Severe Multiple Sclerosis Research Articles

Association of serum vitamin D levels in Japanese patients with multiple sclerosis

Objective Vitamin D levels are one of the most likely environmental factors related to the development of multiple sclerosis (MS). As vitamin D levels differ between ethnicities, the associated risk of MS also differs. We aimed to determine the associations of serum vitamin D levels in Japanese patients with MS. Methods Serum levels of 25-hydroxyvitamin D (25[OH]D), 1,25-dihydroxyvitamin D (1,25[OH]2D), and vitamin D-binding protein (DBP) were measured in 29 patients with relapsing-remitting (RR) and secondary-progressive (SP) MS, and in 34 healthy controls. Results The serum levels of 25(OH)D in SPMS patients were significantly decreased compared with those of controls and RRMS patients at remitting phase (7.9 ± 7.2 nM vs 24.2 ± 14.2 nM vs 22.5 ± 13.2 nM, respectively; P < 0.05, P < 0.01, respectively). DBP levels in RRMS and SPMS patients were also decreased compared with controls (419.4 ± 76.2 μg/mL vs 416.7 ± 65.9 μg/mL vs 527.6 ± 149.4 μg/mL, respectively; P < 0.01, P < 0.05, respectively). Furthermore, serum 25(OH)D was found to correlate negatively with disease severity in patients with RRMS in the remitting phase and SPMS using the Expanded Disability Status Scale and the Multiple Sclerosis Severity Score. Conclusions Our results suggest that low 25(OH)D levels are associated with an increased risk of developing SPMS, and a likelihood of developing more severe MS with a worse prognosis in Japanese patients. [Correction added on 2 August 2013, after first online publication: ‘serum 25 (OH)D was found to correlate negatively with 1,25(OH)2D levels in patients’ has been corrected to ‘serum 25(OH)D was found to correlate negatively with disease severity in patients’ in the Results section of the abstract.]

Fingolimod for the treatment of relapsing multiple sclerosis

Fingolimod 0.5 mg (Gilenya™, Novartis Pharmaceuticals Corporation, FL, USA) is the first once-daily oral therapy approved for relapsing forms of multiple sclerosis (MS) in the USA and for rapidly evolving severe MS or highly active disease despite IFN-β treatment in Europe. An extensive clinical development program has established fingolimod as an effective therapy that reduces relapses by approximately half compared with placebo or intramuscular IFN-β1a. Over 2 years of postmarketing experience in >63,000 MS patients (with >73,000 patient-years of exposure) across the world has contributed to a well-characterized safety profile for fingolimod, and its side effects are manageable through patient monitoring. This article discusses the unique mechanisms of action of fingolimod in the immune and nervous systems, the key data underlying its efficacy and safety profile and perspectives on the role of fingolimod in current and future treatment strategies for MS.

Group exercise training for balance, functional status, spasticity, fatigue and quality of life in multiple sclerosis: a randomized controlled trial

Objective: To determine the effectiveness of group exercise training on balance, functional status, spasticity, fatigue and quality of life in patients with multiple sclerosis. Design: A randomized single-blind controlled study. Setting: University hospital, outpatient physical therapy department. Subjects: Ambulatory patients with multiple sclerosis. Interventions: Exercise group completed a 12-week group exercise programme under the physical therapists’ supervision. Control group was included in the waiting list. Main measures: The primary outcome measures were the Berg Balance Scale, 10-metre walk test, 10-steps climbing test and secondary outcome measures were the Modified Ashworth Scale, Fatigue Severity Scale and Multiple Sclerosis International Quality of Life. Results: Ninety-nine patients completed the study. There were statistically significant improvements for all outcome measures in the group exercise group (n = 51) (p < 0.01). In the control group (n = 48), there were statistically significant negative change in the Berg Balance Scale and 10-metre walk test measures (p = 0.002, p = 0.001) and statistically significant increment only in the Fatigue Severity Scale score (p = 0.002). The Berg Balance Scale score was increased 4.33 in the exercise group, while a decreased of 2.33 in control group. The 10-metre walk test duration (second) was decreased 2.72 in exercise group, while increased 1.44 in control group. In comparing inter-groups changes, both primary and secondary outcome mesures showed significant improvements in favour of the exercise group after the training (p < 0.05). Conclusion: The study demonstrated that supervised group exercise training is effective in improving balance, functional status, spasticity, fatigue and quality of life in moderately affected people with multiple sclerosis, with no worsening of their clinical status.

