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Objective: To assess the long-term emotional state of multiple sclerosis (MS) patients treated with interferon beta (IFNβ) for at least four years. Methods: Patients who had started IFNβ therapy prior to 2000 with a baseline psychological assessment were identified and scheduled for long-term emotional assessment with the following questionnaires-the Hamilton Depression Rating Scale, the Beck Depression Inventory and the State-Trait Anxiety Inventory. Results: A total of 262 patients started IFNβ therapy in our MS clinic within the period 1995-1999. Baseline emotional assessment was available from 246 MS patients. Long-term assessment was conducted on 234 patients. After a mean follow-up of 65 months (43-98), 52 patients (22.3%) had withdrawn from IFNβ therapy. The comparisons, obtained from baseline and follow-up scores, showed an improvement in the depressive and anxiety symptoms of patients who adhered to IFNβ treatment. Logistic regression analysis indicated that an increase in physical disability and the presence of depressive symptoms at baseline were best predictors for long-term depressive symptoms. Conclusions: The present results support the absence of emotional worsening in MS patients treated with IFNβ for a long period of time. Increased disability and the presence of baseline depressive symptoms predicted the presence of depressive symptoms at follow-up.

Introduccion. El natalizumab es un farmaco utilizado en la esclerosis multiple (EM), cuyo principal efecto adverso es el desarrollo de una leucoencefalopatia multifocal progresiva (LMP). Como esta es potencialmente mortal o discapacitante, el tratamiento debe suspenderse inmediatamente ante su sospecha, teniendo en cuenta el posible desarrollo posterior de un sindrome de reconstitucion inmune o rebrote de la EM. Caso clinico. Se describe un caso de LMP, inicialmente asintomatico, en el contexto del tratamiento con natalizumab en una paciente con EM. Como factores de riesgo se determinaron titulos altos de anticuerpos contra el virus John Cunningham (VJC) y mas de dos anos de tratamiento. La reaccion en cadena de la polimerasa para el VJC en el liquido cefalorraquideo resulto negativa en dos determinaciones. El periodo entre el diagnostico radiologico y el inicio de la clinica fue de dos meses. Durante el curso de la enfermedad, la paciente desarrollo un sindrome inflamatorio de reconstitucion inmune y rebrotes de su EM. Presento una buena respuesta tras el inicio de tratamiento con fingolimod, una vez estabilizada la LMP. Conclusion. Este caso ilustra la importancia de una estrecha vigilancia clinicorradiologica en pacientes con EM tratados con natalizumab, sobre todo cuando presentan factores de riesgo para el desarrollo de LMP, asi como su potencial incidencia en la supervivencia y estado funcional final.

Observational studies may provide additional information about the behaviour of different drugs in the post-marketing period. We present the data from a cohort of secondary progressive multiple sclerosis (SPMS) patients treated with interferon beta (IFNbeta-1b) at our MS clinic.This was an independent, open-label, non-randomised, observational study. Within the period 1998 to 2005, all patients with SPMS who started therapy with IFNbeta-1b at our centre were studied. Each patient was included in a follow-up protocol collecting demographic and baseline clinical data.We studied 146 SPMS patients with a median follow-up of 60 months. Over the total study period, 62.2% of patients had confirmed progression. The analysis of the time to con- firmed progression showed that patients with two or more relapses in the 2 years before IFNbeta initiation, had a higher risk of disability increase than those patients with less than two relapses (p = 0.002). Multiple regression analysis showed disease activity in terms of relapses as the only factor to predict increase of disability during the follow-up period. A significant proportion of patients (36%) stopped treatment during the follow-up period. IFNbeta was safe, although some unexpected adverse events were observed.A higher disease activity before the beginning of treatment with IFNbeta in SPMS patients with a given EDSS rank could identify those with faster disability progression after treatment initiation.

The McDonald International Panel accepted the Barkhof/Tintoré criteria for providing MRI evidence of dissemination in space to allow a diagnosis of multiple sclerosis in patients with clinically isolated syndromes (CIS). We applied these criteria in a large cohort of patients with CIS, representative of those seen in a general diagnostic setting, to assess their accuracy in predicting conversion to definite multiple sclerosis and to identify factors that affect this risk.In a collaborative study of seven centres, baseline MRI and clinical follow-up data for 532 patients with CIS were studied, with the development of a second clinical event used as the main outcome. All scans were scored for lesion counts and spatial lesion distribution to assess the fulfilment--ie, at least three out of four--of the Barkhof/Tintoré criteria. We used survival analysis and 2x2 tables to assess the test characteristics of the criteria at baseline.Overall conversion rate was 32.5% with a median survival time of 85.3 months. Fulfilment of the criteria at baseline showed, after a survival time of 2 years, a conversion rate of about 45% (95% CI 37-53) versus about 10% (6-16) in those with no asymptomatic lesions at baseline (p0.0001). For patients with a follow-up of at least 2 years, the fulfilment of the MRI criteria showed an accuracy of 68% (sensitivity 49%, specificity 79%) for predicting conversion and an increase in risk of nearly four times for conversion compared with those not fulfilling the criteria (odds ratio 3.7, 95% CI 2.3-5.9; p0.0001). Cox proportional hazards regression analysis accorded with this increased risk. No effects were recorded on the performance of the criteria by sex, presenting symptoms, or centre. Age at baseline did have a small but significant effect as predictor (hazard ratio 0.97, 0.95-0.99; p=0.002), but did not affect the prognostic value of the MRI criteria.MRI abnormalities have important prognostic value. The cut-off, based on the Barkhof/Tintoré criteria, as incorporated in the McDonald diagnostic scheme yields acceptable specificity, but could have lower sensitivity than previously reported.

