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The diagnostic criteria used in primary progressive (PP) and relapsing-remitting (RR) multiple sclerosis (MS) show substantial differences. This introduces complexity in the diagnosis of MS which could be resolved if these criteria could be unified in terms of the requirements for dissemination in space (DIS). The aim of this study was to assess whether a single algorithm may be used to demonstrate DIS in all forms of MS. Five sets of RRMS criteria for DIS were applied to a cohort of 145 patients with established PPMS (mean disease duration: 11 years - PPMS-1): C1: Barkhof-Tintoré (as in 2005 McDonald's criteria); C2: Swanton et al. (as in JNNP 2006); C3: presence of oligoclonal bands plus two lesions (as in McDonald's criteria); C4 and C5: a two-step approach was also followed (patients not fulfilling C1 or C2 were then assessed for C3). Two sets of PPMS criteria for DIS were applied: C6: Thompson et al. (as in 2001 McDonald's criteria); C7: 2005 McDonald criteria. A second sample of 55 patients with less than 5 years of disease duration (PPMS-2) was also analysed using an identical approach. For PPMS-1/PPMS-2, fulfilment was: C1:73.8%/66.7%; C2:72.1%/59.3%; C3:89%/79.2%; C4:96%/92.3%; C5:96%/85.7%; C6:85.8%/78.7%; C7:91%/80.4%. Levels of fulfilment suggest that the use of a single set of criteria for DIS in RRMS and PPMS might be feasible, and reinforce the added value of cerebrospinal fluid (CSF) findings to increase fulfilment in PPMS. Unification of the DIS criteria for both RRMS and PPMS could be considered in further revisions of the MS diagnostic criteria.

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

Objective: To evaluate the clinical significance of the 2005 modified imaging criteria for dissemination in time in multiple sclerosis stating that detection of a new T2 lesion appearing at any time compared with a reference scan done at least 30 days after the onset of a clinically isolated syndrome implies dissemination in time., Methods: We included consecutive patients younger than 50 years examined at our center within 3 months of a clinical syndrome suggestive of central nervous system demyelination of the type seen in multiple sclerosis and followed for at least 3 years. We classified patients into one of two groups, according to the timing when reference scan was performed: less than 30 days and at least 30 days after symptom onset. We analyzed the interaction in time to relapse between timing of reference scan and new T2 lesion effect., Results: A total of 218 patients were included. The hazard ratio (95% confidence interval) of this interaction was 0.90 (0.31-2.62) (or 1.02 (0.27-3.91) in patients with dissemination in space)., Conclusions: We conclude that new T2 lesions increased relapse risk regardless of timing of the reference scan, supporting the use of scans performed at any time within 30 days of symptom onset for dissemination in time demonstration.

Objectives: To study the management of pregnancy in multiple sclerosis (MS) patients on immunomodulatory therapy (IMT) in routine clinical practice and to analyze pregnancy outcomes and the clinical course of MS around pregnancy., Methods: Retrospective, multicentric study in Spain in MS patients receiving IMT before conception and followed for at least three months post-partum., Results: A total of 1286 medical records were reviewed. Eighty-eight pregnancies were identified in 74 (6%) women, 66% of which were unexposed and 34% exposed pregnancies. In most cases, IMT was discontinued before conception and resumed shortly after delivery. Accidental exposure to IMT did not lead to higher rates of abortions (P = 0.76) or malformations. The relapse rate was decreased during pregnancy (0.31 versus 0.61 in the pre-pregnancy year) and increased after delivery (0.87 on month 3), returning to pre-conception values on month 12. The median EDSS score was not increased during the study., Conclusions: Discontinuation of IMT before conception, and resumption shortly after delivery was the most frequent clinical practice procedure. Accidental exposure to IMT did not affect pregnancy outcomes or increased malformation rates. Pregnancy was associated with a reduced relapse rate. No factor was found to predict the risk of relapses during or after pregnancy.

Clinically isolated syndromes (CIS) classically refer to optic neuritis (ON), brainstem or spinal cord syndromes. Less common first episodes suggestive of central nervous system (CNS) demyelination, such as hemispheric or clinically polyregional syndromes, have been only slightly studied. The aim of this study was to describe these CIS topographies in our cohort of patient with a CIS. We evaluated 320 patients with a CIS, and classified the topographies of the attacks according to clinical symptoms only into CIS of the optic nerve (123), brainstem (78), spinal cord (89), hemispheric (6), polyregional (12) or undetermined (12) topographies. Patients underwent brain MRI within three months of their first attack, and again 12 months later. Conversion to multiple sclerosis (MS), determined either clinically or by magnetic resonance imaging (MRI), was evaluated according to topography. Hemispheric and polyregional syndromes were closer to brainstem or spinal cord syndromes than ON in clinical and MRI conversion terms, although a statistical analysis was not performed because of the small number of patients. There are differences between several studies in the definition, and, therefore, the prevalence of these so-called atypical CIS. Consensus on the denomination and definition of these syndromes must be reached.

Objective: To assess the long-term emotional state of multiple sclerosis (MS) patients treated with interferon beta (IFNbeta) for at least four years., Methods: Patients who had started IFNbeta 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 IFNbeta 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 IFNbeta therapy. The comparisons, obtained from baseline and follow-up scores, showed an improvement in the depressive and anxiety symptoms of patients who adhered to IFNbeta 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 IFNbeta for a long period of time. Increased disability and the presence of baseline depressive symptoms predicted the presence of depressive symptoms at follow-up.

