STKl20-GFP-FGFII-injected mice displayed a three-fold increase in
`BrdU positive cells as compared to control mice. This increase was already
`present one week after the treatment, and persisted at 2 and 3 weeks after
`injection, but disappeared 4 weeks after vector administration.
`
`P576
`Immunoablation using cyclophosphamide Without haematopoietic stem
`cell rescue for refractory multiple sclerosis
`M. K0, G. Katsamakis, D. Stefaski, I. Shammo, 5. Gregory
`Rush University Medical Center (Chicago, USA)
`
`Objective: To assess safety and efficacy of very high dose cyclophos—
`phamide (CYP) without hematopoietic stem cell (HSC) rescue for in-
`tractable multiple sclerosis (MS), as a realistic substitute for autologous
`HSC transplantation.
`Background: Immunoablation without HSC rescue has been beneficial
`in other autoimmune diseases (eg, CIDP, SLE, myasthenia gravis) and may
`thus be a viable therapeutic option for intractable MS. No such data have
`been published. The aldehyde dehydrogenasc mediated resistance of HSCS
`to CYP allows for reconstitution of a potentially advantageous na'i've im-
`mune system.
`_
`Study Design: We initiated an IRB-approved study of ten patients with
`intractable MS, defined as having recurring relapses, worsening clinical
`deficits, and frequent contrast—enhancing lesions on MRI over 6 to 12
`months in spite of conventional therapies with immunomodulators and
`immune suppressants. Patients will receive immunoablative doses of CYP
`200 mg/kg divided over 4 days, similar to previously published studies. On
`day 10, patients will start granulocyte-colony stimulating factor (G-CSF,
`5 iiglkg/day), until the absolute neutrophil count (ANC) rises to 0.5 X
`10/\9/L for 2 days. Following immunoablation, clinical, EDSS, laboratory
`and MRI follow—ups will occur at three to six month intervals over one year.
`Case .Report:‘A 23-year-old woman with relapsing MS for 3 years pre-
`sented with ataxia, cognitive and behavior decline, and increasing burden
`of gadolinium enhancing lesions on serial brain MRIs. She had failed in-
`terferon-beta,‘gluc0corticoids, and three courses of IV CYP (1000 mg/ml).
`Immunoablation resulted in leukopenia (WBC trough of 44 x 105/L by day
`11), and was > 0.5 x 109/L by day 15 (day 6 of G-CSF). No new neurologic
`symptoms or signs developed during and after the treatment period. We
`will show detailed longitudinal clinical,MRI, and laboratory metrics from
`this first in the series of our study subjects.
`Conclusion: To our knowledge, this is the first published report of im-
`munoablation in recalcitrant MS using high dose CYP without HSC rescue.
`
`Page 6 of 6
`
`