CPC-006 Adequacy of Criteria For Starting Natalizumab in Patients with Multiple Sclerosis

BackgroundNatalizumab is a monoclonal antibody authorised as second-line treatment after failure with interferon beta or in rapidly evolving severe relapsing-remitting multiple sclerosis (RRMS). Due to its high cost and safety...

AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN CHILDREN WITH SEVERE RESISTANT MULTIPLE SCLEROSIS

Unique experience of high-dose chemotherapy with consequent autologous hematopoietic stem cell transplantation in children with severe resistant multiple sclerosis (n=7) is shown in this article. At present time there is enough data on chemotherapy with consequent hematopoietic stem cell transplantation in children with severe resistant multiple sclerosis. This method was proved to be efficient and safe with immunoablative conditioning chemotherapy regimen. In patients included in this study the mean rate according to the Expanded Disability Status Scale was 5,94±0,2 (from 3 to 9) points. All the patients had disseminated demyelination loci, accumulating the contrast substance, in the brain and the spinal cord. After cyclophosphamide treatment in combination with anti-monocytes globulin the fast stabilization of the condition and prolonged (the observation period was 3-36 moths) clinical and radiologic as well as immunophenotypic remission with marked positive dynamics according to the Expanded Disability Status Scale were noted. No pronounced side-effects and infectious complications were mentioned. The maximal improvement according to the Expanded Disability Status Scale (EDSS) was 5,5 points, the mean — 2,7±0,1 (from 2 to 5,5) points accompanied with positive dynamics on the magneto-resonance imaging. The efficacy of the treatment was also proved by the positive changes in the lymphocytes subpopulation status in peripheral blood. The timely performed high-dose chemotherapy with consequent hematopoietic stem cell transplantation is an effective and safe method to slowdown the autoimmune inflammatory process. This method can be recommended to use in treatment of children with severe resistant multiple sclerosis.

Documenting outdoor activity and travel behaviour in persons with neurological conditions using travel diaries and GPS tracking technology: a pilot study in multiple sclerosis

Objective: Persons with multiple sclerosis (PwMS) experience several physical and cognitive problems which can influence their travel behaviour. This study aimed to document the number of activities, the activity type and the transport mode of the related trips that are daily made by PwMS. Their outdoor activity and travel behaviour was studied in relation to disease-related disability. Methods: Thirty six PwMS (Expanded Disability Status Scale, EDSS, 1.5–8.0, age 27–63) and 24 healthy controls (age 25–62) were studied, using activity-related travel diaries and GPS tracking devices. Information about overall disability characteristics was gained by standard clinical tests and questionnaires. PwMS were further divided in three subgroups based on EDSS cut-off scores 4.5 and 6.5. Results: Persons with mild ambulatory dysfunction (EDSS 1.5–4.0, n = 17) showed similar travel characteristics to healthy controls, with few restrictions during travelling. Statistically significant changes in activity and travel behaviour were detected in the moderate (EDSS 4.5–6.5, n = 8) and severe MS subgroups (EDSS > 6.5–8.0, n = 11) compared with healthy controls: driving independently became less frequent, significant more trips were made with company and the duration of performed activities had increased. Conclusion: The combination of self-reported travel diaries and objective GPS loggers offered detailed information about the actual outdoor travel behaviour of PwMS, which was significantly changed in PwMS with EDSS greater than 4.Implications for RehabilitationActivity and travel behaviour changes significantly in persons with multiple sclerosis (MS) with moderate to severe disability (EDSS greater than 4).Behavioural therapy could help to develop better coping and problem-solving skills to overcome anxiety in the making of trips by persons with MS with a mild severity.Enhancing community environments could serve as a promising approach to increase the outdoor participation of persons with (more severe) impairments.

