Efficacy and safety of rituximab in relapsing and progressive multiple sclerosis: a hospital-based study.

INTRODUCTION: Rituximab is considered as a potential therapeutic option in relapsing-remitting (RRMS) and progressive forms (PMS) of multiple sclerosis (MS). OBJECTIVE: To investigate the effectiveness and safety of rituximab in MS. PATIENTS AND METHODS: Observational study of effectiveness (clinical and radiological) and safety of rituximab in RRMS and PMS. RESULTS: A total of 90 rituximab-treated patients were collected: 31 RRMS and 59 PMS All patients had an active disease despite standard treatment. The annualized relapse rate (ARR) the year before rituximab was 0.86, 53.3% of patients had gadolinium enhanced lesion, and mean Expanded Disability Status Scale (EDSS) had increased from 4.2 to 4.9. During treatment, the ARR was reduced an 88.4% (p < 0.001). A significant decrease of EDSS to 4.6 was observed (p = 0.01) after 1 year of treatment, which remained stable during the second year in both groups. There was no evidence of disease activity in 70% of total sample, 74.2% of RRMS, and 67% of the PMS patients. Infusion-related symptoms were the most prevalent side effect (18.8%) and most were mild. Three thrombotic events were detected. CONCLUSION: Rituximab could be an effective and safe treatment in aggressive RRMS. Some selected PMS patients could also benefit from this treatment.

Analysis of "task-positive" and "task-negative" functional networks during the performance of the Symbol Digit Modalities Test in patients at presentation with clinically isolated syndrome suggestive of multiple sclerosis.

An abnormal pattern of brain activations has been shown in patients with multiple sclerosis during the performance of several cognitive tasks. The aim of this study is to investigate abnormalities of the patterns of activation/deactivation in the functional networks related to "task-positive" and "task-negative" events during the execution of the Symbol Digit Modalities Test (SDMT) in patients with clinically isolated syndromes (CIS) and preserved cognitive abilities. Eighteen CIS patients within 3 months from their first clinical attack and 15 healthy controls (HC) underwent neuropsychological assessment and performed an adapted functional magnetic resonance imaging (fMRI) version of the SDMT. "Task-positive" responses to task execution and "task-negative" activity of the default mode network were compared between groups. A regression analysis was performed to investigate the correlation between fMRI results and T2 lesion load (T2 LL) and brain atrophy. Neuropsychological performance did not differ between groups. Compared to HC, CIS patients exhibited an enhanced deactivation of the "task-negative" network at the level of the posterior cingulate cortex, whereas no differences between groups were found when the patterns of "task-positive" events were compared. A regression analysis detected a correlation (p < 0.001,r ranging from 0.62 to 0.73) between T2 LL and "task-positive" activations of areas that are part of the attention network, comprising the anterior cingulate gyrus, left prefrontal gyrus and inferior parietal lobe. No correlation was found between patterns of functional modifications and brain atrophy. CIS patients experience an enhanced pattern of brain deactivations during cognitive performances, which might contribute to their normal neuropsychological status.

Autoimmunity as a prognostic factor in sporadic adult onset cerebellar ataxia.

Cerebellar adult onset ataxia is a heterogeneous condition. The aim of this study was to ascertain if there is a heightened autoimmune background in patients with sporadic cerebellar ataxia of unknown origin, and if autoimmunity correlates with a more rapid evolution of the ataxia. We selected patients with sporadic progressive adult onset cerebellar ataxia with a follow-up of >5 years. As controls we included 43 patients with genetically demonstrated hereditary ataxia. All patients were tested for a panel of neuronal (onconeuronal, glutamate-decarboxylase [GAD], IgG/IgA transglutaminase 6 antibodies) and systemic non-neuronal antibodies (including IgG/IgA gliadin and transglutaminase 2, thyroperoxidase, thyroglobulin, antinuclear, striational, smooth muscle, mitochondrial, liver kidney microsomal, and parietal gastric cells antibodies). Correlation between the antibodies and disease progression was studied with Cox regression models and Kaplan-Meier plots. Forty-four patients were included. All patients were negative for onconeuronal or GAD antibodies. There were no significant differences between patients and controls in the prevalence of transglutaminase 6, 2, gliadin, or thyroid antibodies. However, when we studied the panel of systemic non-neuronal autoantibodies as a group, antibodies were more frequent in patients with sporadic ataxia (p = 0.018). The presence of one or more systemic non-neuronal antibodies correlated with a faster evolution to stage 2 (loss of independent gait) (p = 0.03) and shorter survival (p = 0.03) in patients with sporadic ataxia. We conclude that there is probably a heightened autoimmune background in some patients with sporadic cerebellar ataxia of unknown origin. The presence of systemic non-neuronal autoantibodies is a prognostic marker.