Fatigue is one of the most frequent symptoms in multiple sclerosis (MS) but there is a lack of knowledge about its behaviour over time. The aim of our study was to investigate changes in fatigue in a large cohort of MS patients and to determine the relationship between changes in disability and depression with changes in fatigue severity. We studied fatigue in 227 MS consecutive patients and again after one year. During the clinical interview, we recorded the patient’s degree of disability using the Expanded Disability Status Scale and relapses; fatigue was measured by means of the Modified Fatigue Impact Scale (MFIS) and Fatigue Severity Scale (FSS) and depression was measured by the Beck Depression Inventory (BDI). After a mean follow-up of 18 months, 86.8% of patients who were fatigued at study onset remained in a fatigued status, whereas 25% of those without fatigue at onset had become fatigued at the end of follow-up. We observed that only variations on BDI scores positively correlate with variations on fatigue scales, mainly with MFIS (r = 0.49, p

We investigated the phenotype and frequency of circulating myeloid dendritic cells (MDC) and plasmacytoid DC (PDC) in 86 multiple sclerosis (MS) patients and 33 healthy controls (HC). The MS group comprised 20 patients with primary progressive MS (PPMS), 20 patients with secondary progressive MS (SPMS), and 46 patients with relapsing-remitting MS (RRMS) [23 treated with interferon-beta (IFN-beta)]. The frequency of circulating MDC and PDC, and the expression of CD83, CD123, CD80, CD86, and CD40 were analyzed by flow cytometry. The percentage of circulating MDC was decreased in patients with SPMS and PPMS. The expression of CD83, CD80, and CD86 was lower in PPMS patients. Treatment with IFN-beta induced the expression of CD123 in PDC and decreased the number of circulating MDC. These results suggest an impaired maturation state of DC in PPMS patients, and a beneficial effect of IFN-beta favouring the survival of PDC and promoting a Th2 environment.

Our goal was to evaluate the relation between the presence of neutralizing antibodies (NABs) to interferon beta-1b in multiple sclerosis (MS) patients and the clinical evolution in the following years.As we previously reported, we tested NABs in 68 patients treated with interferon beta-1b after 2 years of treatment. We prospectively followed this cohort every three months for a minimum period of 6 years collecting data about relapses, disability, secondary effects and dropouts.During the 6 year follow-up period, the annualized relapse rate did not differ between patients with and patients without NABs. A sustained progression was observed in 33% of positive patients and in 38% of patients without NABs. No differences were found in the proportion of patients who reached an EDSS score of 6. Secondary effects were similar in both groups.Although our results do not vouch for a negative effect of the presence of NABs on the clinical evolution of MS patients treated with interferon beta, further longitudinal studies to clarify the real effect of the presence of NABs in these patients are still much needed.

Multiple sclerosis (MS) often presents with isolated optic neuritis; indeed, a number of patients with isolated optic neuritis eventually develop definite MS. Natural history studies have suggested that such forms of MS may have a better prognosis than those presenting with brainstem syndromes or myelitis. The goal of this study was to compare the rate of conversion with definite MS based on the first clinical presentation (isolated optic neuritis, brainstem syndrome, or myelitis). The authors prospectively evaluated 320 patients with a clinically isolated syndrome (123 with optic neuritis, 78 with brainstem syndromes, 89 with spinal cord syndromes, and 30 with other topographies) who were observed for a median of 39 months. Patients underwent a brain MRI within 3 months of their first attack and again 12 months later. Conversion to MS, determined either clinically or by MRI, was evaluated according to topography. Baseline MRI was normal in 49.2% of patients with optic neuritis compared with 24% of patients with brainstem syndromes, 24% of patients with spinal cord syndromes, and 18.5% of patients with other syndromes. Optic neuritis patients had a lower conversion to clinically definite MS and a smaller proportion of patients fulfilling MRI dissemination in space, time, or both. Nevertheless, when only patients with abnormal cranial MRI results at baseline were selected, no differences for clinical or MRI conversion were found. The authors conclude that even though optic neuritis patients have a smaller risk for conversion to MS, it is the MRI at baseline, not the clinical presentation, which determines the subsequent risk of definite MS. —Valerie Biousse

Background: An increase in MMP-9 levels has been found in relapsing-remitting (RR) multiple sclerosis (MS) showing correlation with magnetic resonance (MR) parameters mainly during relapses. However, data regarding primary progressive (PP) MS is scarce. Objectives: To determine both the pro and active forms of MMP-9 in PPMS and transitional progressive (TP) MS, RRMS and healthy controls (HC), and to assess the relationship between MMP-9 levels and clinical and radiological variables in PP/TPMS. Methods: 73 patients with PP/TPMS, 50 RRMS and 43 HC were studied. Levels of pro and active forms of MMP-9 in serum were measured with ELISA. EDSS and MSFC scores were recorded and T2- and T1-weighted MR scans were obtained at the time of blood sampling and one and two years later for PP/TP MS cases. Results: MMP-9 levels were 202.27 ng/ml for PP/TPMS, 242.20 ng/ml for RRMS and 274.49 ng/ml for HC. MMP-9 levels were significantly lower in PP/TPMS compared to RRMS(P-0.026) and HC (P- 0.001). No significant correlations were found between MMP-9 levels and clinical scores or radiological parameters. Conclusions: These results point to different regulatory mechanisms of MMP-9 production and/or activity between PP/TPMS and RRMS.