Treatment of Severe Relapsing-Remitting Multiple Sclerosis with High-Dose Immunosuppressive Therapy and Autologous Hematopoietic Cell Transplantation: 2-Year Follow-up Results of the HALT MS Clinical Trial (Immune Tolerance Network: ITN033AI)

Treatment of Severe Relapsing-Remitting Multiple Sclerosis with High-Dose Immunosuppressive Therapy and Autologous Hematopoietic Cell Transplantation: 2-Year Follow-up Results of the HALT MS Clinical Trial (Immune Tolerance Network: ITN033AI)

Growth Hormone and Disease Severity in Early Stage of Multiple Sclerosis

Evidence suggests that neurohormones such as GH and IGF-I are involved in the neuroreparative processes in multiple sclerosis (MS). GH and IGF-I blood levels in naïve MS patients with different disease courses were investigated in this study. Serum GH and IGF-I in untreated MS patients (n = 64), healthy controls (HC, n = 62), and patients affected by other neurological diseases (OND, n = 46) were evaluated with a solid-phase-enzyme-labeled-chemiluminescent-immunometric assay. No differences were detected in GH across MS, OND, and HC (MS = 0.87 ± 1.32 ng/mL; OND = 1.66 ± 3.7; and HC = 1.69 ± 3.35; P = 0.858) when considering gender, disease duration, and disease course. However, GH was lower (P = 0.007) in patients with more severe disease (expanded disability scale score, EDSS ≥ 4.0) compared with milder forms (EDSS < 4). IGF-I l did not differ across the 3 groups (P = 0.160), as far as concern disease course, disability, and gender were. Lower IGF-I levels were detected in subjects older than 50 years compared to younger ones for all 3 groups. Lower GH was detected in patients with more severe MS, and age was confirmed as the main factor driving IGF-I levels in all subjects. These findings, relying on the natural course of the disease, could help in shedding lights on the mechanisms involved in autoreparative failure associated with poorer prognosis in MS.

Evaluation of multiple sclerosis (MS) based on Antibody to Aquaporine-4(AQP-4) in urine and serum compared to total IgG antibody

Event Abstract Back to Event Evaluation of multiple sclerosis (MS) based on Antibody to Aquaporine-4(AQP-4) in urine and serum compared to total IgG antibody Afra Khosravi1* and Mozhgan Mohamadrashidi1 1 Ilam University of Medical Sciences, Iran Introduction- Multiple sclerosis (MS) is a disease in which the myelin, which provides a covering for nerves, improves the conduction of impulses along the nerves and also is important for maintaining the health of the nerves is disappeared due to the inflammation. Consequently, the electrical impulses that travel along the nerves decelerate, that is, become slower. In addition, the nerves themselves are damaged. The prevalence of the disease in Ilam is about 13.54 in 100,000 population which is 3 times more than the mean prevalence of whole country. As AQP-4 is important water chanel protein expressing in MS the current study aimed to measure the antibody titer against AQP-4 either in urine and the sera of MS patients compared to the total IgG to evaluate the diagnosis of the disease this way. Materials and Methods- Totally 21MS patients together with 21 healthy people were included in this study. After an informed consent form was completed by each individual a questionnaire including age, sex, health history, the starting symptoms and the diagnosis tests of MS, the category for the onset of symptoms (sensory, skeletal or visional symptoms), the severity or grade of the MS disease, any background disease was completed for each participant. A urine and blood sample was taken and after RBC and WBC count, Hb mesurment, MCV, MCHC and RDW, the total antibody titer (IgG class, IgA and IgM) was measured using Nephlometry. Anti-AQP-4 antibody was measured using ELISA. Data were extracted and analyzed using ANOVA and Peasrson correlation test. Results- The total IgM was similar in both case and control group but there was a higher titer of IgG and IgA in case compared to the control group. The mean anti-AQP-4 IgG antibody was 17.4 and 17.8 in urine and serum respectively. The mean anti-AQP-4 antibody in urine of patients with mild MS was 16.1 while it was 19.3 amongst the patients with moderate and severe MS. The mean anti-AQP-4 antibody was similar in serum of patients with mild and severe MS ( 17.7 and 17.8 respectively). Conclusion- As the antibody titer to AQP-4 in either serum and urine is similar and even it is higher in urine of severe MS patients so the measurements of this antibody in urine could be a noninvasive method of diagnosis of the MS with a high reliability.Anti-AQP-4 can be used a mean for the analysis of the severity of MS. Keywords: Multiple Sclerosis, Aquqporine-4, antibody, severity, Urine, Serum. Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Adaptive Immunity Citation: Khosravi A and Mohamadrashidi M (2013). Evaluation of multiple sclerosis (MS) based on Antibody to Aquaporine-4(AQP-4) in urine and serum compared to total IgG antibody. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00053 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 08 Mar 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Afra Khosravi, Ilam University of Medical Sciences, Ilam, Iran, afrakhosravi@yahoo.co.uk Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Afra Khosravi Mozhgan Mohamadrashidi Google Afra Khosravi Mozhgan Mohamadrashidi Google Scholar Afra Khosravi Mozhgan Mohamadrashidi PubMed Afra Khosravi Mozhgan Mohamadrashidi Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Common values in assessing health outcomes from disease and injury: disability weights measurement study for the Global Burden of Disease Study 2010