Functional magnetic resonance imaging correlates of cognitive performance in patients with a clinically isolated syndrome suggestive of multiple sclerosis at presentation: an activation and connectivity study.

BACKGROUND/OBJECTIVE: To assess whether abnormalities on functional magnetic resonance imaging (fMRI) are related to cognitive function in patients at presentation with clinically isolated syndrome (CIS) suggestive of multiple sclerosis. METHODS: Eighteen patients with CIS and 15 healthy controls (HCs) performed an adapted fMRI version of the Paced Auditory Serial Addition Test (PASAT). According to their PASAT performance, CIS patients were divided into two groups: 10 with a low PASAT performance (<1 SD from the mean value of HCs) were considered 'cognitive impairment' (CI); eight patients were defined as 'cognitively preserved' (CP). Between-group differences in the patterns of brain activations and effective connectivity were assessed. RESULTS: During PASAT, compared to HCs, CIS patients showed increased activations of the bilateral inferior parietal lobe (IPL), bilateral precuneus, bilateral middle frontal gyrus (MFG), left anterior cingulate cortex (ACC), left claustrum, right thalamus and right caudate nucleus. When CIS patients were analyzed, the CI group had a more significant activation of the bilateral IPL than HCs and CP patients. Compared to CP patients, they also had more significant recruitment of the right superior parietal lobe, right cerebellum, left MFG and left ACC. The analysis of effective connectivity showed stronger connections between several regions of the right hemisphere involved in working memory function in CI patients versus CP and HC. CONCLUSIONS: During performance of the PASAT, CIS patients show abnormalities in the patterns of cortical recruitment and connectivity related to the level of their cognitive impairment.

Early diffuse demyelinating lesion in the cervical spinal cord predicts a worse prognosis in relapsing-remitting multiple sclerosis.

OBJECTIVE: To study the long-term outcome and persistence of two patterns of cervical spinal cord abnormality in early relapsing-remitting multiple sclerosis (RRMS). METHODS: RRMS patients with a spinal cord MRI performed during the first 3 years of the disease, a control MRI 5 years later and who have been followed up at least 10 years were included. Patients were grouped according the T2 spinal cord MRI into: (A) nodular pattern, if one or more focal lesions were present; and (B) diffuse pattern, defined as a poorly demarcated high signal area. The end point was defined as the time to reach an Expanded Disability Status Score (EDSS) of 4.0. RESULTS: Twenty-five patients were included; 12 in group A and 13 in group B. Three patients in group A and 9 in group B reached EDSS 4, in a mean time of 11 years in group A and 7 years in group B (log rank 10.3, p = 0.001). Multivariate Cox regression analysis assessing the risk of EDSS 4.0 including sex, age, number of relapses in the first 2 years, number of T2 brain lesions and spinal cord pattern showed higher risk for the diffuse pattern (hazard ratio 7.2, 95% confidence interval 1.4-36.4). Control MRI showed the persistence of the diffuse pattern in all patients, and the development of diffuse pattern in two patients with basal nodular lesions. CONCLUSIONS: The diffuse abnormality in cervical spinal cord at the beginning of the disease is persistent and predicts a worse prognosis in RRMS patients.

The risk of relapse after a clinically isolated syndrome is related to the pattern of oligoclonal bands.

