Multiple Sclerosis recent issues

Evidence of treatment benefit: is seeing believing or obfuscation by statistics?

Cutter, G. — Fri, 06 Nov 2009 06:57:07 PST

High prevalence of multiple sclerosis in the Swedish county of Varmland

Bostrom, I., Callander, M., Kurtzke, J. F, Landtblom, A.-M. — Fri, 06 Nov 2009 06:57:07 PST

Previous epidemiological studies have indicated that the county of Värmland in western Sweden may be a high-risk zone for multiple sclerosis (MS). The objective of this study was to determine the prevalence in the area. Hospital and general practice medical files were scrutinized. The diagnostic criteria of Poser were used, with 31 December 2002 as prevalence day. The prevalence was 170.07 per 100,000 inhabitants. The average annual incidence was 6.39 to 6.46 per 100,000 (1991—1995, 1996—2000). Multiple sclerosis was 2.3 times more common among women than men. There was a variation in prevalence among the 16 municipalities, however it was not statistically significant. The rates seemed highest in the southwestern part of the county, roughly similar in location to findings some 70 years earlier. When the prevalence ratios by geographical units for the county in 1933 were applied to the current prevalence, the distribution from these estimated cases differed from homogeneity with very high significance (p < 0.00001 ). In conclusion, this study supports previous reports indicating that Värmland continues to be a high-risk zone for MS and shares in the diffusion of the disease at the county level which we had presented for the country as a whole.

Excess mortality and cause of death in a cohort of Norwegian multiple sclerosis patients

Smestad, C., Sandvik, L., Celius, E. — Fri, 06 Nov 2009 06:57:07 PST

There are few studies of long-term, cause-specific mortality in multiple sclerosis (MS) relating to population mortality. Our objective was to study survival, excess mortality and causes of death in a cohort of patients with a long history of MS. Patients living in Oslo with definite MS and onset during 1940—80 were included in 2006. Causes of death and mortality in the general population were obtained from the Cause of Death Registry of Statistics Norway. Of the 386 patients included in the study, 263 (68%) had died at inclusion. Median survival from onset was 35 years (Kaplan—Meier: 95% confidence interval 33—37). Primary progressive MS was associated with shorter survival, but mean age at death was similar for relapsing-remitting and primary progressive MS patients. The most frequent underlying cause of death was MS (50%), and infection was often registered as a contributory cause (56%). The all-cause standardized mortality ratio was 2.47. Excess mortality was most marked during the second decade after onset of MS. We conclude that infections are probably the main cause of death in patients with MS, but the frequency is underestimated due to misleading information on death certificates. Excess mortality in patients with MS first appeared during the second decade of the disease. Survival seems to be age-dependent rather than related to disease course.

Serum levels of CXCL13 are elevated in active multiple sclerosis

Fri, 06 Nov 2009 06:57:07 PST

There is increasing recognition of the important role that B cells play in the pathogenesis of multiple sclerosis (MS). Recently it was reported that the B cell chemokine CXCL13 is elevated in MS serum and cerebrospinal fluid. Here we study whether serum levels of CXCL13 are associated with active MS. We measured serum levels of CXCL13 by enzyme-linked immunosorbent assay in 74 patients with relapsing MS randomized to interferon beta 1b or glatiramer acetate and examined with monthly 3 T brain MRI scans optimized for detection of gadolinium-enhancement for up to 2 years. The median (range) serum levels of CXCL13 pre-treatment were 40 (3—171) pg/ml. Serum levels of CXCL13 were significantly higher at times of active brain MRI scans (p < 0.01). Furthermore, serum levels were higher in patients who never reached MRI remission compared with those in complete (p < 0.01) or partial (p = 0.01) remission. There was a significant positive correlation between the pattern of serum levels of CXCL13 and MRI activity during the first (r = 0.33, p < 0.05) and the full 2 years (r = 0.35, p < 0.01) of the study. Treatment with interferon beta 1b or glatiramer acetate did not affect serum CXCL13. We conclude that the serum levels of the B cell chemokine CXCL13 are associated with active MS.

25-Hydroxyvitamin D in cerebrospinal fluid during relapse and remission of multiple sclerosis

Fri, 06 Nov 2009 06:57:07 PST

Hypovitaminosis D may play a role in multiple sclerosis (MS), but little is known about intrathecal vitamin D. 25-Hydroxyvitamin D was measured in cerebrospinal fluid and sera from 36 patients with relapsing-remitting MS, 20 patients with other inflammatory neurological diseases and 18 patients with non-inflammatory neurological diseases with liquid chromatography-mass spectrometry. There were no significant differences in cerebrospinal fluid concentrations of 25-hydroxyvitamin D, but the cerebrospinal fluid:serum ratio was significantly lower in MS compared with other inflammatory neurological diseases (p=0.0012) and non-inflammatory neurological diseases (p=0.041) patients. The concentrations of 25-hydroxyvitamin D in cerebrospinal fluid and serum were positively correlated and their ratio was similar to that of albumin. Neither the concentrations of 25-hydroxyvitamin D in cerebrospinal fluid or serum nor their ratio were associated with the presence of relapses or gadolinium-enhanced lesions. These results do not support that 25-hydroxyvitamin D is actively transported to the cerebrospinal fluid, or that the cerebrospinal fluid or serum levels or their ratio exert a major impact on MS activity.