Measurement of the global burden of disease with disability-adjusted life-years (DALYs) requires disability weights that quantify health losses for all non-fatal consequences of disease and injury. There has been extensive debate about a range of conceptual and methodological issues concerning the definition and measurement of these weights. Our primary objective was a comprehensive re-estimation of disability weights for the Global Burden of Disease Study 2010 through a large-scale empirical investigation in which judgments about health losses associated with many causes of disease and injury were elicited from the general public in diverse communities through a new, standardised approach. We surveyed respondents in two ways: household surveys of adults aged 18 years or older (face-to-face interviews in Bangladesh, Indonesia, Peru, and Tanzania; telephone interviews in the USA) between Oct 28, 2009, and June 23, 2010; and an open-access web-based survey between July 26, 2010, and May 16, 2011. The surveys used paired comparison questions, in which respondents considered two hypothetical individuals with different, randomly selected health states and indicated which person they regarded as healthier. The web survey added questions about population health equivalence, which compared the overall health benefits of different life-saving or disease-prevention programmes. We analysed paired comparison responses with probit regression analysis on all 220 unique states in the study. We used results from the population health equivalence responses to anchor the results from the paired comparisons on the disability weight scale from 0 (implying no loss of health) to 1 (implying a health loss equivalent to death). Additionally, we compared new disability weights with those used in WHO's most recent update of the Global Burden of Disease Study for 2004. 13,902 individuals participated in household surveys and 16,328 in the web survey. Analysis of paired comparison responses indicated a high degree of consistency across surveys: correlations between individual survey results and results from analysis of the pooled dataset were 0·9 or higher in all surveys except in Bangladesh (r=0·75). Most of the 220 disability weights were located on the mild end of the severity scale, with 58 (26%) having weights below 0·05. Five (11%) states had weights below 0·01, such as mild anaemia, mild hearing or vision loss, and secondary infertility. The health states with the highest disability weights were acute schizophrenia (0·76) and severe multiple sclerosis (0·71). We identified a broad pattern of agreement between the old and new weights (r=0·70), particularly in the moderate-to-severe range. However, in the mild range below 0·2, many states had significantly lower weights in our study than previously. This study represents the most extensive empirical effort as yet to measure disability weights. By contrast with the popular hypothesis that disability assessments vary widely across samples with different cultural environments, we have reported strong evidence of highly consistent results. Bill & Melinda Gates Foundation.

Simultaneous Pml-Iris After Discontinuation of Natalizumab in A Patient With MS

Gheuens et al.1 presented a case of progressive multifocal leukoencephalopathy–immune reconstitution inflammatory syndrome (PML-IRIS) 2 months after natalizumab discontinuation. Their patient had an active history of ethanol abuse, which can be considered a 'functional' equivalent to immunosuppression. Interestingly, prior use of immunosuppressants has been included in the recently developed risk-stratification algorithm for PML.2 This case underscores the need for clinicians to adopt a wider concept of immunosuppression, rather than restricting it solely to the use of pharmacologic agents. We and others published 3 cases of definitive severe multiple sclerosis (MS) rebound about 2 months following natalizumab discontinuation,3-5 and further implied that younger patients are more prone to such relapses.5 However, Gheuens et al. concluded that new enhancing MRI lesions after natalizumab withdrawal may also be the manifestation of PML-IRIS.1 As experience from patients discontinuing natalizumab and switching to other therapies mounts, a high degree of clinical vigilance for both incidences (i.e., MS rebound and PML) should follow the immediate post-natalizumab period. However, until official guidelines are issued, it is unclear exactly how patients should be treated in the interval between natalizumab and the next therapeutic choice.