B ackground and aim: C onversion to multiple sclerosis (MS) after optic neuritis and myelitis has been thoroughly studied; however, limited data are available regarding conversion to MS after a clinically isolated syndrome of the brainstem (CISB). The aim of this study was to investigate conversion to MS in patients with C ISB. Methods: Fifty-one patients with C ISB were prospectively studied. C ranial magnetic resonance imaging (MRI), determination of oligoclonal bands (OBs) in the cerebrospinal fluid (C SF) and evoked potentials (EPs) were performed. Based on conversion to MS at follow-up, the sensitivity, specificity, accuracy and positive and negative predictive values of these tests were calculated. Results: C linically definite MS developed in 18 (35%) patients after a mean follow-up of 37 months. Paty’s MRI criteria showed a sensitivity of 89%, a specificity of 52% and an accuracy of 65%; Fazekas’ criteria showed a sensitivity of 89%, a specificity of 48% and an accuracy of 63%; Barkhof’s criteria showed a sensitivity of 78%, a specificity of 61% and an accuracy of 67%. The presence of O Bs in the C SF showed a sensitivity of 100%, a specificity of 42% and an accuracy of 63%. No differences for neurophysiological parameters were found between patients who did and those who did not convert to MS. C onclusion: Fulfilling Paty’s, Fazekas’ or Barkhof’s MRI criteria and the presence of O Bs in the C SF are associated with a higher risk of conversion to MS in patients with C ISB. Determinatio n of O Bs in the C SF has the greatest sensitivity of all tests. Barkhof’s MRI criteria have greater specificity (although less than previously published for mixed cohorts of clinically isolated syndromes) in predicting conversion to MS for C ISB than either Paty’s or Fazekas’ criteria.

Clinical trials with interferons in relapsing-remitting multiple sclerosis have shown a modest effect on disability using fixed definitions of treatment failure to measure disease progression. However, in the course of the disease, treatment failure may be influenced by interrater variability and frequent remissions. Thus, the purpose of this study was to assess the clinical usefulness of different treatment failure criteria in a cohort of relapsing-remitting multiple sclerosis patients treated with interferon beta. We studied 252 patients with a follow-up of more than 2 years. We used four different criteria of treatment failure with increasing stringency (1 Expanded Disability Status Scale [EDSS] point increase confirmed at 3 months, 1 EDSS point increase confirmed at 6 months, 1.5 EDSS points increase confirmed at 3 months, and 1.5 EDSS points increase confirmed at 6 months). We divided treatment failure into permanent treatment failure and transient treatment failure. We considered permanent treatment failure when treatment failure was confirmed on the last two scheduled visits and transient treatment failure when treatment failure was not confirmed on these visits at different time points (9, 12, 18, and 24 months). We calculated the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the different criteria of treatment failure to identify patients who achieved a high degree of disability after 4 years of follow-up. Regardless of the stringency of treatment failure definitions, a variable proportion of patients with treatment failure had transient treatment failure depending on the criterion applied. Patients with transient treatment failure had a significantly lower EDSS at entry compared with those with permanent treatment failure or no treatment failure. The number of relapses in patients with transient treatment failure did not differ from that of patients with permanent treatment failure. The criterion of confirmed 1 EDSS point increase at 6 months showed the best sensitivity (76.5%), with satisfactory specificity (89%). Our study shows that a large proportion of patients treated with interferon experience transient treatment failure that may affect outcome interpretation in clinical trials. Using a more strict criterion, as extending time to confirmation of EDSS deterioration, and longer follow-up may reduce this proportion of patients with transient treatment failure and improve the validity of the results attained in clinical trials.

In some rare cases, demyelinating plaques appear on contrast-enhanced T1-weighted images as pseudotumoral, cyst-like lesions (hypointense, ring enhancing). Serial proton MR spectroscopy, T2 relaxometry and magnetization transfer ratios (MTR) were performed on three pseudotumoral demyelinating lesions to obtain information about their pathological basis. Baseline and 1-month MTR and T2 values were similar to those of cerebrospinal fluid, while spectra showed lactate, lipids and choline. Three-month and 1 year exams showed recovery of MTR, T2 and N-acetylaspartate, approaching the contralateral values, while creatine and choline were normal or surpassed contralateral values. Lipids and lactate gradually disappeared. These results suggest that pseudotumoral, cyst-like, ring-enhancing lesions may be characterized by an accumulation of oedema in the extracellular space with an almost complete absence of cells. Reduction of the oedema allows restoration of the tissue to its original location, indicating that cellular destruction was less important than was expected after the first exam. Thus, the evolution of this kind of lesion should be kept in mind when considering lesion volume from T1-weighted images as a marker of disability or irreversible cellular destruction in MS.