Disease progression among multiple sclerosis patients before and during a disease-modifying drug program: a longitudinal population-based evaluation

Fri, 06 Nov 2009 06:57:07 PST

Randomized controlled trials have demonstrated the efficacy of disease-modifying drugs (DMDs) in persons with relapsing—remitting multiple sclerosis (MS) and secondary progressive MS with superimposed relapses. However, these brief studies of selected patients have focused mainly on reducing attacks and must be complemented by evaluations in ‘realworld’ clinical settings to establish the effectiveness of DMD programs in slowing disease progression and to inform health policy and program decision-making. We assessed the effectiveness of DMDs as administered in a comprehensive publicly funded drug insurance program that provides DMDs to a geographically defined population of MS patients who meet specific eligibility criteria. Data from 1752 MS patients (10,312 assessments) seen between 1980 and 2004 at a regional MS Clinic serving the entire population of Nova Scotia, Canada were analysed. Using survival methods we observed a statistically significant reduction in disease progression to specific Expanded Disability Status Scale endpoints following the introduction of this program. Subgroup analyses of patients eligible for treatment using hierarchical linear regression methods also suggested that disease progression was slowed in patients treated with the first DMD prescribed. These findings provide evidence supporting DMD program effectiveness that can be used to inform the broader implementation of such programs.

Clinically isolated acute transverse myelitis: prognostic features and incidence

Young, J., Quinn, S., Hurrell, M., Taylor, B. — Fri, 06 Nov 2009 06:57:07 PST

Demyelinating acute transverse myelitis may be the first presentation of multiple sclerosis or remain a clinically isolated syndrome. North Canterbury, New Zealand provides a well circumscribed population to study acute transverse myelitis. Objective: to identify prognostic features, clinical outcomes and incidence of ATM in North Canterbury, New Zealand. All patients with acute transverse myelitis as a first neurological presentation diagnosed from January 2001 to December 2005 at a single institution providing all neurological care for North Canterbury were assessed for clinical data, MRI findings, cerebrospinal fluid results and clinical outcomes. CHAMPS, Barkhof/Tintore and Swanton criteria were applied to brain MRI. Sixty-one patients were identified with a mean duration of follow-up of 30 ± 17 months. Fifty percent of patients with ATM with brain lesions by CHAMPS criteria converted to clinically definite multiple sclerosis. No patients with idiopathic acute transverse myelitis converted to clinically definite multiple sclerosis. There was a strong association with conversion to clinically definite multiple sclerosis and abnormal brain MRI by CHAMPS criteria (hazard ratio, 5.63; 1.83—17.3), Barkhof/Tintore criteria (hazard ratio, 6.43; 2.31—17.9) and Swanton criteria (hazard ratio, 4.53; 1.67—12.3). The age standardized annual incidence of acute transverse myelitis was 24.6 (18.2—31.1) per million, of definite and possible idiopathic acute transverse myelitis was 6.2 (2.9—9.6) per million, and of acute transverse myelitis with brain lesions was 4.7 (1.9—7.6) per million. Patients with idiopathic acute transverse myelitis are at low risk for conversion to clinically definite multiple sclerosis. Abnormal brain MRI by CHAMPS criteria is a sensitive predictor of conversion to clinically definite multiple sclerosis. The annual incidence of acute transverse multiple sclerosis in North Canterbury, New Zealand is significantly higher than previously reported.

Revision of the risk of secondary leukaemia after mitoxantrone in multiple sclerosis populations is required

Fri, 06 Nov 2009 06:57:07 PST

The objective in this paper is to compare the cumulative incidence and incidence density of therapy-related acute myeloid leukaemia in two cohorts of patients with multiple sclerosis treated with mitoxantrone, and with previously reported data in the literature. Six new cases of acute myeloid leukaemia were observed by prospectively following two Spanish series of 142 and 88 patients with worsening relapsing multiple sclerosis and secondary-progressive disease treated with mitoxantrone. A literature review shows 32 further cases of acute myeloid leukaemia reported, 65.6% of which are therapy-related acute promyelocytic leukaemia. Five cases in the cohorts fulfilled the diagnostic criteria for acute promyelocytic leukaemia, and one patient was diagnosed with pre-B-acute lymphoblastic leukaemia. Acute myeloid leukaemia latency after mitoxantrone discontinuation was 1 to 45 months. The accumulated incidence and incidence density was 2.82% and 0.62%, respectively, in the Valencian cohort, and 2.27% and 0.44% in the Catalonian cohort. In the only seven previously reported series, the accumulated incidence varied from 0.15% to 0.80%. The real incidence of acute myeloid leukaemia after mitoxantrone therapy in the multiple sclerosis population could be higher as evidenced by the growing number of cases reported. Haematological monitoring should continue for at least 5 years after the last dose of mitoxantrone. These data stress the necessity of re-evaluating this risk.