We prospectively assessed the risk of second relapse in 192 patients with clinically isolated syndromes (CIS) divided into three groups: patients lacking oligoclonal IgG bands (OC-IgG, 25.7%), those showing OC-IgG (52.4%), and those with both OC-IgG and lipid-specific IgM bands (LS-OC-IgM, 22%). OC-IgG increased 9.3-fold the risk compared to lacking OC-IgG; OC-IgG+LS-OC-IgM increased the risk 39.6-fold compared to not having OC-IgG and 4.4-fold compared to having only OC-IgG. Median time to second relapse was 0.7 years for patients with OC-IgG+LS-OC-IgM and 3.3 years for those with only OC-IgG. Therefore, CSF analysis identifies CIS patients at risk of second relapse.

Response to interferon in multiple sclerosis is related to lipid-specific oligoclonal IgM bands.

The objective of this study was to investigate whether the presence of lipid-specific oligoclonal IgM bands (LS-OCMB) in cerebrospinal fluid (CSF) influences the response to treatment with beta-interferon in relapsing-remitting multiple sclerosis (RRMS) patients. We performed a collaborative prospective study including RRMS patients with brain MRI and LS-OCMB studies performed before starting interferon treatment. The primary endpoint was the risk of having a relapse after treatment initiation. Secondary endpoints included relapse rate, relapse-rate reduction, proportion of relapse-free patients and proportion of patients with sustained disability increase during follow-up. One-hundred and two patients were included. After a mean follow-up of 37.4 months, the risk of suffering a relapse was two-fold higher in patients with LS-OCMB (hazard ratio 2.0, 95% confidence interval 1.1-3.8). LS-OCMB+ patients showed lower reduction in relapse rate (51.8% versus 80.8%; p < 0.0001), higher relapse rate in the first year (0.8 versus 0.2; p = 0.001), lower proportion of relapse-free patients (25% versus 61.3%; p = 0.003), and higher proportion of patients with sustained 1.0 increase in the Expanded Disability Status Score (45% versus 12.9%; p = 0.0003). In conclusion, LS-OCMB can have an influence on the response to interferon treatment in RRMS patients. They could be used as a biological marker to predict high inflammatory activity after treatment.

Characteristics of multiple sclerosis at onset and delay of diagnosis and treatment in Spain (the Novo Study).

Multiple sclerosis (MS) is a disease supposedly of autoimmune origin, with reactivity directed against myelin antigens. From the neuropathological point of view, MS produces inflammation, demyelination and axonal and neuronal degeneration. Inflammatory phenomena are predominant in the initial phase of the disease, followed later by neurodegenerative processes. Over the last decade, early treatment, during the most inflammatory phase of the disease, has been considered the best strategy to treat MS. Accordingly, we decided to determine the periods of delay between the first symptoms and the time to the first medical visit, the time to referral to a specialised MS unit, the delay in undertaking clinical and paraclinical tests, the diagnostic criteria used and the overall delay in diagnosis and treatment. The median time from onset of first symptoms to the first visit to a physician was 19.2 months, which represented the greatest delay. The median time between this initial medical consultation and the confirmation of the diagnosis by a specialised MS unit was 5.7 months, and the overall time from symptom onset to diagnosis was 24.9 months (2.08 years). The median time between onset of the first symptoms and the decision to give the first treatment was 2 years. The most important delay was that from symptom onset to the first medical visit, with the other delays being less. Thus, it is during this initial period that greater effort is required in order to reduce the time to diagnosis, by increasing awareness of the problem of MS among the general population and primary care physicians.

[Study of the relationship between white matter lesions in the magnetic resonance imaging and patent foramen ovale]. / Estudio de la relación entre lesiones de sustancia blanca en la resonancia magnética y foramen oval permeable en pacientes con migraña.

