001_170_Suppl_II_05_JON 31.05.2005 14:58 Uhr Seite 95
`
`J Neurol (2005) 252 [Suppl 2]: II/95–II/170
`DOI 10.1007/s00415-005-2003-5
`
`study will assess the frequency and severity of ISRs associated with these
`treatments in patients with relapsing-remitting MS.
`BRIGHT is a multicentre, international, non-randomised, prospective
`study with two treatment arms: 250 mcg IFNB-1b sc eod and 44 mcg IFNB-
`1a sc tiw. Patients entering BRIGHT must have started treatment within 3
`months prior to recruitment, and completed the titration phase. Use of an
`autoinjector is recommended, but manual injection is also acceptable. In-
`jections will be administered by the patient, and the self-assessed severity
`of pain recorded for 15 consecutive injections using a 0–100 mm visual
`analogue scale diary immediately after injection, and 30 and 60 minutes
`post-injection. Patients will also rate the quality of pain after the 1st, 7th and
`15th injections using the McGill pain questionnaire. The occurrence and
`severity of ISRs will be determined using a 4-point categorical scale. In-
`terim data will be presented.
`The BRIGHT study will determine the influence of ISP on patient sat-
`isfaction with therapy and highlight any differences in ISRs and severity of
`pain between the two high-dose, high-frequency IFNB treatments in a rou-
`tine clinical setting.
`
`P353
`Prolactin and multiple sclerosis
`M. Paschalidou, M. Gelagoti, T. Afrantou, S. Birka, E. Mamaloukas, E.
`Vafeiadou, I. Giovos, N. Taskos, I.Milonas
`Aristotle University of Thessaloniki (Thessaloniki, GR)
`
`Introduction: Prolactin is a mammotropic neuropeptide produced by the
`pituitary and extrapituitary cells and has potent immunomodulating
`properties.
`Aim: To investigate the possible correlation of prolactin with MS forms
`and activity.
`Patients-Methods: 33 females (mean age 34) and 7 males with MS
`(mean age 34) were studied.
`Males: mean EDSS: 3.6, Relapsing-Remitting: 4, and Secondary-Pro-
`gressive: 3.
`Females: mean EDSS: 3.2, Relapsing-Remitting: 20 and Secondary-Pro-
`gressive: 13.
`We divided female patients in two groups:
`Group 1: Relapse, n = 13
`Group 2: Remission, n = 20
`
`Prl was measured in serum using immunoradiometric assay (IRMA) be-
`fore steroid administration in the relapsed patients.
`Results: Prl levels in females range from 93–1104 mIU/l (normal lev-
`els = 64–395 mIU/l) compared to males from 144–503 mIU/l (normal
`range = 78–380 mIU/l). Two men had PRL levels higher than normal. In fe-
`males the results in the two groups were: Group 1: mean Prl level = 401.69
`mIU/l and Group 2 = 368.5 mIU/l.
`We did not find any correlation between Prl levels and disease type,
`EDSS, duration disease, and patient age. Thirteen of the females had Prl
`levels higher than normal. Three of them, with PRL levels ranging from
`1026–1104 had severe episodes of bilateral optic neuritis.
`Conclusions: The high levels of Prl in women on exacerbation may sug-
`gest its effect in the disease activity. Whether this effect is primary or sec-
`ondary, cannot be easily confirmed. Prl, a hormone of the hypothalamopi-
`tuitary axis with immunomodulatory properties, could affect the disease
`characteristics. In patients with visual disturbances, their symptoms may
`be connected with lesions close to hypothalamus.
`
`Poster session 3
`
`Cerebrovascular disorders
`
`P354
`Assessment of endothelial dysfunction in acute stroke patients: a clinical
`and laboratory study
`M. Mostafa, N. Adel, I. Fahmy, H. Gabr, Y. Baghdady
`Cairo University (Cairo, EGY)
`
`The endothelium plays an integral part in the atherosclerotic process and
`the occurrence of thrombotic and ischaemic events in the vascular system.