Background and Objective: Fatigue is one of the most limiting symptoms in multiple sclerosis (MS) and the mechanisms underlying its origin are poorly understood. Our aim was to test whether fatigue in MS is associated with endocrine markers., Methods: We longitudinally studied 73 progressive MS patients. Fatigue was assessed at baseline and at 3, 6, 12 and 24 months using the Fatigue Severity Scale (FSS). Given the longitudinal design of our study, patients were labelled as sustained fatigued when FSS scores were >5.0 at all time points, and as non-fatigued when FSS scores were < or = 5.0 at all time points. Serum levels of dehydroepiandrosterone (DHEA), its sulphated conjugate (DHEAS) and cortisol were measured at each time point., Results: Twenty-nine patients scored >5.0 in the FSS at all time points, and 9 patients (12.3%) scored 5.0 at all time points. Mean baseline levels of DHEAS and DHEA were lower in MS patients with sustained fatigue when compared to patients without fatigue (P = 0.01 and P = 0.03 respectively). Analysis of DHEAS and DHEA over time showed significantly lower hormone levels in patients with fatigue [F(1,31) = 6.14, P=0.019 for DHEAS; F(1,32) = 6.63, P=0.015 for DHEA]., Conclusions: Fatigue in progressive MS could be related to low serum levels of DHEA and DHEAS. Our results suggest that these hormones should be considered as biological markers of fatigue in MS patients and that hormone replacement may thus be tested as an option to treat fatigue in MS patients.

Background: Awareness of the factors influencing discontinuation of immunomodulatory drugs (IMD) treatment in multiple sclerosis (MS) can help to find approaches to patient management with the aim of establishing more specific indications and also attaining more optimal patient selection in future clinical trials., Objective: To identify the causes that influence adhesion to IMD therapy within the clinical practice in a large cohort of patients with MS., Patients and Methods: We have studied all MS patients who have initiated IMD in our hospital. All patients took part in training sessions where treatment expectations and side effects were explained and they received training in the administration technique. Reasons for stopping therapy were recorded during follow-up., Results: We studied 632 MS patients (mean follow-up was 47.1 (28.7) months). At the time of analysis, 107/632 patients (17%) were no longer receiving IMD. Almost half of the patients who stopped IMD (52/107) did so within the first two years on therapy. Fifty-six patients stopped IMD because of lack of efficacy. Only 27 patients (4.3%) discontinued treatment for reasons other than inefficacy or side effects. The proportion of patients with secondary progressive MS that stopped IMD therapy was 30%, while only 13.5% of the patients with relapsing remitting MS stopped therapy (P < 0.0001). Expanded Disability Status Scale (EDSS) score at entry was the main factor that predicted interruption of therapy., Conclusions: The proportion of patients interrupting IMD in our centre is low, possibly due to individualized care. Higher EDSS, mainly in the first two years of treatment, is the main factor related with interruption. Close follow-up of these patients would be useful in avoiding early discontinuation of therapy.

Background: As a symptom of multiple sclerosis (MS), fatigue is difficult to manage because of its unknown etiology, the lack of efficacy of the drugs tested to date and the absence of consensus about which would be the ideal measure to assess fatigue., Objective: Our aim was to assess the frequency of fatigue in a sample of MS patients and healthy controls (HC) using two fatigue scales, the Fatigue Severity Scale (FSS) and the Modified Fatigue Impact Scale (MFIS) with physical, cognitive and psychosocial subscales. We also studied the relationship fatigue has with depression, disability and interferon beta., Methods: Three hundred and fifty-four individuals (231 MS patients and 123 HC) were included in this cross-sectional study. Fatigue was assessed using the FSS and MFIS. Depression was measured by the Beck Depression Inventory (BDI), and disability by the Expanded Disability Status Scale (EDSS). A status of fatigue was considered when the FSS > or =5, of non-fatigue when the FSS < or =4, and scores between 4.1 and 4.9 were considered doubtful fatigue cases., Results: Fifty-five percent of MS patients and 13% of HC were fatigued. The global MFIS score positively correlated with the FSS in MS and HC (r =0.68 for MS and r =0.59 for HC, p <0.0001). Nonetheless, the MFIS physical subscale showed the strongest correlation score with the FSS (r =0.75, p <0.0001). In addition, a prediction analysis showed the physical MFIS subscale to be the only independent predictor of FSS score (p <0.0001), suggesting other aspects of fatigue, as cognition and psychosocial functions, may be explored by the FSS to a lesser extent. Depression also correlated with fatigue (r =0.48 for the FSS and r =0.7 for the MFIS, p <0.0001) and, although EDSS correlated with fatigue as well, the scores decreased after correcting for depression. Interferon beta showed no relationship with fatigue., Conclusions: Fatigue is a frequent symptom found in MS patients and clearly related with depression. Each fatigue scale correlates with one another, indicating that they are measuring similar constructs. Nevertheless, spheres of fatigue as cognition and psychosocial functions are probably better measured by the MFIS, although this hypothesis will need to be confirmed with appropriate psychometrical testing.