Aim of the study: To evaluate and compare the capacity of oligoclonal bands (OB) and three sets of MR imaging criteria to predict the conversion of clinically isolated syndromes (CIS) to clinically definite multiple sclerosis (CDMS). Patients and methods: One hundred and twelve patients with CIS were prospectively studied with MR imaging and determination of OB. Based on the clinical follow-up (conversion or not conversion to CDMS), we calculated the sensitivity, specificity accuracy, positive and negative predictive value of the OB, and MR imaging criteria proposed by Paty et al, Fazekas et al and Barkhof et al. Results: CDMS developed in 26 (23.2%) patients after a mean follow-up of 31 months (range 12-62). OB were positive in 70 (62.5%) patients and were associated with a higher risk of developing CDMS. OB showed a sensitivity of 81%, specificity of 43%, accuracy of 52%, positive predictive value (PPV) of 30% and negative predictive value (NPV) of 88%. Paty and Fazekas criteria showed the same results with a sensitivity of 77%, specificity of 51%, accuracy of 57%, positive predictive value of 32% and negative predictive value of 88%. Barkhof criteria showed a sensitivity of 65%, specificity of 70%, accuracy of 69%, PPV of 40% and NPV of 87%. The greatest accuracy was achieved when patients with positive OB and three or four Barkhof's criteria were selected. Conclusions: We observed a high prevalence of OB in CIS. OB and MR imaging (Paty's and Fazekas' criteria) have high sensitivity. Barkhof's criteria have a higher specificity. Both OB and MR imaging criteria have a high negative predictive value.

Lesion location might turn out to be an important factor in long-term disability prediction in patients with primary progressive multiple sclerosis (MS). Using a lesion probability mapping approach, researchers have identified brain regions where the presence of MS lesions predicts an early need for bilateral walking support.

The objective of this study was to characterize and compare the proton magnetic resonance spectrum of a voxel, containing lesions or normal-appearing white matter (NAWM), in primary-progressive (PP) and secondary-progressive (SP) multiple sclerosis (MS) patients. Single-voxel proton magnetic resonance spectroscopy and magnetic resonance imaging were performed in 35 MS patients (17 PP and 18 SP) and 17 controls. Spectra from an 8 ml voxel located in the parieto-occipital region were obtained with a spin-echo pulse sequence (1600 ms/135 ms/ 256, TR/TE/acquisitions). Resonance areas due to N-acetylaspartate (NAA), creatine/phosphocreatine (Cr) and choline compounds (Cho) were determined, and results expressed in terms of area in arbitrary units or as metabolite ratios. With respect to the control group, there were significant reductions in NAA and NAA/Cho ratio in the PP-lesion, SP-lesion, PP-NAWM and SP-NAWM groups. There were no significant differences between the PP-NAWM and SP-NAWM groups. These results support the existence of metabolic changes in the white matter of PP and SP patients and suggest that there is neuronal damage and/or loss in both clinical courses. Finally, characterization of the parieto-occipital region showed no significant differences in the spectral pattern of NAWM between PP and SP clinical courses of MS.

The acquisition of information is an important part of scientific work. In recent years, available information sources have multiplied exponentially, and as a result, we have come to find ourselves immersed in an “information overload”. Although we feel committed to keeping up to date with the advances in neurology by using our information seeking skills, paradoxically the new, widely expanded information technologies have made it more and more difficult to gain knowledge about relevant literature sources and to retrieve information. Under the pressure of this situation, many of us have resorted to the passiveness of searching only the most commonly used databases such as Medline and Current Contents to acquire the information we need. In the frequent practice of retrieving information needed for patient assistance, it is accepted that the use of Medline gives good results for European and North American countries. However, in searches directed towards investigation, we suspected that other, perhaps less accessible databases, could provide valuable additional information. …

Fundamento y objetivo Evaluar la relacion entre la presencia de anticuerpos neutralizantes (AN) de interferon beta-1 b (IFN-s-1 b) en pacientes con esclerosis multiple (EM) y su evolucion clinica en los anos siguientes. Pacientes y metodo Tal y como se ha descrito previamente, determinamos la presencia de AN en 68 pacientes con EM tratados con IFN-s-1 b a los 2 anos de tratamiento. Prospectivamente, hemos seguido esta cohorte durante un periodo minimo de 6 anos y se han recogido datos sobre los brotes, la discapacidad, los efectos secundarios y los abandonos de la medicacion. Resultados Durante el periodo de observacion de 6 anos, la tasa anual de brotes no fue diferente en los pacientes con y sin AN. Se observo una progresion confirmada de la discapacidad en el 38% de los pacientes con AN y en el 33% de los que no tenian AN. Tampoco se hallaron diferencias en la proporcion de pacientes que alcanzaron una puntuacion en la escala de discapacidad de Kurtzke (EDSS) de 6. Los efectos secundarios fueron similares en ambos grupos. Conclusiones Nuestros resultados no apoyan el efecto negativo de la presencia de AN en la evolucion clinica de los pacientes con EM tratados con IFN-s-1 b.

