AAN Meeting: Multiple Sclerosis Abstracts (Apr 13-20, Denver)

[Wise Young]

Abstracts

[Wise Young]

[P06.083] Gabapentin in the Treatment of Tremor in Multiple Sclerosis
Charles T. Bakhos, Mazen G. Jabre, Katia G. Habib, Raymond Chemaly, Boulos-Paul W. BejjaniÂ*HDF, Beirut, Lebanon; Byblos, Lebanon
OBJECTIVE: To assess the efficacy and tolerability of gabapentin in the treatment of tremor in multiple sclerosis.
BACKGROUND: Cerebellar tremor in multiple sclerosis is a disabling symptom, which rarely responds to pharmacological treatment. Gabapentin proved effective in essential tremor and in reducing spasticity in multiple sclerosis. The presence of abnormal utterances of GABAergic pathways in cerebellar tremor favors the consideration of gabapentin in the management of tremor in multiple sclerosis.
DESIGN/METHODS: In this 14-week, prospective, single-blind, crossover, placebo controlled study, five multiple sclerosis patients with cerebellar tremor were randomly assigned to either gabapentin or placebo over six weeks with a two-week washout period. Patients were scored at baseline and at after six weeks of treatment using the Tremor Clinical Rating Scale. Evaluations were respectively performed at 1600 mg, 2400 mg of gabapentin or placebo.
RESULTS: Two patients withdrew prematurely, mostly because of adverse experiences (worsening hypotonia and somnolence). After 2 and 6 weeks of gabapentin therapy, the improvement of the Tremor Clinical Rating Scale score in the remaining three patients was not clinically significant from baseline score (17% and 21%, respectively) or placebo effect (18.5% after both periods). Nevertheless, two patients reported a marked functional improvement when on gabapentin therapy. Most reported adverse events were at 2400 mg of gabapentin and included: somnolence, increased appetite and improved sexual performances.
CONCLUSIONS: Gabapentin was not clinically effective in the treatment of tremor in multiple sclerosis despite the reported functional gain in some patients. Disease stage, progression rate and extend of cerebellar damage can highly influence gabapentin effect. A larger controlled study is warranted to confirm our findings.
Category - MS and Related Diseases
SubCategory - Therapeutic Trials

[Wise Young]

[P03.083] Functional MRI and Neural Activation Patterns Associated with Recognition Memory Performance in Multiple Sclerosis
Lorri J. Lobeck, Julie A. Bobholz, Sally Durgerian, Judy Zaferos, David Miller, Julia Rao, Catherine L. Elsinger, Eric F. Maas, Steve M. RaoÂ*Milwaukee, WI
OBJECTIVE: This study was done to assess changes in patterns of activation on functional magnetic resonance imaging and their relationship to encoding or retrieval deficits in patients with mutliple sclerosis and abnormal memory function.
BACKGROUND: Forty-five to sixty percent of patients with multiple sclerosis will experience cognitive deficits during the course of their illness. The extent of disease burdun or white matter lesions present on conventional T2 weighted MRI scans correlates with the severity of cognitive deficits. Memory functions, including new learning are frequently compromised in cognitively impaired patients. Whether this is due to encoding or retrieval difficulties is not known.
DESIGN/METHODS: 15 patients with multiple sclerosis and 8 demographically matched control subjects underwent fMRI and FLAIR imaging. To test encoding memory, subjects made a sematic decision (abstract versus concrete) regarding 60 nouns, presented every 4.5 seconds. Thirty minutes later subjects were tested for recognition memory by testing 60 targets and 60 foils.
RESULTS: Recognition accuracy was similar for the two groups. However, when investigating the relationship between lesion load and the patterns of neural activation, activation in the bilateral dorsolateral prefrontal cortex and lateral cerebellum was more common in patients with higher lesion load. Lower lesion load was associated with increased activation in the left hipppocampal gyrus.
CONCLUSIONS: Even when recognition memory is normal, the neural systems involved in encoding appear to shift from long-term (left hippocampus) to working memory (bilateral dorsolateral prefrontal cortex and lateral cerebellum) strategies as lesion burden increases in multiple sclerosis.
Supported By: Biogen
Fourteen Cambridge Center
Cambridge, Massachusetts 02142
Category - MS and Related Diseases
SubCategory - Cognition

[Wise Young]

