Ingrid Galán

Defining the response to interferon-β in relapsing-remitting multiple sclerosis patients

Many patients with multiple sclerosis (MS) are currently receiving treatment with interferon (IFN)–β. Early identification of nonresponder patients is crucial to try different therapeutic approaches. We investigated various criteria of treatment response to assess which criterion better identifies patients with a poor response.

Does the Modified Fatigue Impact Scale offer a more comprehensive assessment of fatigue in MS

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≥ 5, of non-fatigue when the FSS≤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.

Defining high, medium and low impact prognostic factors for developing multiple sclerosis.

Natural history studies have identified factors that predict evolution to multiple sclerosis or risk of disability accumulation over time. Although these studies are based on large multicentre cohorts with long follow-ups, they have limitations such as lack of standardized protocols, a retrospective data collection or lack of a systematic magnetic resonance imaging acquisition and analysis protocol, often resulting in failure to take magnetic resonance and oligoclonal bands into account as joint covariates in the prediction models. To overcome some of these limitations, the aim of our study was to identify and stratify baseline demographic, clinical, radiological and biological characteristics that might predict multiple sclerosis development and disability accumulation using a multivariate approach based on a large prospective cohort of patients with clinically isolated syndromes. From 1995 to 2013, 1058 patients with clinically isolated syndromes were included. We evaluated the influence of baseline prognostic factors on the risk for developing clinically definite multiple sclerosis, McDonald multiple sclerosis, and disability accumulation (Expanded Disability Status Scale score of 3.0) based on univariate (hazard ratio with 95% confidence intervals) and multivariate (adjusted hazard ratio with 95% confidence intervals) Cox regression models. We ultimately included 1015 patients followed for a mean of 81 (standard deviation = 57) months. Female/male ratio was 2.1. Females exhibited a similar risk of conversion to multiple sclerosis and of disability accumulation compared to males. Each younger decade at onset was associated with a greater risk of conversion to multiple sclerosis and with a protective effect on disability. Patients with optic neuritis had a lower risk of clinically definite multiple sclerosis [hazard ratio 0.6 (0.5-0.8)] and disability progression [hazard ratio 0.5 (0.3-0.8)]; however, this protective effect remained marginal only for disability [adjusted hazard ratio 0.6 (0.4-1.0)] in adjusted models. The presence of oligoclonal bands increased the risk of clinically definite multiple sclerosis [adjusted hazard ratio 1.3 (1.0-1.8)] and of disability [adjusted hazard ratio 2.0 (1.2-3.6)] independently of other factors. The presence of 10 or more brain lesions on magnetic resonance increased the risk of clinically definite multiple sclerosis [adjusted hazard ratio 11.3 (6.7-19.3)] and disability [adjusted hazard ratio 2.9 (1.4-6.0)]. Disease-modifying treatment before the second attack reduced the risk of McDonald multiple sclerosis [adjusted hazard ratio 0.6 (0.4-0.9)] and disability accumulation [adjusted hazard ratio 0.5 (0.3-0.9)]. We conclude that the demographic and topographic characteristics are low-impact prognostic factors, the presence of oligoclonal bands is a medium-impact prognostic factor, and the number of lesions on brain magnetic resonance is a high-impact prognostic factor.

Assessment of different treatment failure criteria in a cohort of relapsing–remitting multiple sclerosis patients treated with interferon β: Implications for clinical trials

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 β. 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.

A functional magnetic resonance proof of concept pilot trial of cognitive rehabilitation in multiple sclerosis