Introduccion. El tratamiento inmunomodulador modifica el curso de la enfermedad en los pacientes con esclerosis multiple. Es fundamental que el paciente cumpla adecuadamente con el tratamiento pautado. Objetivo. Conocer la adhesion real al tratamiento inmunomodulador de primera linea e intentar averiguar que factores pueden influir en el adecuado cumplimiento del tratamiento. Pacientes y metodos. Es un estudio longitudinal retrospectivo observacional de los pacientes en seguimiento por el Centre d�Esclerosi Multiple de Catalunya del Hospital Universitari Vall d�Hebron que recogieron tratamiento inmunomodulador de primera linea (interferones o acetato de glatiramero) entre el 1 de enero de 2010 y el 30 de septiembre de 2011. La adhesion se midio utilizando el indice de posesion de medicacion �medication possession ratio (MPR)�: se consideraron adherentes los pacientes con MPR mayor o igual al 80%. Resultados. Estudiamos 975 pacientes. El tiempo medio de exposicion a los inmunomoduladores durante el periodo de recogida fue de 13,4 ± 7,1 anos. El 85,2% de los pacientes tuvo una adecuada adhesion al tratamiento inmunomodulador. De 975 pacientes tratados, 134 precisaron cambiar a un segundo farmaco y 12 pacientes a un tercero. El cambio de farmaco mejoro la adhesion (p = 0,001). La tasa anual de brotes fue de 0,23. Unicamente la presencia de brotes (p = 0,029) y el farmaco utilizado (p = 0,044) tuvieron influencia en la adhesion al tratamiento, de forma individual. Conclusiones. La proporcion de pacientes con adecuada adhesion al tratamiento en nuestro centro es alta. La tasa de brotes y el farmaco empleado son determinantes para ello. Se requiere un seguimiento estrecho y asesoramiento individualizado para mantener un buen cumplimiento terapeutico.

Multiple sclerosis is the most frequent disabling neurological disease in young adults. Its development includes independent processes of inflammation, demyelination, neurodegeneration, gliosis and repair, which are responsible for the heterogeneity and individual variability in the expression of the disease, its prognosis and response to treatment. As part of personalised medicine, the progress made in the search for new biomarkers has identified promising candidates that may be useful for the early diagnosis of the disease, for detecting prognostic and developmental profiles of the disease, and for monitoring the response to treatment. Unfortunately, few of them have been validated adequately, which prevents them from being applied in clinical practice. In view of the latest findings, the experts recommend orienting research in another direction, not so much towards the discovery of new molecules or imaging techniques, but instead towards a clinical validation of these markers, with the aim of fostering translational research. This review offers an update on the information about the biomarkers in multiple sclerosis that have currently been validated and are thus potential candidates, as well as looking at their value in the diagnosis, prognosis, evaluation of the development of the disability caused by the disease and the response to therapy.

Recent articles1,2on the association of vitamin B12deficiency and multiple sclerosis (MS) have revived interest in vitamin B12metabolism in MS. In both disorders, demyelination is a noteworthy feature; however, MS is clearly different from vitamin B12deficiency. Vitamin B12deficiency is usually a disorder of the middle or late stage of life and rarely occurs in the age range typical for the presence of MS.3Mild but significant macrocytosis has been found in patients with MS compared with an age- and sex-matched neurological control group.4Significant lowering of the serum vitamin B12concentration has also been reported in patients with MS.5This association, however, remains unclear because convincing evidence of clinical abnormalities attributable to vitamin B12deficiency in patients with MS was not documented by the authors. Although the serum vitamin B12assay is an extremely sensitive

To investigate, during the 5-year period without treatment after termination of a 2-year clinical trial of interferon beta-1b for the treatment of primary progressive multiple sclerosis, differences in the evolution of clinical variables and magnetic resonance imaging results between trial arms and to investigate correlations between in-trial changes in Multiple Sclerosis Functional Composite (MSFC) score and magnetic resonance imaging variables and Expanded Disability Status Scale (EDSS) score evolution.Five-year clinical trial follow-up.Clinical Neuroimmunology Unit, Multiple Sclerosis Centre of Catalonia, Autonomous University of Barcelona, Spain. Patients Seventy-three patients received interferon beta-1b or placebo during the trial.After 5 years without treatment, the EDSS and MSFC measures were scored for 63 and 59 patients, respectively. Neuropsychological and magnetic resonance imaging assessments were performed for 59 and 50 patients, respectively.After 5 years without treatment, the interferon beta-1b group had better 9-Hole Peg Test (P = .02) and Word List Generation Test (P .001) scores, and their magnetization transfer ratio measures in the normal-appearing white matter were significantly higher (P = .02, P = .009, and P = .03 for the mean, peak location, and peak height magnetic transfer ratios, respectively). During the entire study period (from trial baseline to assessment at 5 years without treatment), the placebo group showed a greater decrease in brain parenchymal fraction (P = .004). The in-trial increase of lesions correlated with the worsening of the EDSS score during the 5-year period without treatment (P = .004).Modest but beneficial effects of interferon beta-1b on clinical variables and brain atrophy development were observed 5 years after trial termination. Moreover, in-trial lesion activity correlated with EDSS progression after trial termination. Therefore, we provide evidence to consider immunomodulation as a sensible approach to treat primary progressive multiple sclerosis.