Thalamic stimulation in multiple sclerosis: evidence for a 'demyelinative thalamotomy'

Fri, 06 Nov 2009 06:57:07 PST

The mechanism of action of deep brain stimulation (DBS) in the alleviation of tremor in multiple sclerosis (MS) and other neurological disorders is unknown. Moreover, whether the trauma accompanying this surgery is responsible for the induction of new MS plaques is controversial. Here we report the first description of the post-mortem imaging and pathologic findings in the brain of a MS patient who underwent thalamic DBS for the treatment of MS-induced tremor. MR imaging of formalin-fixed brain slices was carried out at 1.5, 3 and 7 Tesla and correlated with the histopathology. There were numerous demyelinative plaques in the white mater, cortex and deep gray matter. There were no plaques along the DBS tract within the sections that sampled the deep hemispheric white matter. However, deep within the thalamus focal demyelination approximated the tract, particularly in the region corresponding to the electrical field. The findings in this single case raise the possibility that focal demyelination may be induced by the electrical field and this may be responsible for long-lasting alleviation of tremor in the absence of continued electrostimulation.

Hypothalamic stimulation for trigeminal neuralgia in multiple sclerosis patients: efficacy on the paroxysmal ophthalmic pain

Cordella, R., Franzini, A., La Mantia, L., Marras, C., Erbetta, A., Broggi, G. — Fri, 06 Nov 2009 06:57:07 PST

Trigeminal neuralgia is a disorder characterized by paroxysmal pain arising in one or more trigeminal branches; it is commonly reported in multiple sclerosis. In multiple sclerosis patients the ophthalmic branch may be frequently involved and the risks carried by neurosurgical ablative procedures are higher including major adverse effects such as corneal reflex impairment and keratitis. The objective of this works is to assess the role of posterior hypothalamus neuromodulation in the treatment of trigeminal neuralgia in multiple sclerosis patients. Five multiple sclerosis patients suffering from refractory recurrent trigeminal neuralgia involving all three trigeminal branches underwent deep brain stimulation of the posterior hypothalamus. The rationale of this intervention emerges from our earlier success in treating pain patients suffering from trigeminal autonomic cephalalgias. After follow-up periods that ranged from 1 to 4 years after treatment, the paroxysmal pain arising from the first trigeminal branch was controlled, whereas the recurrence of pain in the second and third trigeminal branches necessitated repeated thermorhizotomies to control in pain in two patients after 2 years of follow-up. In conclusion, deep brain stimulation may be considered as an adjunctive procedure for treating refractory paroxysmal pain within the first trigeminal division so as to avoid the complication of corneal reflex impairment that is known to follow ablative procedures.

Reflexology for the treatment of pain in people with multiple sclerosis: a double-blind randomised sham-controlled clinical trial

Hughes, C., Smyth, S., Lowe-Strong, A. — Fri, 06 Nov 2009 06:57:07 PST

Multiple sclerosis (MS) results in pain and other symptoms which may be modified by conventional treatment, however, MS is still not curable. Several studies have reported positive effects of reflexology in the treatment of pain, however, no randomised controlled clinical trials for the treatment of pain have been conducted within this population. The objective of this study was to investigate the effectiveness of reflexology on pain in and MS population. We randomly allocated 73 participants to receive either precision or sham reflexology weekly for 10 weeks. Outcome measures were taken pre-and post-treatment with follow-up at 6 and 12 weeks by a researcher blinded to group allocation. The primary outcome measure recorded pain using a Visual Analogue Scale (VAS). A significant (p < 0.0001) and clinically important decrease in pain intensity was observed in both groups compared with baseline. Median VAS scores were reduced by 50% following treatment, and maintained for up to 12 weeks. Significant decreases were also observed for fatigue, depression, disability, spasm and quality of life. In conclusion, precision reflexology was not superior to sham, however, both treatments offer clinically significant improvements for MS symptoms via a possible placebo effect or stimulation of reflex points in the feet using non-specific massage.