Treatment of Severe Relapsing-Remitting Multiple Sclerosis with High-Dose Immunosuppressive Therapy and Autologous Hematopoietic Cell Transplantation: 2-Year Follow-up Results of the HALT MS Clinical Trial (Immune Tolerance Network: ITN033AI)

AbstractAbstract ▪962▪This icon denotes a clinically relevant abstractMost patients with relapsing-remitting multiple sclerosis (RRMS) do not achieve a sustained remission after disease-modifying therapy. A phase II clinical trial of high-dose immunochemotherapy (HDIT; BCNU, etoposide, ara-C, melphalan and antithymocyte globulin) and autologous hematopoietic cell transplantation (HCT) was conducted in patients with highly active RRMS who had failed conventional therapy to assess if a high rate of sustained remission could be induced. Eligibility required an EDSS of 3.0 (moderate disability, fully ambulatory) to 5.5(severe disability, ambulatory only 100 meters without aids) and >2 relapses on treatment in previous 18 months. Treatment-failure was defined as a composite endpoint including 1) mortality 2) relapse 3) new MRI lesions or 4) disability increase >0.5 EDSS points. Adverse events (AE) were recorded according to NCI-CTCAE v3.0.25 patients at a median age of 38(27-53) years were treated with G-CSF to mobilize the autograft; prednisone was given at the same time to prevent MS flares. The autograft was CD34-selected (Baxter, Isolex). One patient withdrew after mobilization secondary to HIT/pulmonary embolus. 24 patients had HDIT/HCT according to protocol. Median follow-up was 131 (52, 282) weeks. After initially stabilizing, one patient died from progressive loss of neurological function at 32 months. No patient had delayed recovery of blood counts. In the 1st year after HDIT, there were 42 grade 3 and 6 grade 4 non-hematopoietic AE. Grade 4 AE included: one suicide attempt (with 3 grade 4 AE); hyperuricemia; hypokalemia; and elevated ALT. In the 2ndyear, there were 13 grade 3 and 1 grade 4 non-hematopoietic AE. The 1-year and 2-year probabilities of event-free survival (i.e. without treatment-failure) were 95.8% (90% CI: 80.2%-99.2%) and 82.8% (90% CI: 65.0%-92.0%), respectively. Progression-free and relapse-free survival at 1 year were 100% (90% CI: 100%-100%) and 95.8% (90% CI: 80.2%-99.2%) and at 2 years were 91.7% (90% CI: 75.7%-97.3%) and 91.7% (90% CI: 75.7%-97.3%), respectively. The probability of freedom from disease activity detected by brain MRI was 95.8% (90% CI: 80.2%-99.2%) at both year 1 and 2. In comparison, a randomized clinical trial of placebo vs natalizumab (Havrdova E et al, Lancet Neurology, 2009) showed that 7% and 37% of RRMS patients were free of disease activity (i.e. progression, relapse and MRI) at 2 years, respectively.T2-weighted MRI scans measure disease burden from MS. T2 lesion volume was significantly reduced by 6 months and was sustained at 2 years (Table 1). T1 lesion volume was increased at 1 year. There was a significant loss of brain volume at 6 months but stabilized after this time point.Flow cytometry of peripheral blood was done at baseline and at 1, 2, 6 and 12 months. There was near complete depletion of naïve CD4 and CD8 T cells (CD45RA+) at 1 month. Memory CD4 and CD8 T cells (CD45RO+) were not completely eliminated from the blood after in vivo depletion from HDIT. Within 2 months of transplant, there was rapid expansion of memory CD8 T cells. The numbers of CD4 naïve and memory T cells were not recovered at 1 year. CD4 and CD8 recent thymic emigrants (CD45RA+, CD31+) were increased at 1 year compared to the nadir at 1 month but did not completely recover. Recovery of naïve and memory B cells was complete between months 6 and 12.HDIT/HCT for highly active RRMS resulted in profound immunosuppression and induced a high rate of sustained remissions at 2 years. The small increase in T1-weighted lesion volume in the absence of persistent brain inflammation may have resulted from damage due to previous brain injury. No further loss in brain volume was observed after 6 months. Follow-up is planned through 5 years. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Natalizumab treatment during pregnancy - effects on the neonatal immune system