INTRODUCTION: Previous studies have described a higher prevalence of white matter lesions (WML) in the brain magnetic tesonance imaging (MRI) in patients with migraine. A higher frequency of right-to-left shunt (RLS) in patients with migraine with aura (MA) than in general population has been reported. This study has aimed to investigate a possible association between the existence of WML and the presence or non-presence of RLS in patients with migraine. METHODS: We have reviewed migraine patients suffering MA or migraine without aura (MWA) with an MRI studied in whom left-right shunt had been determined previously by transcranial doppler (TCD). The presence of WML was determined (white matter hyperintensities in T2-weighted MR images (T2WI) and FLAIR, without signal alteration in T1WI). The presence of WML was related with the type of migraine and presence or non-presence of RLS by univariate statistics. RESULTS: Forty four patients with migraine, 13 male and 31 female, mean age 39 years (23-66) were studied. Twelve patients had MA and 32 MWA. Fourteen patients had WML (31.8%), 29 patients (65.9%) RLS; 26.7% of the patients with WML also had RLS, and 34.5% of the patients with RLS had WML. Non-statistically significant differences were observed (p=0.738). CONCLUSIONS: We could not demonstrate a relationship between RLS and WML in the brain MRI of our patients. We do not know the nature of the association between is the association between WML and migraine, but these findings suggest that the link would not be by paradoxical embolism.

Effect of relapses over early progression of disability in multiple sclerosis patients treated with beta-interferon.

Observational study designed to explore the effect of demographical variables and number of relapses over the disability progression in the two first years of beta-interferon treatment for multiple sclerosis. One hundred and sixty two patients treated with beta-interferon for at least two years were included, 70.9% females, mean age 33.4 years, mean disease duration 75.1 months, mean EDSS 2.4, previous year relapse rate 1.3. Main end-point was defined as a sustained EDSS increase (1.5 if previous EDSS 0-2.0; 1.0 if previous EDSS 2.5-4.0; 0.5 if previous EDSS 4.5 or higher). 62.3% of patients presented one or more relapses and 32.7% patients reached sustained disability increase. The univariate and multivariate Cox regression analysis only showed statistical significance for the relapses in the two first years after the treatment (HR 1 relapse: 3.4, p = 0.05; HR > or = 2 relapses: 4.3, p < 0.001). The Kaplan-Meier survival analysis showed a higher probability of EDSS progression for patients with one relapse (log rank 10.9, p = 0.02) and with > or = 2 relapses (log rank 17.7, p < 0.001), with no differences between them (p = 0.38). In conclusion, patients with one or more relapses in the first two years of interferon treatment developed an earlier sustained progression of the disability.

Evaluación prospectiva del tratamiento de brotes de sclerosis múltiple con megadosis oral de metilprednisolona: datos de respuesta y seguridad / Prospective assessment of the treatment of multiple sclerosis relapses with oral high-dose methylprednisolone: response and tolerability data

Objetivo. Evaluación de la respuesta y seguridad del tratamiento de brotes de esclerosis múltiple (EM) con dosis altas de metilprednisolona oral (MPO), y análisis de la correlación entre la escala de Kutzke (EDSS) y la escala funcional compuesta (EFC) en la evaluación de los cambios posbrote. Método. Se incluyeron consecutivamente pacientes diagnosticados de EM clínicamente definida con un brote de menos de 3 semanas de evolución. Los pacientes fueron evaluados y tratados con 1.000 mg de MPO en dosis única durante 3 días sin pauta de reducción. De todos disponíamos de una EDSS basal y al menos tres medidas de la EFC. Ambas escalas se completaron el día 0, antes del tratamiento, y las semanas 1, 4 y 12 después del mismo. Consideramos buena respuesta a la mejoría de al menos 1 punto en la EDSS respecto al día 0 o la recuperación de la EDSS basal. Resultados. Se trataron 21 brotes en 20 pacientes. EDSS basal media, 2,5; z-score de la EFC basal medio, 0,15; tiempo medio de evolución del brote, 6,8 días. Durante el brote la EDSS empeoró a 3,8 y el z-score a -0,57. Hubo buena respuesta en el 33,4 % de los brotes en la semana 1 y en el 85,7% en las semanas 4 y 12. Aunque ambas escalas mejoraron significativamente en la primera semana, la EDSS media no recuperó su valor basal hasta la semana 4 y la EFC lo hizo en la semana 12. Las escalas se correlacionaron en cada evaluación y respecto a los cambios debidos al brote (p<0,01). No se registraron acontecimientos adversos graves. Discusión. La megadosis de MPO es un tratamiento seguro y eficaz de los brotes de EM. EDSS y EFC son sensibles a los cambios posbrote, aunque su dinámica de recuperación es diferente, proporcionándonos cada una información complementaria (AU)