`vWF (von Willebrand Factor) and t-PA (tissue plasminogen activator) are
`haemostatic markers reflecting endothelial function.
`
`II/95
`
`Objective: The present study was designed to assess endothelial func-
`tion in acute ischaemic stroke patients by estimating the levels of certain
`haemostatic markers in serum, and to investigate the possible relationship
`of these markers to demographic, clinical and imaging data.
`Subjects and Methods: 50 patients with acute ischaemic stroke and 27
`matched controls were included in this study. All participants were sub-
`jected to careful clinical evaluation, laboratory work-up and neuroimaging
`of the brain.
`Results: Mean vWF level was significantly higher and mean t-PA level
`was significantly lower in stroke patients compared to controls (p = 0.02,
`0.001 respectively). Significantly higher vWF levels and lower t-PA levels
`were also detected among smokers and diabetics of the patient group as
`compared to those of the control group. Significant increase in vWF and
`decrease in t-PA levels were observed as the number of risk factors for ath-
`erosclerosis increases in the patient group (p = 0.03, 0.002 respectively). No
`significant correlation was found between vWF and t-PA levels and prog-
`nosis of stroke. Levels of vWF and t-PA differed significantly between
`stroke patients and controls regardless of the presence or absence of risk
`factors, which indicates that vWF and t-PA can be considered as indepen-
`dent risk factors for cerebrovascular ischemic events.
`In conclusion: vWF and t-PA are useful haemostatic markers reflecting
`endothelial function in ischemic stroke patients and predicting occur-
`rence of future thrombotic events.
`
`P355
`Carotid duplex studies in young strokes with a prothrombotic state
`D. Khurana, V. Lal, G. Grewal, S. Prabhakar
`PGIMER (Chandigarh, IND)
`
`Prothrombotic states like protein C deficiency, protein S deficiency, an-
`tithrombin deficiency, the antiphospholipid antibody syndrome, factor V
`Leiden and hyperhomocysteinemia has been implicated in the etiology of
`young strokes. These, however, are responsible only for a minor population
`(~4–6 %). The occurrence of carotid lesions in young strokes is of low
`prevalence.
`Aims and Objectives: To prospectively determine the incidence of
`carotid/vertebral artery disease in patients of young stroke with a pro-
`thrombotic state.
`Methods: Patients were recruited from the young strokes attending the
`Neurology outpatient at PGIMER, Chandigarh who were found to be
`positive for one or more prothrombotic states viz. Protein C, Protein S or
`Antithrombin deficiency, Antiphospholipid antibody syndrome, Lupus
`anticoagulant positive, Factor V Leiden positive or hyperhomocystein-
`emia. Carotid duplex studies were carried out on these patients which in-
`cluded B-mode, color and pulsed doppler studies.
`Results: 186 young stroke patients have been enrolled till December
`2004. 63 (33.8 %) patients have been found to be positive for either one or
`more of the prothrombotic states. 13 patients (20.63 %) have some abnor-
`mality in the carotid duplex studies. 6 patients (46.15 %) had Protein S de-
`ficiency only, 1 (7.69 %) patient had Protein C deficiency only, 2 (15.38 %)
`patients were deficient in both Protein C and Protein S, 3 (23 %) patients
`were positive for Lupus anticoagulant whereas 1 patient was positive for
`both Lupus anticoagulant and Anticardiolipin antibodies.
`Conclusions: 1. Carotid atherosclerosis is an important contributor to
`strokes of prothrombotic origin. 2.Protein S Deficiency appears to be the
`most common abnormality to be associated with abnormal carotid duplex
`findings. 3.These findings could help in formulating an effective screening
`strategy to search for prothrombotic states in young strokes.