Introduccion. La extensa aplicacion de estudios de resonancia magnetica (RM) conlleva un aumento en la deteccion de alteraciones de la sustancia blanca del sistema nervioso central. Objetivo. Investigar la evolucion de pacientes sin sintomas neurologicos previos, con hallazgos de RM altamente sugestivos de esclerosis multiple (EM). Pacientes y metodos. Estudio descriptivo de once pacientes con RM sugestiva de EM. Mediante seguimiento longitudinal se determinaron la progresion radiologica y la conversion a sindrome neurologico aislado y EM clinicamente definida. Resultados. Se identifico a 11 pacientes (7 mujeres y 4 varones), con una edad media de 36 anos (rango: 28-48 anos), sometidos a RM por cefalea (n = 2), prolactinoma (n = 2), radiculalgia (n = 3), traumatismo craneoencefalico (n = 1), sincope (n = 1), patologia nerviosa periferica (n = 1) y crisis epileptica (n = 1). El numero medio de criterios Barkhof-Tintore en la RM inicial fue de 3. El estudio de bandas oligoclonales fue positivo en 6 casos y en 9 pacientes se realizaron potenciales evocados visuales (3 patologicos). El seguimiento medio fue de 2,9 anos (rango: 2 meses-11,9 anos). El tiempo medio entre la primera y la segunda RM fue de 2,03 anos. Se identifico una progresion radiologica en 7 casos (5 de ellos con captacion de gadolinio). Cinco pacientes convirtieron a sindrome neurologico aislado, con un tiempo medio desde la RM inicial de 4,13 anos. De ellos, tres pacientes presentaron conversion a EM clinicamente definida, dos en forma recurrente-remitente (tras 8,54 anos de media desde la RM inicial) y otro en forma primaria progresiva. Conclusion. La identificacion de lesiones incidentales altamente sugestivas de EM podria ayudar a constituir un grupo de sujetos con riesgo aumentado de desarrollar EM.

Fundamento Se ha descrito la aparicion deanticuerpos neutralizantes (AN) en un terciode los pacientes con esclerosis multiple tratadoscon interferon beta. Este estudio examinala frecuencia de aparicion de dichosanticuerpos y sus implicaciones clinicas. Pacientes y metodos Se han estudiado 68 pacientes.La determinacion de AN se realizomediante la tecnica de la proteina A del mixovirus. Resultados Se detectaron AN en el 13% delos pacientes a los 2 anos. Conclusiones No parece existir una relacionentre la presencia de AN y una peor evolucionde la esclerosis multiple.

Background Barkhof criteria have been adopted to demonstrate dissemination in space in the new multiple sclerosis diagnostic criteria because of their high specificity for predicting conversion to multiple sclerosis. One of the 4 Barkhof criteria is the presence of an infratentorial lesion. In clinically isolated syndromes (CIS) of the brainstem (CISB), the infratentorial criterion does not demonstrate dissemination in space, raising the possibility that the criteria may be less specific in CISB, as compared with specificity in other CIS, in which all 4 criteria demonstrate dissemination in space. Objective To compare the validity indices of Barkhof criteria in CISB with those in other CIS. Design Inception cohort with median follow-up of 34 months for CISB and 40 months for other CIS. Setting Institutional ambulatory referral center. Patients A sample of 51 patients with CISB and 102 patients with other CIS (46 with myelitis and 56 with optic neuritis) was analyzed. Barkhof criteria, with a cutoff of 3 of 4, were applied to magnetic resonance imaging performed at baseline. Four combinations each containing 3 parameters were also applied, with a cutoff of 2 of 3. Main Outcome Measure Specificity of unmodified Barkhof criteria and of the 4 combinations to predict conversion to clinically definite multiple sclerosis. Results The specificity of the criteria in CISB was 61% against 73% in other CIS. The combinations that retained the infratentorial lesion parameter had lower specificities in the CISB group; in analysis of the group with other CIS, no such differences were found. Conclusion The infratentorial lesion criterion is responsible for the lower specificity of Barkhof criteria in CISB.

The presence of oligoclonal bands (OCB) of immunoglobulin G (IgG) is in our days the most useful finding in the study of the CSF for the diagnosis of multiple sclerosis (MS). The most sensitive method for the detection of OCB is the isoelectric focusing followed by immunoblotting. The prevalence of OCB changes in different populations with a rank of results from 60 to 95 97%. We have determined the prevalence of OCB in our population and the sensitivity and the specificity of the technique used in our laboratory. We have included 391 patients in whom we analysed the presence of OCB, subdivided in; Group 0: Diagnosed of MS, group 1: First episode of demyelinating process, group 2: Neurological disorders considered noninflammatory or nonautoimmune (NINA),group 3: Neurological disorders considered inflammatory, infectious or autoimmune (IIA). The presence of OCB was searched in CSF and serum simultaneously using isoelectric focusing and immunoblotting. In order to standardize the technique we achieved and internal and external validation. Internal validation: sensitivity and specificity (using as a control group first the group NINA and after the group IA). External validation: we choose 10 pairs of CSF/serum from patients with different diagnostics and sent to a reference laboratory ( Karolinska Institute Medical School) that was blind of our results and of the diagnostics. The prevalence of OCB in each group has been: group 0 (MS): 87.7%, group 1: 54.8%, group 2 (NINA): 17.5%, group 3(IIA): 52.7%. Sensitivity: 97.7%, specificity using group NINA as control 82.5% and using group IIA 45.7%. Concordance with the reference laboratory in 9/10 determinations. We conclude that in our population the prevalence of OCB, in patients with MS, is lower than in Northern Europe. The OCB appear in may inflammatory, autoimmune diseases, their specificity for the diagnostic of MS is low.