Gender differences in health-related quality of life in multiple sclerosis

Fri, 06 Nov 2009 06:57:07 PST

Women have about twice the risk of developing multiple sclerosis (MS) compared with men, a ratio that seems to be increasing. Most studies show that female patients seem to have a more favourable outcome of the disease. We studied the gender-specific impact of MS on health-related quality of life. We surveyed the population prevalence of MS patients in Ferrara, Italy. Data were extracted from the MS registry of the study area. Health-related quality of life was assessed using the MSQOL54 questionnaire. We analysed 370 patients (105 men and 265 women). They had worse scores than the general population in all health-related quality of life dimensions, ranging from 2.5 standard deviations (SD) lower for physical functioning to less than 0.5 standard deviations for mental health. Health-related quality of life scores were inversely correlated with disability scores. The impact of disability on health-related quality of life was higher for men than women regarding physical functioning (p < 0.01), vitality (p < 0.001), social functioning (p < 0.001), emotional wellbeing (p < 0.05) and mental health (p < 0.01). For scales reflecting mental health, a marked reduction with increasing disability was seen for men, while a linear reduction in the range of Expanded Disability Status Scale score 0—5 was reported for women, followed by no clear decrease for higher scores. We conclude that MS affects health-related quality of life in all of its dimensions. The impact of disability seems to be stronger among men, in particular for scales related to mental well-being. This could indicate that interventions should to be gender specific in order to better meet patients’ needs.

Burden and health-related quality of life of Spanish caregivers of persons with multiple sclerosis

Fri, 06 Nov 2009 06:57:07 PST

Little information exists about caregivers of persons with multiple sclerosis (MS). Our aims were to describe the characteristics of a sample of caregivers of persons with MS, assess their perceived burden, health-related quality of life, and investigate factors influencing this burden. We studied 278 caregivers of persons with MS, recruited from a Spanish cross-sectional survey, measuring health-related quality of life by the 36-Item Short-Form Health Survey (SF-36) and burden by the Zarit Caregiver Burden Interview. Of the caregivers, 56.8% were female and their mean age was 50.1 ± 12.6 years. Their main relationship with the person with MS was spouse/partner (52.9%) and son or daughter (25.9%). Caregiver General Health, Mental Health, Bodily Pain, and Role-emotional Functioning were the most affected dimensions on the SF-36. Multiple regression analysis showed that independent and significant predictors of burden were Role-emotional Functioning and Vitality dimensions SF-36 scores of caregivers, and the Expanded Disability Status Scale scores. The total adjusted variance explained by these variables (adjusted R²) was 0.512. Emotional factors and the disability of the person with MS were major predictors of burden. Psychological and social support should be considered to reduce caregiver burden.

First trimester interleukin 8 levels are associated with postpartum relapse in multiple sclerosis

Fri, 06 Nov 2009 06:57:07 PST

Pregnancy has an ameliorating effect on multiple sclerosis (MS), but directly after delivery the risk of a relapse is increased. The pro-inflammatory chemokine interleukin 8 is associated with disease activity. We aimed to investigate whether pregnancy-induced fluctuations of interleukin 8 correlate with periods of enhanced and diminished disease activity. Thirty-six women with MS were prospectively studied before, during and after pregnancy. Serum levels of interleukin 8 were significantly decreased during the third trimester (p = 0.03). High first trimester serum levels of interleukin 8 were associated with a high risk of postpartum relapse (p = 0.007). These results help us to further understand the altered disease course during pregnancy.

Severe relapses after the first infusion of natalizumab in active relapsing--remitting multiple sclerosis

Rinaldi, F., Perini, P., Calabrese, M., Rinaldi, L., Gallo, P. — Fri, 06 Nov 2009 06:57:07 PST

We describe three patients suffering from a very active form of relapsing—remitting multiple sclerosis (MS), who experienced severe disease worsening, associated with a marked increase in brain inflammation, a few days after the first administration of natalizumab. In line with preclinical studies, our observations suggest that natalizumab, when administered during active disease phases, may worsen disease evolution possibly by modifying the regulatory network in the brain. We suggest that relapsing—remitting MS patients having had a recent relapse should be treated with natalizumab only after achieving complete clinical and radiological remission.

Cigarette smoking and risk of MS in multiplex families

Jafari, N., Hoppenbrouwers, I. A, Hop, W. C., Breteler, M. M., Hintzen, R. Q — Fri, 06 Nov 2009 06:57:07 PST

Recent studies suggest that a history of cigarette smoking is a risk factor for multiple sclerosis (MS). We aimed to test the smoking effect in multiplex families, matching for both environmental and genetic factors. In a matched case-control study, 136 MS patients from 106 multiplex MS families were compared with their 204 healthy siblings as controls. Participants completed self-report questionnaires. Conditional logistic regression was used to analyse smoking and MS risk association while controlling for confounding by age and sex. Smoking history was classified in different variables. Within our survey the smoking history of MS patients and the controls did not differ. The odds of MS were comparable for different smoking levels. However, more intense exposure and women showed higher odds ratios, although non-significant. Association studies in families with relatively high genetic loading are unlikely to be confounded by smoking history.