Pregnancies in women with severe relapsing-remitting multiple sclerosis treated with natalizumab constitute a major challenge, because withdrawal of the drug may cause relapses but continuation might have unknown effects on the infantile immune system. To identify the impact of maternal natalizumab treatment during pregnancy on basic immune functions of the newborn. Basic immunological testing and assessment of the chemotaxis rate of freshly isolated T lymphocytes in the presence and absence of CXCL12 was performed in two neonates, whose mothers were treated with natalizumab until the 34th week of pregnancy (pw). Both children had an uneventful birth. However, a reduction in the CXCL12-induced T-cell chemotaxis was found in both children. In contrast, the chemotaxis rate of unstimulated T lymphocytes was not altered. The distribution of the lymphocyte subpopulations was investigated only in case 1 and was normal. Here, we present to our knowledge the first assessment of T lymphocytes chemotaxis rate in two natalizumab-exposed newborns. A significant reduction in the CXCL12-induced chemotaxis rate of T lymphocytes has been observed and may compromise host defence function in early life. More clinical and immunological data on natalizumab-exposed neonates are warranted.

Severe multiple sclerosis reactivation under fingolimod 3 months after natalizumab withdrawal

We report the case of a woman with multiple sclerosis who developed a severe neurological condition following natalizumab (NZB) withdrawal and soon after fingolimod (FTY) initiation. FTY was started 3.5 months after a two-year NZB treatment. Fifteen days later, she suffered partial repetitive seizures followed by a tonicoclonic seizure. This was associated with attention difficulties and an increased asthenia. Brain MRI follow-up disclosed large demyelinating active lesions in favour of disease reactivation. This case suggests that FTY introduction may occur less than three months after NZB withdrawal.

Mechanisms of pain in multiple sclerosis: A combined clinical and neurophysiological study

In this clinical and neurophysiological study, we examined the clinical characteristics and underlying mechanisms of neuropathic pain related to multiple sclerosis. A total of 302 consecutive patients with multiple sclerosis were screened for neuropathic pain by clinical examination and the DN4 tool. In patients selected for having ongoing extremity pain or Lhermitte’s phenomenon, we recorded somatosensory evoked potentials, mediated by Aβ non-nociceptive fibres, and laser evoked potentials, mediated by Aδ nociceptive fibres. Of the 302 patients, 92 had pain (30%), and 42 (14%) neuropathic pain. Patients with neuropathic pain had more severe multiple sclerosis, as assessed by the expanded disability severity score, than those without pain. Whereas, in patients with ongoing neuropathic pain, laser evoked potentials were more frequently abnormal than somatosensory evoked potentials, we found the opposite in patients with Lhermitte’s phenomenon.Our data underline the clinical importance of pain in multiple sclerosis and indicate that a more severe disease is associated with a higher risk of developing neuropathic pain. The prevalence of pain that we found, which was lower than that reported in previous studies, may reflect the lesser disease severity in our patients. Neurophysiological data show that whereas ongoing extremity pain is associated with spinothalamic pathway damage, Lhermitte’s phenomenon is related to damage of non-nociceptive pathways. These findings may be useful in designing a new therapeutic approach to neuropathic pain related to multiple sclerosis.