Introduction Hypertrophic pachymeningitis is an infrequent condition which starts with a thickening of the dura mater and whose pathogenesis is unknown. We present two new cases of unknown aetiology. Clinical case Case 1. A 53 year old man complained of occipital headache, tinnitus and deafness since February 1981. In October 1981 he was admitted to hospital with a worse headache, perio-orbital pain, dysgeusia and ipsilateral peripheral facial palsy. In December he had generalized tonic-clonic seizures and paralysis of the VII and XI right cranial nerves and IX, X and XII left cranial nerves. In February 1982 he developed right trigeminal neuralgia. He was readmitted in November 1983 with continuous headache, vomiting and a behavior disorder. On CT there was marked attenuation of the posterior dura mater, which the neurosurgical department considered unsuitable for biopsy. He died in March 1985. On necropsy there was hypertrophic pachymeningitis. Case 2. A 62 year old patient consulted in November 1995 complaining of right hypoacusia for the past six months, progressively accompanied by ipsilateral paralysis of the II, IV, VI, VII and VIII cranial nerves but with no other alterations on physical examination. Analytical and serological investigations were normal. Cranial MR showed an extraparenchymatous infiltrating lesion in the middle cranial fossa. Biopsy was decided on when no clinical improvement was seen with corticosteroid treatment. The pathologist reported hypertrophic pachymeningitis. Treatment was started with cyclophosphamide in monthly doses and the condition has remained stable to date. Conclusion With these two cases we wish to establish a pathogenic relation between the Tolosa-Hunt syndrome and orbital pseudotumor and show the role played by immunosuppressive treatment in the control of hypertrophic pachymeningitis.

Introduction The incidence of sarcoidosis in our country is one of the lowest in Europe. Neurosarcoidosis affects only 5% on patients with sarcoidosis. Clinical cases. We describe four patients in which neurologic disfunction was the presenting finding. Initial neurological symptoms include status epilepticus, headache, fever and nerve cranial palsies. MRI showed a spectrum of protean central nervous abnormalities: 1. Hypotalamic infiltrating lesion; 2. Brain parenchyme enhanced masses; 3. Leptomeningeal enhancement, and 4. Focal white-matter lesions. Thoracic CT scan, bronchoscopy, Gallium scintigraphy and pulmonary biopsy yielded to diagnosis in three patients. Biopsy of the meninges was required in one patient because systemic involvement was not found. Histological examination of an intracranial mass was also performed in another patient to rule out tumoral lesions. ACE in serum was normal in all patients. CSF ACE was determine in only one patient and was also normal. Three patients started treatment with corticosteroids but one of them required adjuvant treatment with immunosuppressor. Cranial nerve palsy resolved spontaneously in the last patient. Conclusions Clinical and radiological polymorphism explained the delay before diagnosis and the problems in ruling out other diseases. MRI is highly useful for the diagnosis and follow up treatment.

Interferon-α (IFN-α) is widely used for the treatment of chronic viral hepatitis. There have been some reports concerning the development of autoimmune diseases, particularly thyroid disease, in patients under treatment with IFN.1 Disorders including autoimmune haemolytic anaemia, pernicious anaemia, thrombocytopenic purpura, systemic lupus erythematosus, Raynaud′s disease, parotiditis, and epididymitis have been reported. Some neurological problems have also been described2; although most such adverse events have involved the CNS, several cases of peripheral nervous system involvement have been reported—namely, axonal polyneuropathy,3 neuralgic amyotrophy, multiple mononeuropathies, and myasthenia gravis.4 On the other hand, some authors have reported that IFN-α may be an effective alternative therapy in patients with chronic inflammatory demyelinating polyneuropathy …

Introduction Retino-cerebellar hemangioblastomatosis or Von Hippel-Lindau (VHL) disease is a phacomatosis with a dominant autosomal pattern of inheritance, which is characterized by the presence of hemangioblastomas of the central nervous system (cerebellum and spinal medulla), retinal angiomas and tumors (pheochromocytoma, clear cell carcinoma) or cysts of the abdominal viscera. Clinical case We present the case of a 22 year old female with Von Hippel-Lindau disease, in whom a cystic hemangioblastoma of the basal ganglia of the left hemisphere was diagnosed when she complained of difficulty in carrying out fine movements of the right hand and tremor for some months. The supratenorial site of cystic hemangioblastomas in the clinical context of Von Hippel-Lindau disease is very rare and clinical presentation of a parkinsonian hemisyndrome is exceptional. In our search through the literature we have found tumors with many types of histology (meningiomas, glial tumors, craniopharyngioma, epidermoid cysts) in the origin of tumoral parkinsonism. Conclusions However, we have found no previous case of cystic hemangioblastomas. We also emphasize that there was full resolution of the condition after total removal of the tumour.

INTRODUCTION Demonstration of the efficacy of interferon beta IB in the reduction of outbreaks of multiple sclerosis has led to it being used in Spain. DEVELOPMENT Discussion of the current situation regarding the use of interferon beta IB in Spain, diagnostic criteria, side-effects and future outlook. CONCLUSIONS Use of interferon beta IB in Spain has followed criteria established by a Committee of Experts, and there is a lower rate of non-completion of treatment than in the U.S.A. New possibilities arise with the appearance of new drugs which are still awaiting evaluation.