[P06.077] Reduction in Gadolinium Enhancing Lesions, and Clinical Stability in Multiple Sclerosis Patients Receiving a Combination of Cyclophosphamide and Filgrastim (G-CSF) in Preparation for Stem Cell Mobilization
Mark S. Freedman, Harold L. Atkins, Douglas Arnold, Marjorie J. Bowman, the Canadian MS BMT Study GroupÂ*Ottawa, ON, Canada; Montreal, QC, Canada
OBJECTIVE: To demonstrate the safety of stem cell mobilization for autologous stem cell transplants in multiple sclerosis using a combination of cyclophosphamide together with filgrastim (G-CSF).
BACKGROUND: There have been previous reports of clinical exacerbations in both rheumatoid arthritis and multiple sclerosis patients receiving G-CSF alone, in preparation for stem cell mobilization as part of the lead up to autologous stem cell transplantation (ASCT) as a treatment for the autoimmune disease. This has been attributed to activation of inflammatory immune cells by the G-CSF. We postulated that the co-administration of a potent chemotherapeutic agent such as cyclophosphamide with G-CSF would prevent the activation of the immune cells and guard against clinical exacerbations.
DESIGN/METHODS: A phase II study targeting MS as an autoimmune disease with intensive immunoablative therapy and immunological reconstitution using ASCT has begun in a tri-city Canadian study involving 32 MS patients, 24 of whom will receive the active therapy and 8 who will receive "best medical treatment". This non-randomized study began in 2001 with a staggered entry of patients to assure safety. Following an initial back-up bone-marrow harvest, stem cell mobilization is initiated using 4.5g/m2 cyclophosphamide i.v. followed by 10 days of filgrastim (G-CSF) (10mg/kg/day) s.c. Clinical and neurological assessments and MRI studies using gadolinium are performed prior to entry, at baseline and between 7 and 10 days following the initial cyclophosphamide dosing. Stem cells are then collected by leukopheresis.
RESULTS: All patients were clinically stable at entry and throughout the first phase of treatment. No clinically apparent relapses or worsening was noted. Gadolinium enhancing lesions were seen on MRI in all patients at entry. In all three patients, a marked reduction in the number of enhancing lesions was noted on MRI studies performed during the administration of G-CSF. Successful highly purified stem cell grafts were obtained as well from these first three patients. Detailed results of these and probably a further 2-3 patients will be presented.
CONCLUSIONS: These results confirm the safety of using G-CSF stem cell mobilization in MS patients after treatment using high dose cyclophosphamide, with no observed exacerbations either clinically or by MRI. The high dose cyclophosphamide regimen is probably responsible for the marked reduction observed in the number of gadolinium enhancing lesions. Mobilization using this procedure yields successful grafts for stem cell transplantation.
Supported By: A grant from the Multiple Sclerosis Foundation of Canada.
Category - MS and Related Diseases
SubCategory - Therapeutic Trials

[Wise Young]