Objective: This study aims to assess the response and safety of the treatment of multiple sclerosis (MS) episodes with high oral doses of methylprednisolone (MP) and to investigate the correlation between expanded disability status scale (EDSS) and MS functional composite (MSFC) during recovery from relapses. Method: Patients consecutively diagnosed of clinically defined MS with an episode of less than three weeks course were included. They were evaluated and treated with a single dose of 1,000 mg of MP for three days without oral tapering. Baseline EDSS and at least three MSFC scale measurements were available. Patients were scored with EDSS and MSFC before the treatment and after 1, 4 and 12 weeks. Adverse events were also recorded. Response to treatment was defined as the recovery of at least 1 point in the EDSS or the return to baseline EDSS. Results: Twenty one episodes in 20 patients were treated. Mean baseline EDSS was, 2.5; mean baseline z-score was, 0.15, and mean relapse duration was, 6.8 days. During relapse, mean EDSS worsened to 3.8 and mean z-score to -0.57. At week 1, 33.4% of relapses had responded to treatment, and at weeks 4 and 12, 85.7% had responded. Although mean EDSS and mean z-score had already improved at week 1, mean EDSS did not reach baseline value until week 4 and mean z-score until week 12. EDSS correlated significantly to MSFC in each evaluation as well as to scale changes related to relapse (p;0.05). No serious adverse events were seen. Discussion: Oral high-dose of MP is a safe and effective therapy for MS relapses. Both EDSS and MSFC were sensitive to changes related to relapses although the dynamics of recovery was different, providing complementary information (AU)

Evaluation of response of multiple sclerosis (MS) relapse to oral high-dose methylprednisolone: usefulness of MS functional composite and Expanded Disability Status Scale.

To compare the usefulness of multiple sclerosis functional composite (MSFC) to the Expanded Disability Status Scale (EDSS) in assessing functional changes related to relapse. A prospective 12-week follow-up study after relapse was conducted among 14 multiple sclerosis (MS) patients treated with oral high-dose (1 g) methylprednisolone for 3 days. MSFC and the EDSS were assessed on day 0, before treatment and, 1, 4 and 12 weeks afterwards. In relapses, EDSS (2.5 +/- 1.2 to 3.8 +/- 1.0) and z-score of the MSFC (0.15 +/- 0.58 to -0.59 +/- 0.70) worsened. After 1 week of treatment, the EDSS improved (3.3 +/- 1.2; P = 0.002) while the MSFC did not change significantly. At week 4, EDSS improvement was maximal (2.8 +/- 1.3; P = 0.001). At week 12, EDSS remained stable whereas z-score continued improving (0.26 +/- 0.74). z-9peg-hole-test was the most sensitive subtest. There was correlation between baseline values of both scales (-0.620, P < 0.05) and between changes due to relapse (-0.535, P < 0.05). 78.5% of patients had improved at week 4 (35.7% at week 1). There were no serious adverse effects. MSFC and the EDSS were sensitive to changes due to relapses, although the dynamics for restoring baseline function were different. Our data support the usefulness of both scales in clinical trials, providing complementary information about outcome of MS patients with relapses.

[Prospective assessment of the treatment of multiple sclerosis relapses with oral high-dose methylprednisolone: response and tolerability data]. / Evaluación prospectiva del tratamiento de brotes de esclerosis múltiple con megadosis oral de metilprednisolona: datos de respuesta y seguridad.