Use of Long-Term Intrathecal Methotrexate in Progressive Forms of MS (P04.139)

Objective: To establish the safety and tolerability of long-term therapy with intrathecal methotrexate (ITMTX) in patients with treatment-resistant progressive forms of multiple sclerosis (MS). Background Currently there are no treatment options that successfully treat progressive MS, especially in the most severely disabled patients (EDSS > 6.0). We previosuly reported results of IT administration of MTX in the treatment of 121 patients with severe MS for up to 8 treatments. However, long-term safety has not been reported. This study is a IRB-approved retrospective chart analysis of patients who have had 18 or more treatments (3-6 years) to further examine the long-term safety and tolerability of ITMTX in this select cohort of advanced MS patients. Design/Methods: Thirty three patients, 27 secondary progressive (SPMS) and 6 primary progressive (PPMS) were clinically assessed every two months while receiving ITMTX at a dose of 12.5mgs every 8-11 weeks for a period of 3-6 years (range of 18 to 38 treatments). Assessments included EDSS, documentation of infections, other adverse events and hospitalizations. Results: There were no deaths or hospitalizations related to ITMTX and no serious adverse effects occurred. Headaches occurred at least once in 12% of patients, possibly minimized by the use of 25-gauge spinal needles and transient fatigue was reported in 6%. No cases of MTX associated leukoencephalopathy were seen. Almost all patients with SPMS had stable EDSS scores over the study period wheres the 6 PPMS patients had a mean decline on EDSS of 0.7. Conclusions: ITMTX was remarkably well tolerated over a period of 3-6 years in progressive MS patients with no serious adverse effects noted. Although this study was not controlled there was evidence of disease stabilization given the poor natural history of severe progressive MS. These findings support the use of ITMTX treatment as an inexpensive and relatively safe treatment for progressive MS. Supported by: MSRCNY funding. Disclosure: Dr. Stark has nothing to disclose. Dr. Dulak has nothing to disclose. Dr. Sadiq has nothing to disclose.

Severe multiple sclerosis relapse under fingolimod therapy: Incident or coincidence?

Fingolimod is the first orally administered disease-modifying drug that has been approved for treatment of relapsing-remitting multiple sclerosis (MS). After phosphorylation it acts as a nonselective functional antagonist of the sphingosine-1-phosphate receptor family (S1P1/3/4/5), trapping B and T lymphocytes in secondary lymphoid tissues. ### Case report. A 26-year-old woman was diagnosed with relapsing-remitting MS in February 2009 after an episode of mild sensory deficits. She was treated with interferon β-1a which was stopped in January 2010 due to elevated liver enzymes, and switched to interferon β-1b 2 months later. Despite 7 steroid-responsive relapses her Expanded Disability Status Scale (EDSS) remained stable (1.0 to 1.5) until the end of April 2010 (figure, A and B), when she had her first moderate relapse (EDSS 2.5). Assuming a lack of treatment efficacy, the patient discontinued interferon therapy but refused treatment with natalizumab due to safety concerns. Eventually she was enrolled in an open-label fingolimod trial on June 19, 2010. Figure Disease course, imaging, and laboratory results (A) The patient's disease course: bottom: results of blood immunophenotyping. (B) On May 3, 2010, 6 weeks before initiation of fingolimod therapy, the cerebral MRI (axial T2 and T1+Gd) disclosed several supratentorial and infratentorial multiple sclerosis lesions without gadolinium enhancement. The MRI was obtained immediately after a high-dose IV steroid treatment. (C) MRI at admission in September 2010. Left: the cerebral MRI (axial T2 and T1+Gd) disclosed 29 supratentorial and infratentorial ovoid as well as confluent active lesions, some with ring-like gadolinium enhancement. Moreover, there was a large lesion in the left cerebellar peduncle, without diffusion restriction in diffusion-weighted imaging (not shown). Right: MRI of the cervical and thoracic spinal …

Surgical therapy for multiple sclerosis tremor: a 12‐year follow‐up study

Severe multiple sclerosis (MS) tremor causes disability poorly responsive to medication. Deep brain stimulation (DBS) or thalamotomy can suppress tremor, but long-term outcomes are unclear. Nine patients with MS tremor underwent disability measures at baseline and 12 months post-surgery (six thalamotomy, three DBS) in 1997-1998 (previously reported, Matsumoto et al., Neurology 2001;57:1876-82). We report the prospective 12-year follow-up of this cohort for tremor, disability, and death. Surgery was initially successful in all. Tremor recurred in all patients within median 3 months, although two DBS patients were tremor-free for 5 years. Median tremor-free survival (tremor-free time/survival time) was 4.3%. At 12-year follow-up, four survivors (two thalamotomy, two DBS) (Expanded Disability Status Scale scores 8-8.5) were severely disabled. Five patients were dead (four thalamotomy, one DBS) median 5.8 years post-operative. Surgery benefit for severe tremor was overall short-lived (median 3 months), with long-term poor prognosis. Although two DBS patients had sustained 5-year tremor-suppression, the observed progressive disability and death in this cohort bear importance for long-term success in future MS tremor surgery trials.