Celiac disease, Behcet, and idiopathic thrombocytopenic purpura in siblings of a patient with multiple sclerosis

Yamout, B., Usta, J., Itani, S., Yaghi, S. — Fri, 06 Nov 2009 06:57:07 PST

Multiple sclerosis (MS) is a demyelinating disease of uncertain etiology. Many genetic and environmental risk factors have been associated with this disease including certain human leukocyte antigen haplotypes, Epstein-Barr virus infection, and vitamin D deficiency. We report a 30-year-old woman with MS, the product of consanguineous marriage, and three siblings with three different autoimmune diseases: idiopathic thrombocytopenic purpura, celiac disease, and Behçet’s disease.

Consideration of preanalytical impact of blood sampling on measurement of matrix metalloproteinases and their inhibitors as precondition to evaluate their relationship to clinical data

Jung, K. — Fri, 06 Nov 2009 06:57:07 PST

Matrix metalloproteinase-9 and matrix metalloproteinase-2 as biomarkers of various courses in multiple sclerosis

Benesova, Y. — Fri, 06 Nov 2009 06:57:07 PST

Multiple sclerosis patients with bladder dysfunction have decreased symptoms after electro-acupuncture

Tjon Eng Soe, S., Kopsky, D., Jongen, P., de Vet, H., Oei-Tan, C. — Fri, 06 Nov 2009 06:57:07 PST

Severe liver dysfunction in a patient with multiple sclerosis: the guilty party is not always the disease-modifying therapy

Hotermans, C., Belachew, S., Moonen, G., Delwaide, J. — Fri, 06 Nov 2009 06:57:07 PST

2009 ACTRIMS ABSTRACTS: Oral Presentations

Fri, 06 Nov 2009 06:57:07 PST

2009 ACTRIMS ABSTRACTS: Poster Presentations

Fri, 06 Nov 2009 06:57:07 PST

Early treatment of multiple sclerosis: a Latin American Experts Meeting

Wed, 21 Oct 2009 07:38:50 PDT

Patients with clinically isolated syndrome (CIS) by definition do not have multiple sclerosis (MS) but are at risk of developing it. While studies show earlier immunomodulating drug use is effective, treatment must consider likely patient prognosis. In this paper we review current diagnosis, prognosis, and treatment literature for patients with CIS within Latin American clinical settings. Latin American MS experts, convened by ACINDES (The Civil Association for Research and Development in Health), reviewed current CIS (and early MS) literature and drew consensus conclusions. Three subgroups addressed separate questionnaires on CIS issues: prognosis, diagnosis, and treatment. MRI can contribute to predicting MS risk in patients with CIS; in Latin America, investigation of haplotype presence associated with CIS would be appropriate. McDonald’s criteria and subsequent revisions enable earlier, more accurate MS diagnosis. Type A evidence exists supporting all leading immunomodulating MS drugs for effective treatment of CIS with a high risk of conversion to MS. In conclusion, patients with CIS are usually young, with often-limited symptomatic manifestations, and must be adequately prepared to receive preventive treatment. This consensus review should contribute to the dialogue between physicians and patients. Multiple Sclerosis 2009; 15: S1—S12. http://msj.sagepub.com

'Time is brain' also in multiple sclerosis

Freedman, M. S. — Fri, 16 Oct 2009 07:20:22 PDT

Experimental autoimmune encephalomyelitis-induced upregulation of tumor necrosis factor-alpha in the dorsal root ganglia

Fri, 16 Oct 2009 07:20:22 PDT

Background: Multiple sclerosis (MS) is a chronic, neurological disease characterized by targeted destruction of central nervous system (CNS) myelin. The autoimmune theory is the most widely accepted explanation of disease pathology. Circulating Th₁ cells become activated by exposure to CNS-specific antigens such as myelin basic protein. The activated Th₁ cells secrete inflammatory cytokines, which are pivotal for inflammatory responses. We hypothesize that enhanced production of inflammatory cytokines triggers cellular events within the dorsal root ganglia (DRG) and/or spinal cord, facilitating the development of neuropathic pain (NPP) in MS. NPP, the second worst disease-induced symptom suffered by patients with MS, is normally regulated by DRG and/or spinal cord.

Objective: To determine gene and protein expression levels of tumor necrosis factor-alpha (TNF) within DRG and/or spinal cord in an animal model of MS.

Methods: Experimental autoimmune encephalomyelitis (EAE) was induced in adolescent female Lewis rats. Animals were sacrificed every 3 days post-disease induction. DRG and spinal cords were harvested for protein and gene expression analysis.

Results: We show significant increases in TNF expression in the DRG and of EAE animals at peak disease stage, as assessed by clinical symptoms.

Conclusion: Antigen-induced production of inflammatory cytokines such as TNF within the DRG identifies a potential novel mechanism for MS-induced NPP.