[P06.075] Assessing the Effects of IFNb-1a on Health Related Quality of Life in Secondary-Progressive MS Patients: Results from the IMPACT Study
Deborah M. Miller, Jeffrey A. Cohen, Elisa C. Tsao, Mariska F. Kooijmans, Nancy A. SimonianÂ*Cleveland , OH; Cambridge, MA
OBJECTIVE: To determine the impact of IFNb-1a treatment on self-reported health related quality of life (HRQoL) using the Multiple Sclerosis Quality of Life Inventory (MSQLI) in a group of patients with secondary progressive disease. An additonal objective is to assess if HRQoL data are distinct from clinician obtained measures of impairment and disability.
BACKGROUND: As previously reported, the IMPACT study demonstrated the benefit of IFNbeta-1a (Avonex) on disease progression as measured by the Multiple Sclerosis Functional Composite (MSFC) in patients with secondary progressive multiple sclerosis (SP-MS). The effect of treatment on health related quality of life (HRQoL) in this study has not been reported in detail. Our objective is to evaluate differences in HRQoL between treated and placebo subjects and to assess if the MSQLI provides information distinct from clinician-derived data. The MSQLI is a comprehensive MS-specfic HRQoL battery developed by a reseach group sponsored by the Consortium of MS Centers and funded by the National Multiple Sclerosis Society. It was initally validated with a group of 300 patients who represented the spectrum of MS-disability and were drawn from 4 MS centers in the US and Canada. The MSQLI includes the generic SF-36 (2 scales), and 9 condition-specific measures. Those disease and symptom-specific measures assess fatigue, bladder control, bowel control, sexual satisfaction, visual impairment, preceived cognitive deficits, mental health, pains and disturbing sensations and, social support.
DESIGN/METHODS: IMPACT was a randomized, double-blind, placebo-controlled, two-arm trial. Subjects were randomized to IFNb-1a (60 mcg) or placebo by weekly IM injection for 24 months. MSFC and EDSS were collected at baseline and every 3 months. MSQLI was collected at basline and months 12 and 24.
RESULTS: 436 subjects were enrolled, 219 to placebo and 217 to IFNb-1a. Eight of 11 MSQLI scales were statistically better and the other 3 trended to improvement in the treatment group. The placebo group trended to worsening in 10 of 11 scales. Consistent with those findings, correlations between MSFC change and MSQLI change over the 2- year period were significantly correlated for 6 of the 11 MSQLI components. The significiant change corrlations ranged from r=-.22 (p=0.003) for the relation between change in the Modified Fatigue Impact Score and MSFC change to r=-.17 (p=.0066)for the relation between pain effects scale change and MSFC change. There were significant differences in 9 of the MSQLI scales when comparing patients who were in the highest and lowest MSFC change quartiles
CONCLUSIONS: Patients who received IFNb-1a had significantly better HRQoL. The consistent trend for association between MSQLI and MSFC supports their validity as outcome measures. None the less, variability in the strength and significance of those associations indicates that the MSQLI and MSFC provide unique information and are distinct outcomes indicators.
Supported By: This study was conducted with funding provided by Biogen, Inc. Cambridge, MA.
Category - MS and Related Diseases
SubCategory - Clinical Trials

[Wise Young]

[P06.046] Epstein-Barr Virus in Pediatric Multiple Sclerosis
Suad F. Alotaibi, Helen Heurter, Elizabeth Ford-Jones, Brenda L. BanwellÂ*Toronto, ON, Canada
OBJECTIVE: To study the seropositivity for Epstein-Barr Virus (EBV) in children with Multiple Sclerosis (MS) compared to age- matched controls.
BACKGROUND: Multiple sclerosis (MS) is a chronic, demyelinating disease of the CNS. Pathogenesis is complex, and likely multifactorial. Considerable support exists for the hypothesis that MS is an autoimmune disease triggered by prior infection with a common virus, and propagated by mechanisms of molecular mimicry. Infection of human T lymphocytes by EBV induces T-cell surface expression of a variety of proteins also expressed in the CNS. Thus, peripheral priming of T cells by EBV may initiate or propagate the immune mediated attack against these CNS proteins. Increased seropositivity for EBV has been shown in MS-affected adults, although the ubiquitous nature of EBV infection by adulthood has made interpretation of this data difficult. EBV infection is not ubiquitous in early childhood. Thus, if exposure to EBV is important in the pathogenesis of MS, children with MS should have a higher seropositivity rate than age-matched peers.
DESIGN/METHODS: The presence of antibodies directed against the EBV viral capsid antigen (VCA), which is a marker of past infection with EBV, was determined by enzyme linked immunosorbent assay (ELISA) in serum samples from 19 children with MS and 38 age-matched controls. Two control samples for each case, matched within 4 years of case age, were selected from children enrolled the Encephalitis registry at the Hospital for Sick Children. The medical charts of all control patients were reviewed. Control samples were obtained from previously healthy children admitted to the hospital with acute fever and encephalopathy, but without clinical or neuroradiological evidence of demyelination. All MS-affected children met criteria for clinically definite MS, as per Poser et al, and all are followed at the Pediatric Multiple Sclerosis Clinic in our hospital. The proportion of EBV-VCA seropositive cases and controls were compared using the z-test. The Welch t-test was used to compare the average age for each group, and all tests were two-tailed with alpha = 0.05
RESULTS: Nineteen pediatric MS and 38 control samples were studied. The mean age of the MS patients was 13.5 years (±3.7 SD), mean age of controls was 11.8 (±3.0 SD). Seventeen of 19 MS patients (89.5%) compared to 18 of 38 controls (47.4%) were seropositive for EBV-VCA (p<0.001).
CONCLUSIONS: EBV seropositivity is significantly higher in MS-affected children than in age-matched controls. These results support the hypothesis that early exposure to a putative viral trigger may play a role in the pathogenesis of MS.
Category - MS and Related Diseases
SubCategory - Other