OBJECTIVE: This study aims to assess the response and safety of the treatment of multiple sclerosis (MS) episodes with high oral doses of methylprednisolone (MP) and to investigate the correlation between expanded disability status scale (EDSS) and MS functional composite (MSFC) during recovery from relapses. METHOD: Patients consecutively diagnosed of clinically defined MS with an episode of less than three weeks course were included. They were evaluated and treated with a single dose of 1,000 mg of MP for three days without oral tapering. Baseline EDSS and at least three MSFC scale measurements were available. Patients were scored with EDSS and MSFC before the treatment and after 1, 4 and 12 weeks. Adverse events were also recorded. Response to treatment was defined as the recovery of at least 1 point in the EDSS or the return to baseline EDSS. RESULTS: Twenty one episodes in 20 patients were treated. Mean baseline EDSS was, 2.5; mean baseline z-score was, 0.15, and mean relapse duration was, 6.8 days. During relapse, mean EDSS worsened to 3.8 and mean z-score to -0.57. At week 1, 33.4% of relapses had responded to treatment, and at weeks 4 and 12, 85.7% had responded. Although mean EDSS and mean z-score had already improved at week 1, mean EDSS did not reach baseline value until week 4 and mean z-score until week 12. EDSS correlated significantly to MSFC in each evaluation as well as to scale changes related to relapse (p;0.05). No serious adverse events were seen. DISCUSSION: Oral high-dose of MP is a safe and effective therapy for MS relapses. Both EDSS and MSFC were sensitive to changes related to relapses although the dynamics of recovery was different, providing complementary information.

Axonal loss is progressive and partly dissociated from lesion load in early multiple sclerosis.

OBJECTIVE: To assess the relationship between the spectroscopically measured axonal damage in the normal-appearing white matter of the brainstem, the total brain T2-hyperintense lesion volume (T2LV), and disability in patients with early relapsing-remitting multiple sclerosis (RRMS). METHODS: Forty-three RRMS patients and 10 sex- and age-matched healthy controls were prospectively studied for 2 years. T2-weighted magnetic resonance (MR) images and proton MR spectroscopy were acquired at the time of recruitment and at year 2. Brainstem was considered, where large tracts join together, as a suitable region to detect early axonal damage. The T2LV was calculated with a semiautomatic program; N-acetylaspartate (NAA), creatine (Cr), and choline (Cho) resonances areas were integrated with the jMRUI program, and the ratios were calculated for the sum of the volume elements represented at brainstem. RESULTS: The basal NAA/Cho ratio was significantly decreased in patients compared with controls. After 2-year follow-up, there was a decrease in the NAA/Cho (-9%; p = 0.002) and NAA/Cr (-13%; p = 0.001) ratios, and an increase in the T2LV (19%; p = 0.043) in multiple sclerosis patients, whereas control subjects had no significant metabolic changes. Significant NAA/Cr ratio decreases were observed in both patients, with and without relapses, whereas T2LV only increased in patients with relapses. The final Expanded Disability Status Scale (EDSS) score correlated with T2LV at baseline, but no significant correlations were found between metabolic values, T2LV change, or EDSS score over the study period. CONCLUSIONS: Our data reveal an early and progressive axonal damage in relapsing-remitting multiple sclerosis. Axonal loss and T2 lesion volume seem to be at least partly dissociated processes in early stages of the disease.

No association of the Val66Met polymorphism of brain-derived neurotrophic factor (BDNF) to multiple sclerosis.

Brain-derived neurotrophic factor (BDNF), a neurotrophin produced by neurons and immune cells, promotes neuronal survival and repair during development and after CNS injury. The BDNF-Val66Met polymorphism is functional and induces abnormal intracellular trafficking and decreased BDNF release. Therefore, we investigated the impact of the BDNF-Val66Met polymorphism on the susceptibility and clinical course in a case-control study of 224 multiple sclerosis (MS) Spanish patients and 177 healthy controls. We found no evidence for association to susceptibility or severity of the disease in our population. Moreover, we did not observe, in a subgroup of 12 MS patients, that the methionine substitution at position 66 in the prodomain had negative impact in the capacity to produce BDNF by peripheral blood mononuclear cells (PBMC).