Season of birth and not vitamin D receptor promoter polymorphisms is a risk factor for multiple sclerosis

Fri, 16 Oct 2009 07:20:22 PDT

Both genetic and environmental factors contribute to multiple sclerosis, the most common neurodegenerative disorder with onset in young adults. The objective of the current study is, based on the hypothesis that environmentally predisposed individuals are at risk for multiple sclerosis, to investigate whether they also carry genetic variants within the vitamin D machinery. Using medical files and DNA samples from 583 trios (a patient and both parents) of the French Multiple Sclerosis Genetics Group as well as data from the French Statistics Bureau, we aimed to assess whether: (1) a seasonality of birth was observed in French multiple sclerosis patients; (2) three single nucleotide polymorphisms within the promoter region of the vitamin D receptor were associated with multiple sclerosis susceptibility; and (3) the combination of a high risk month of birth and vitamin D receptor polymorphisms were correlated to multiple sclerosis incidence. We observed a significantly reduced number of individuals born in November who were later diagnosed as multiple sclerosis patients. However, we found no association between the three studied vitamin D receptor polymorphisms and multiple sclerosis. In conclusion, our data suggest that high levels of vitamin D during the third trimester of pregnancy could be a protective factor for multiple sclerosis.

Antiacquaporin 4 antibodies detection by different techniques in neuromyelitis optica patients

Fri, 16 Oct 2009 07:20:22 PDT

Background: Antibodies against aquaporin-4 (AQP4), a water channel particularly expressed on perivascular astrocytic podocytes, are proposed as a marker for the diagnosis of neuromyelitis optica (NMO). However, a consensus on seroprevalence and optimal detection method has not yet been reached.

Objectives: To investigate the performance of different assays to detect anti-AQP4 antibodies.

Methods: We set up five different assays. Two of them were capable to detect perivascular IgG reactivity on brain tissue by immunofluorescence (NMO-IgG). Other three assays have been set to detect anti-AQP4 antibodies: immunofluorescence and flow cytometry on AQP4-expressing cells, and a radioimmunoprecipitation assay. We assessed sensitivity and specificity of these assays by interrogating sera of 33 NMO patients, 13 patients at high risk to develop NMO (hrNMO), 6 patients affected by acute partial transverse myelitis (APTM), 20 patients with multiple sclerosis (MS), and 67 age- and sex-matched healthy controls.

Results: We found that the presence of serum NMO-IgG and anti-AQP4 reactivity is almost exclusively restricted to patients with NMO and hrNMO. Seroprevalence and sensitivity ranged from 30 to 47%, depending on the assay. Specificity ranged from 95 to 100%. Comparing results obtained in the five assays, we noticed lack of concordance in some samples.

Conclusions: Detection of NMO-IgG or anti-AQP4 antibodies may represent a valuable tool to assist neurologists in the differential diagnosis between patients with NMO, hrNMO, APTM, or MS. The current lack of a gold standard to detect anti-AQP4 antibodies implies the necessity to standardize the detection of these antibodies.

Cognitive decline in multiple sclerosis: impact of topographic lesion distribution on differential cognitive deficit patterns

Tiemann, L., Penner, I., Haupts, M., Schlegel, U., Calabrese, P. — Fri, 16 Oct 2009 07:20:22 PDT

Background: Multiple sclerosis (MS) is often accompanied by cognitive dysfunction. A negative correlation between cerebral lesion load and atrophy and cognitive performance has been pointed out almost consistently. Further, the distribution of lesions might be critical for the emergence of specific patterns of cognitive deficits.

Objective: The current study evaluated the significance of total lesion area (TLA) and central atrophy for the prediction of general cognitive dysfunction and tested for a correspondence between lesion topography and specific cognitive deficit patterns.

Methods: Thirty-seven patients with MS underwent neuropsychological assessment and magnetic resonance imaging. Lesion burden and central atrophy were quantified. Patients were classified into three groups by means of individual lesion topography (punctiform lesions/periventricular lesions/confluencing lesions in both periventricular and extra-periventricular regions).

Results: TLA was significantly related to 7 cognitive variables, whereas third ventricle width was significantly associated with 20 cognitive parameters. The three groups differed significantly in their performances on tasks concerning alertness, mental speed, and memory function.

Conclusion: Third ventricle width as a straight-forward measure of central atrophy proved to be of substantial predictive value for cognitive dysfunction, whereas total lesion load played only a minor role. Periventricular located lesions were significantly related to decreased psychomotor speed, whereas equally distributed cerebral lesion load did not. These findings support the idea that periventricular lesions have a determinant impact on cognition in patients with MS.

Review: Treatment of early multiple sclerosis: the value of treatment initiation after a first clinical episode

Goodin, D., Bates, D. — Fri, 16 Oct 2009 07:20:22 PDT

Multiple sclerosis is a chronic, demyelinating disorder of the central nervous system. It is characterised by progressive neurological disability, which is likely to occur as a result of permanent axonal damage. Such damage may be reflected by brain atrophy, which can be identified early in the course of the disease. Patients who present with an initial episode of inflammatory demyelination, commonly referred to as a clinically isolated syndrome, are at high risk of developing clinically definite multiple sclerosis, especially if their magnetic resonance imaging studies suggest the presence of multi-focal disease. Treatment with disease-modifying therapies at the initial episode of demyelination may postpone this development. In this review we present an overview of evidence supporting early treatment initiation. We focus on three large placebo-controlled trials of interferon beta therapy: Controlled High-Risk Avonex^® Multiple Sclerosis Prevention Study, Early Treatment of Multiple Sclerosis and Betaferon^® in Newly Emerging Multiple Sclerosis for Initial Treatment. Results from these early treatment studies are presented, and the impact of using interferon beta treatment in the early stages of disease is discussed with the aim of considering optimal therapeutic strategies to improve long-term patient outcome.