Background: Cognitive impairment is frequent in multiple sclerosis (MS) and lacks effective treatment. Cognitive rehabilitation is widely applied in neurorehabilitation settings. Functional magnetic resonance imaging (fMRI) may help in investigating changes in brain activity and provide a tool to assess the efficacy of rehabilitation. Aim: To investigate the effect on brain activity as measured by fMRI of a cognitive rehabilitation programme in patients with MS and cognitive impairment. Method: Fifteen patients with MS and cognitive impairment and five healthy subjects were recruited. Neuropsychological assessments were performed in patients with MS at study entry and after rehabilitation to assess cognitive changes. fMRI scans were performed at week −5 (baseline), week 0 (immediately before rehabilitation) and week 5 (immediately after rehabilitation). The fMRI paradigm was the Paced Auditory Serial Addition Test (PASAT). The cognitive rehabilitation programme was composed of 15 computer-aided drill and practice sessions and five non-computer-aided cognitive stimulation group sessions (over 5 weeks). Strict guidelines ensured comparability of all rehabilitation interventions. Results: Patients had increased brain fMRI activity after rehabilitation in several cerebellar areas when compared with healthy subjects. After rehabilitation, patients had significantly improved their performance on the backward version of the Digit Span Test (p = 0.007) and on a composite score of neuropsychological outcomes (p = 0.009). Conclusion: The results of the present study indicate that this cognitive rehabilitation programme increases brain activity in the cerebellum of cognitively impaired patients with MS. The role of fMRI in the assessment of neurorehabilitation schemes warrants further investigation.

Interferon beta in relapsing-remitting multiple sclerosis. An eight years experience in a specialist multiple sclerosis centre.

Background and objectiveLong–term observational studies may provide additional information about the behaviour of different drugs in the post–marketing period. We present the data of our cohort of relapsing–remitting multiple sclerosis (RRMS) patients treated with interferon beta (IFNβ).MethodsWe analysed RRMS patients followed for at least 2 years. From 1995, we initiated therapy with IFNβ.As they became available, patients were allocated to one of the IFNs at standard doses (IFNβ–1b, IFNβ–1a i. m. or IFNβ–1a s. c.). Each patient was included in a follow–up protocol containing demographic and baseline clinical data.ResultsBetween 1995 and 2004, 382 patients have completed at least 2 years of follow–up. Significant differences at entry were observed. Patients on IFNβ–1b had a higher disease activity and disability at baseline than those on IFNβ–1a i. m. or IFNβ–1a s. c. A significant reduction in the relapse rate was observed for the three drugs (70 % for IFNβ–1b, 64% for IFNβ–1a i. m. and 74 % for IFNβ–1a s. c.). We observed a sustained progression of disability in 11% of patients on IFNβ–1b, 17% on IFNβ–1a i. m. and 19% on IFNβ–1a s. c.; and at four years of follow–up in 24% of patients on IFNβ–1b, 23% on IFNβ–1a i. m. and 35% on IFNβ–1a s. c. No unexpected major adverse events were observed with any of the drugs.ConclusionsInterferon beta is safe and well tolerated. The various registered interferon beta drugs provide a comparable efficacy in a large non–selected cohort of RRMS patients.

Different antiganglioside antibody pattern between relapsing-remitting and progressive multiple sclerosis.

Introduction— Multiple sclerosis (MS) is an autoimmune disorder, but an unique antigen has not been found. Antiganglioside antibodies (AGA) have been reported in MS, nevertheless, a clinical significance of AGA in MS has not been established. The aims of this study were to study AGA in sera of MS patients and to investigate relationships between AGA and clinical course of MS. Material and methods— 42 patients with MS who fulfilled the criteria of clinically definite disease (59% RRMS, 21% SPMS, 20% PPMS), 89 patients with systemic lupus erythematosus and 36 healthy controls were studied. A modification of previously described ELISA techniques was used to estimate serum IgG and IgM anti‐GM1, asialoGM1 and anti‐GDla antibodies. Results— 47.6% of the patients showed AGA reactivity. Anti‐GM1 was found in 38% of MS patients, anti‐asialoGM1 in 23.8% and anti‐GDla in 33.3%. IgG was the isotype more commonly found. A correlation between presence of AGA and progressive disease and between anti‐GDla and PPMS was found. Conclusions— The presence of AGA in MS patients is elevated. In contrast with the results of others authors, a strong correlation between AGA and progressive disease is showed in our study.