`
`P356
`Dissection of the vertebral artery presenting with C5 radiculopathy
`M. Hardmeier, S. Haller, E. W. Radue, A. Steck, P. Lyrer, S. Engelter, S. Renaud
`University Hospitals Basel (Basel, CH)
`
`Background: Flaccid paresis of C5 innervated muscles may be due to idio-
`pathic brachial plexopathy or to compression of the C5 nerve root by
`spondylopathy or discopathy. We describe a case of vertebral artery dis-
`section (VAD) causing C5 radiculopathy and give a review of the literature.
`Case report: A 52-year-old male was referred for evaluation of proximal
`weakness of the left arm. Ten days before he fell onto his right side getting
`some bruises at the lateral chest. Thereafter he developed some pain in the
`neck on the left side, responding to Ibuprofen. Three days later he could
`neither elevate nor rotate the left shoulder. He had no pain and no sensory
`deficit was noted. Preceding infection was denied. The patient received
`vaccination for polio and hepatitis three months before.
`On admission he presented with severe weakness of m. deltoideus
`(M2), m. suprascapularis (M2), m. infraspinatus (M2) and m. biceps
`
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`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 with
`active MS patients as compared to patients in remission.
`Conclusion: Our data show that the diurnal rhythmicity of immuno-
`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.
`
`randomized to receive BG00012 120 mg PO once daily (120 mg/day),
`120 mg PO three times daily (360 mg/day), 240 mg 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 of BG00012. 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-
`ondary MRI 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 T1-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.
`
`P573
`Glatiramer acetate induces pro-apoptotic mechanisms involving Bcl-2,
`Bax and Cyt-c in peripheral lymphocytes from multiple sclerosis patients
`M. Ruggieri, C. Avolio, S. Scacco, C. Pica, A. Lia, G. B. Zimatore, S. Papa, P.
`Livrea, M. Trojano
`University of Bari, University of Foggia (Bari, Foggia, I)
`
`P575
`A helper dependent adenovirus efficiently delivers bioactive FGF-II to the
`CNS
`E. Butti, C. Porcheri, A. Bergami, E. Brambilla, A. Cattalini, A. Recchia, A.
`Stornauiolo, F. Mavilio, G. Martino, R. Furlan
`San Raffaele Scientific Institute (Milan, I)
`
`Apoptotic deletion of autoreactive T-cells is defective in patients with Mul-
`tiple Sclerosis (MS). Glatiramer 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-
`1 were quantified by western blot followed by densitometric scanning and
`Bax/Bcl-2, cytosolic Cyt-c/Bcl-2 and APAF-1/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-c/Bcl-2 ratio showed a trend to increase
`during 9 months of GA treatment in MS patients.An increase of 85 % 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. Kappos, D. Miller, R. Gold, E. Havrdova, C. Polman, V. Limmroth, G.
`O’Neill, R. Conaghan
`University Hospitals Basle, Institute of Neurology, University of Goettin-
`gen, General Teaching Hospital Prague, VU Medical Centre, University
`Hospital Essen, Biogen Idec (Basle, CH; London, UK; Goettingen, D;
`Prague, CZ; Amsterdam, NL; Essen, D; Cambridge, USA)
`
`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-enhancing (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.
`Design: 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 5.0. In addition, patients must have either experi-
`enced at least 1 relapse within 12 months prior to randomization with le-
`sions on cranial MRI consistent with MS, or had Gd+ lesions on a cranial
`MRI performed within 6 weeks of randomization. Eligible patients were
`
`We tested a FGF-II-expressing HD-Ad vector called STK120-GFP-FGFII in
`naïve 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 STK120-GFP-FGFII; control mice re-
`ceived the “empty”STK120-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
`immunochemistry and counted BrdU positive cells near the lateral ventri-
`cles. STK120-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. Ko, G. Katsamakis, D. Stefoski, J. Shammo, S. 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 dehydrogenase mediated resistance of HSCs
`to CYP allows for reconstitution of a potentially advantageous naïve 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 µg/kg/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, glucocorticoids, and three courses of IV CYP (1000 mg/m2).
`Immunoablation resulted in leukopenia (WBC trough of 44 x 106/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.
`
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