Glatiramer acetate in combination with minocycline in patients with relapsing--remitting multiple sclerosis: results of a Canadian, multicenter, double-blind, placebo-controlled trial

Fri, 16 Oct 2009 07:20:22 PDT

Minocycline is proposed as an add-on therapy to improve the efficacy of glatiramer acetate in relapsing—remitting multiple sclerosis. The effect of minocycline plus glatiramer acetate was evaluated in this double-blind, placebo-controlled study by determining the total number of T1 gadolinium-enhanced lesions at months 8 and 9 in patients who were starting glatiramer acetate and had at least one T1 gadolinium-enhanced lesion on screening magnetic resonance imaging. Forty-four participants were randomized to either minocycline 100 mg twice daily or matching placebo for 9 months as add-on therapy. They were assessed at screening and months 1, 3, 6, 8 and 9. Forty participants completed the study. Compared with glatiramer acetate/placebo, glatiramer acetate/minocycline reduced the total number of T1 gadolinium-enhanced lesions by 63% (mean 1.47 versus 2.95; p = 0.08), the total number of new and enlarging T2 lesions by 65% (mean 1.84 versus 5.14; p = 0.06), and the total T2 disease burden (p = 0.10). A higher number of gadolinium-enhanced lesions were present in the glatiramer acetate/minocycline group at baseline; this was incorporated into the analysis of the primary endpoint but makes interpretation of the data more challenging. The risk of relapse tended to be lower in the combination group (0.19 versus 0.41; p = NS). Treatment was safe and well tolerated. We conclude that efficacy endpoints showed a consistent trend favoring combination treatment. As minocycline is a relatively safe oral therapy, further study of this combination is warranted in relapsing—remitting multiple sclerosis.

A single-center, randomized, double-blind, placebo-controlled study of interferon beta-1b on primary progressive and transitional multiple sclerosis

Fri, 16 Oct 2009 07:20:22 PDT

Inflammation and neurodegeneration may have differential impacts on disease evolution in the different forms of multiple sclerosis. However, a beneficial effect of immunomodulatory drugs should not be ruled out in primary progressive multiple sclerosis. Our aim is to investigate the safety and efficacy of interferon beta-1b in primary progressive multiple sclerosis. We conducted a double-blind, stratified, randomized, parallel group, phase II pilot study where patients with primary progressive multiple sclerosis or ‘transitional’ forms of multiple sclerosis received interferon beta-1b at doses of 8 MIU or placebo for 24 months. The main objective of the study was to investigate the safety and tolerability of interferon beta-1b. The primary efficacy variable was the time to neurological deterioration (Expanded Disability Status Scale) confirmed at 3 months. Seventy-three patients were included and three dropped out the study. More patients in the treatment arm had at least one related adverse event (94.4% versus 45.9%; p < 0.001); no other significant differences in safety endpoints were observed. Time to neurological deterioration was not different between trial arms (log-rank test, p = 0.3135). Statistically significant differences favoring treatment were observed for the Multiple Sclerosis Functional Composite score at several timepoints, T1 and T2 lesion volume changes at 12 and 24 months, mean number of active lesions and proportion of patients with active lesions at 24 months. We conclude that interferon beta-1b is safe and well tolerated in patients with primary progressive multiple sclerosis and transitional multiple sclerosis. Positive effects of interferon beta on secondary clinical and magnetic resonance imaging outcomes were observed, but a beneficial effect on Expanded Disability Status Scale progression was not demonstrated.

Treatment with the phosphodiesterase type-4 inhibitor rolipram fails to inhibit blood--brain barrier disruption in multiple sclerosis

Fri, 16 Oct 2009 07:20:22 PDT

Rolipram, a prototypic phosphodiesterase-4 inhibitor, is highly effective in suppressing Th1 autoimmunity in multiple animal models, including experimental autoimmune encephalomyelitis. In addition, rolipram has been extensively studied as a potential neuroprotective agent. Based on its anti-inflammatory activity, we tested the efficacy of rolipram in suppressing inflammatory disease activity in multiple sclerosis in a proof-of-principle phase I/II open-label clinical trial. Enrolled MS patients were evaluated by monthly MRI and clinical examinations during 3 months (four MRIs) of pretreatment baseline and 8 months of rolipram therapy. The primary outcome was a change in contrast-enhanced lesions between baseline and the last 4 months of rolipram therapy. Previously defined biomarkers of rolipram-mediated immunomodulation were evaluated during the study. The trial was stopped prematurely because the drug was poorly tolerated and because of safety concerns: we observed an increase, rather than decrease, in the brain inflammatory activity measured by contrast-enhanced lesions on brain MRI. At the administered doses rolipram was active in vivo as documented by immunological assays. We conclude that the reasons underlying the discrepancy between the therapeutic efficacy of rolipram in experimental autoimmune encephalomyelitis versus multiple sclerosis are at present not clear.