Significant clinical worsening after natalizumab withdrawal: Predictive factors

We aimed to single out multiple sclerosis (MS) cases with poor outcome after natalizumab withdrawal and to identify predictive variables. We ascertained 47 withdrawals, and compared their pre- and post-natalizumab periods. We objectively defined significant clinical worsening after natalizumab withdrawal as a 2-step increase in Expanded Disability Status Scale (EDSS). We performed regression models. As a group, post-natalizumab annualized relapse rate (ARR) was lower in the post-natalizumab period, and there were no differences in the mean number of gadolinium (Gd)-enhancing lesions between pre- and post-natalizumab magnetic resonance imaging (MRI). Corticosteroid treatment did not change the outcomes. Eight patients (19%) presented significant clinical worsening after natalizumab withdrawal, which was predicted by a higher baseline EDSS and a 1-step EDSS increase while on natalizumab.

Neurofilament light chain level is a weak risk factor for the development of MS

Objective: To determine the prognostic value of selected biomarkers in clinically isolated syndromes (CIS) for conversion to multiple sclerosis (MS) and disability accrual. Methods: Data were acquired from 2 CIS cohorts. The screening phase evaluated patients developing clinically definite MS (CIS-CDMS) and patients who remained as CIS during a 2-year minimum follow-up (CIS-CIS). We determined levels of neurofascin, semaphorin 3A, fetuin A, glial fibrillary acidic protein, and neurofilament light (NfL) and heavy chains in CSF (estimated mean [95% confidence interval; CI]). We evaluated associations between biomarker levels, conversion, disability, and magnetic resonance parameters. In the replication phase, we determined NfL levels (n = 155) using a 900 ng/L cutoff. Primary endpoints in uni- and multivariate analyses were CDMS and 2010 McDonald MS. Results: The only biomarker showing significant differences in the screening was NfL (CIS-CDMS 1,553.1 [1,208.7–1,897.5] ng/L and CIS-CIS 499.0 [168.8–829.2] ng/L, p < 0.0001). The strongest associations were with brain parenchymal fraction change (rs = −0.892) and percentage brain volume change (rs = −0.842) at 5 years. NfL did not correlate with disability. In the replication phase, more NfL-positive patients, according to the cutoff, evolved to MS. Every 100-ng/L increase in NfL predicted CDMS (hazard ratio [HR] = 1.009, 95% CI 1.005–1.014) and McDonald MS (HR = 1.009, 95% CI 1.005–1.013), remaining significant for CDMS in the multivariate analysis (adjusted HR = 1.005, 95% CI 1.000–1.011). This risk was lower than the presence of oligoclonal bands or T2 lesions. Conclusions: NfL is a weak independent risk factor for MS. Its role as an axonal damage biomarker may be more relevant as suggested by its association with medium-term brain volume changes.

Contribution of the symptomatic lesion in establishing MS diagnosis and prognosis

Objective: To study the contribution of the symptomatic lesion in establishing multiple sclerosis (MS) diagnosis and prognosis. Methods: We performed an observational study based on a prospective clinically isolated syndrome (CIS) cohort of 1,107 patients recruited for clinical and brain MRI follow-up from 1995 to 2014. Eligible patients (n = 954) were divided into 4 groups according to baseline MRI: patients with a normal MRI (n = 290); patients with a single asymptomatic lesion (n = 18); patients with a single cord/brainstem symptomatic lesion (n = 35); and patients with more than 1 lesion (n = 611). For each group, we studied the risk of second attack, with 2005 McDonald MS and Expanded Disability Status Scale 3.0, using univariable and multivariable regression models adjusted by age, sex, oligoclonal bands, and disease-modifying treatments. We tested the diagnostic performance of a modified dissemination in space (DIS) criterion that includes symptomatic lesions in the total count and compared it to the DIS criteria (at least 1 asymptomatic lesion in at least 2 of the 4 MS characteristic MS locations) for all patients and for the subgroup of patients with brainstem or spinal cord topography. Results: Patients with a cord/brainstem single symptomatic lesion have a higher risk of second attack and disability accumulation than patients with 0 lesions but have a similar risk compared to patients with 1 asymptomatic lesion. Diagnostic properties are reasonably maintained when the symptomatic lesion qualifies for DIS. Conclusions: Despite the recommendations of the 2010 McDonald criteria, symptomatic lesions should be taken into account when considering the diagnosis and prognosis of patients with CIS.