The Use of Bone Marrow Derived Mesenchymal Stromal Cells for Treatment of Patients with Multiple Sclerosis and Neurodegenerative Disorders – Achievements and Future Goals

Future treatment of multiple sclerosis (MS) aims at restoring myelination and neurological functions as well as re-induction of self-tolerance. We studied the role of mesenchymal stromal stem cells (MSC), known to be anti-inflammatory on the one hand and multi-potent on the other, in experimental autoimmune encephalitis (EAE), and found that treatment of mice with bone marrow derived MSCs resulted in significant suppression of anti-self reactivity and improved clinical and pathological disease manifestations. Using green fluorescent donors, we documented that in addition to down regulation of autoimmunity, neural differentiation of these cells may occur in vivo. These observations suggested that treatment with MSCs might be used for immune regulation and neuroprotection for patients with MS. Our preliminary results of a phase I/II open clinical trial to evaluate the feasibility and safety of intrathecal and intravenous administration of autologous bone marrow derived MSCs in patients with severe MS failing conventional modalities suggested that treatment with MSCs is feasible, safe and potentially effective. No major side effect were developed or reported during a follow up period of nearly 4 years. Based on our successful preliminary pilot study in 13 patients with MS and 14 with ALS, a total of >150 patients were treated with autologous bone marrow derived MSCs, mostly >100 patients with MS alone were treated at our center with MSCs administered partially intrathecally (106 MSC/Kg) and additional 5 - 10x105/Kg intravenously. The treatment was uneventful with headache due to lumbar puncture being the most frequent complaint (70%) and self-limited subfebrile temperature in 25% and no serious side effect. A total of 60 % of patients reported improved outcome, in some with very significant objective improvement of disease manifestations with subjective and objective improvement of EDSS score. More recently, we have discovered a new proprietary technology which allows differentiation of both bone marrow, adipose tissue derived and cord/placenta derived MSCs into neural stem cells, motor neurons, dopaminergic neurons, astrocytes and myelin basic protein secreting oligodendrocytes that in principle may be used to induce remyelination. These results suggest that treatment with MSCs may provide the most suitable approach for treatment of MS, which could also be applicable for treatment of other neurodegenerative disorders.

Long-term efficacy of autologous haematopoietic stem cell transplantation in multiple sclerosis at a single institution in China

Autologous haematopoietic stem cell transplantation (AHSCT) is a promising treatment for multiple sclerosis (MS) patients who have not adequately responded to conventional therapies. We retrospectively evaluated the safety and long-term clinical outcome of AHSCT in MS patients in China. Twenty-five patients with various types of MS were treated with AHSCT. Peripheral blood stem cells were derived by leukapheresis after mobilized with granulocyte colony-stimulating factor. Then CD34+ cell selection of the graft was performed and anti-thymocyte globulin was given for T-cell depletion, with the conditioning regimen BEAM adopted and early and late toxicities recorded. Long-term responses were evaluated by the expanded disability status scale (EDSS), progression-free survival and gadolinium-enhanced magnetic resonance imaging scans. 10, 7 and 8 patients experienced neurological improvement, stabilization and progression, respectively. The median EDSS scores observed over 1-year follow-up after transplantation (5.5-7.0) were consistently lower than the baseline (8.0). The progression-free survival rate was 74, 65 and 48% at 3, 6 and 9 years post-transplant. 58% cases (7/12) had active lesions at baseline and all turned to inactive status in the years of follow-up. 25% cases (3/12) experienced progression after transplantation but had no active lesions in MRI over the whole follow-up period. 17% cases (2/12) without active lesions at baseline progressed active lesions in MRI. The major early toxicity resulted in fever and late toxicity caused transplantation-related mortality due to severe pneumonia and varicella-zoster virus hepatitis, respectively. AHSCT is a feasible treatment for severe MS and its long-term efficacy is favorable.