Walking and talking: an investigation of cognitive--motor dual tasking in multiple sclerosis

Hamilton, F., Rochester, L., Paul, L., Rafferty, D., O'Leary, C., Evans, J. — Fri, 16 Oct 2009 07:20:22 PDT

Background: Deficits in motor functioning, including walking, and in cognitive functions, including attention, are known to be prevalent in multiple sclerosis (MS), though little attention has been paid to how impairments in these areas of functioning interact.

Objectives: This study investigated the effects of performing a concurrent cognitive task when walking in people with MS. Level of task demand was manipulated to investigate whether this affected level of dual-task decrement.

Method: Eighteen participants with MS and 18 healthy controls took part. Participants completed walking and cognitive tasks under single- and dual-task conditions.

Results: Compared to healthy controls, MS participants showed greater decrements in performance under dual-task conditions in cognitive task performance, walking speed and swing time variability. In the MS group, the degree of decrement under dual-task conditions was related to levels of fatigue, a measure of general cognitive functioning and self-reported everyday cognitive errors, but not to measures of disease severity or duration.

Conclusions: Difficulty with walking and talking in MS may be a result of a divided attention deficit or of overloading of the working memory system, and further investigation is needed. We suggest that difficulty with walking and talking in MS may lead to practical problems in everyday life, including potentially increasing the risk of falls. Clinical tools to assess cognitive—motor dual-tasking ability are needed.

The development and validation of the Unidimensional Fatigue Impact Scale (U-FIS)

Meads, D., Doward, L., McKenna, S., Fisk, J., Twiss, J., Eckert, B. — Fri, 16 Oct 2009 07:20:23 PDT

Background: The multidimensional assessment of fatigue is complicated by the interrelation of its multiple causes and effects.

Objective: The purpose of the research was to develop a unidimensional assessment of fatigue (U-FIS).

Methods: Data collected with the Fatigue Impact Scale (FIS) were subjected to Rasch analysis to identify potential problems with the scale. Additional items for the U-FIS were generated from interviews with UK MS patients. The U-FIS was tested for face and content validity in patient interviews and included in a validation survey to determine dimensionality (Rasch model), reliability and validity.

Results: The original FIS was not unidimensional when subscale items were combined. The modification of the FIS and addition of a number of items allowed the development of a 22-item unidimensional scale (U-FIS) that was reliable (Cronbach Alpha = 0.96; test-retest = 0.86,) and valid given correlations with the Nottingham Health Profile and ability to distinguish between MS severity groups. There was no significant difference in U-FIS scores according to MS type.

Conclusion: It is valid to conceptualize the functional impact of fatigue as unidimensional. The U-FIS is a reliable and valid questionnaire that will allow the measurement of this construct in clinical studies.

The functional index for living with multiple sclerosis: development and validation of a new quality of life questionnaire

Wesson, J., Cooper, J., Jehle, L., Lockhart, S., Draney, K., Barber, J. — Fri, 16 Oct 2009 07:20:23 PDT

Addressing health-related quality of life is considered a desirable component of routine care for patients with multiple sclerosis. However, use of available health-related quality of life surveys is not part of routine multiple sclerosis care, possibly due to administration, scoring, and interpretation challenges presented by available questionnaires. The 25-item Functional Index for Living with Multiple Sclerosis (FILMS) questionnaire was developed and validated to allow providers to monitor and easily apply health-related quality of life information to the patient encounter. The development and pilot test processes and the results of the validation study are reported here. Convergent validity, internal consistency reliability, and test—retest reproducibility were evaluated. Strong correlations of Functional Index for Living with Multiple Sclerosis subscales with control questionnaires were demonstrated by Pearson’s correlation coefficients from 0.73 to 0.88. Internal consistency reliabilities ranged from 0.80 to 0.90, demonstrating that items were grouped into the appropriate subscale domains and that the subscale domains and the questionnaire as a whole exhibited good directionality. Test—retest reproducibility was 0.91.

Abstracts: Oral Presentations

Tue, 08 Sep 2009 06:22:34 PDT

Posters I: Diagnosis and differential diagnosis

Tue, 08 Sep 2009 06:22:34 PDT

Posters II: MS Variants - 2

Tue, 08 Sep 2009 06:22:34 PDT

Parallel Session 13 -- Late Breaking News

Tue, 08 Sep 2009 06:22:34 PDT