We carried out a prospective study of the prevalence and characteristics of anticardiolipin antibodies (aCL) and migraine on 103 consecutive patients with systemic lupus erythematosus (SLE) derived from three European referral university centers. We also included a control group of 58 patients with migraine not associated with SLE. We interviewed all patients using a data collection form designed to provide a complete record of the clinical characteristics of headache. Fifty-four (52%) patients with SLE suffered recurrent headache. We diagnosed migraine in 32 patients, tension headache in 21, and cluster headache in one. Thirty (29%) patients with SLE had aCL. Migraine was present in five patients with aCL and in 27 patients without aCL (17% versus 37%, p = 0.07). No migraine control patient had aCL. Our study highlights the frequency of headache in SLE, but does not support an association between the presence of aCL and migraine in this disease.

A 62 year old man suddenly presented with a pure left sensory deficit involving only pain and temperature sensations. CT scan and MRI showed a small haemorrhage in the dorsolateral part of the right midbrain. This suggested a lesion limited to the right dorsal spinothalamic tract.

Pathogenesis of neuropsychiatric manifestations of systemic lupus erythematosus (SLE) has not been clearly defined, and the search for pathogenic mechanisms has focused on the importance of several autoantibodies. There is increasing evidence that antibodies against gangliosides may have a pathogenic role in some neurological disorders. The aim of the present study was to examine the association between antibodies against gangliosides and neuropsychiatric SLE. We found anti-type II ganglioside antibodies in two out of 32 patients with multiple sclerosis (6.25%) and in 10 out of 60 patients with SLE (16.6%); five of 17 patients with neurological abnormalities also had high levels of these antibodies (29.4%). Five of the 10 patients with SLE and positive antiganglioside antibody assays had only IgM antibodies, three had IgG antibodies and two had both isotypes. By chi-square analysis, the incidence of anti-type II ganglioside antibodies was not significantly higher in patients with symptoms related to the nervous system than in SLE patients without neurological involvement (P > 0.2). No clear correlation was found between antibodies against gangliosides and cardiolipin.

BACKGROUND AND PURPOSE: Detection of disease activity, defined as new/enlarging T2 lesions on brain MR imaging, has been proposed as a biomarker in MS. However, detection of new/enlarging T2 lesions can be hindered by several factors that can be overcome with image subtraction. The purpose of this study was to improve automated detection of new T2 lesions and reduce user interaction to eliminate inter- and intraobserver variability. MATERIALS AND METHODS: Multiparametric brain MR imaging was performed at 2 time points in 36 patients with new T2 lesions. Images were registered by using an affine transformation and the Demons algorithm to obtain a deformation field. After affine registration, images were subtracted and a threshold was applied to obtain a lesion mask, which was then refined by using the deformation field, intensity, and local information. This pipeline was compared with only applying a threshold, and with a state-of-the-art approach relying only on image intensities. To assess improvements, we compared the results of the different pipelines with the expert visual detection. RESULTS: The multichannel pipeline based on the deformation field obtained a detection Dice similarity coefficient close to 0.70, with a false-positive detection of 17.8% and a true-positive detection of 70.9%. A statistically significant correlation ( r = 0.81, P value = 2.2688e-09) was found between visual detection and automated detection by using our approach. CONCLUSIONS: The deformation field–based approach proposed in this study for detecting new/enlarging T2 lesions resulted in significantly fewer false-positives while maintaining most true-positives and showed a good correlation with visual detection annotations. This approach could reduce user interaction and inter- and intraobserver variability.

Interferon-beta1b treatment in relapsing-remitting multiple sclerosis can frequently induce systemic side effects such as flu-like symptoms with fever. In vitro stimulation of peripheral blood leukocytes with interferon-beta1b before the beginning of therapy shows that patients who develop fever generally have increased levels of interleukin-6.

Background: Recently developed diagnostic criteria for MS (McDonald criteria) indicate that in patients with a single demyelinating episode (clinically isolated syndromes [CIS]), evidence for dissemination in space and time, essential for diagnosis, may be provided by MRI. Objective: To assess the usefulness of these new criteria in patients with CIS suggestive of MS. Methods: A total of 139 patients with CIS followed for a median of 3 years underwent brain MRI within 3 months of their first attack and again 12 months later. The number and location of lesions at baseline, the development of new lesions at follow-up, and the results of CSF examination (which, if positive, requires fewer MR abnormalities for diagnosis) were analyzed. The new McDonald criteria (incorporating MRI) were compared to the existing Poser diagnostic criteria and their accuracy was evaluated. Results: At 12 months, 11% had clinically definite MS according to the Poser criteria compared to 37% with the McDonald criteria. Eighty percent of patients fulfilling these new criteria developed a second clinical episode within a mean follow-up of 49 months. The new criteria showed a sensitivity of 74%, specificity of 86%, and accuracy of 80% in predicting conversion to clinically definite MS. Conclusion: One year after symptom onset, more than three times as many patients with CIS were diagnosed with MS using new diagnostic criteria incorporating MRI results compared to older criteria. However, the proposed MRI criteria require further prospective studies to optimize sensitivity and specificity.