Joaquín Castilló

Measures in the first year of therapy predict the response to interferon β in MS

Background and objective Several criteria for treatment response to interferon beta (IFNβ) have been proposed, although there is no consensus among different investigators. Hence, the aim of this study was to investigate magnetic resonance imaging (MRI) and clinical predictors of response during the first 12 months of therapy. Methods This is a prospective and longitudinal study of relapsing-remitting multiple sclerosis (RRMS) patients treated with IFNβ. Patients were classified based on the presence of new lesions on MRI, relapses, confirmed disability increase, or combinations of all these variables after 1 year of therapy. Regression analysis was performed in order to identify variables of response after a follow-up of 3 years. Results We included 222 RRMS patients. The logistic model demonstrated that only the combination of new active lesions on MRI with the presence of relapses (OR 4.4; 95% CI 1.6–12.5) or disability progression (Odds Ratio (OR) 7.1; 95% Confidence Interval (CI) 1.6–33.9), or both (OR 6.5; 95% CI 1.9–23.4) achieved significant values to identify those patients with a poor outcome. Conclusions In RRMS patients treated with IFNβ, the combination of measures of disease activity and the presence of new active lesions on MRI may have a prognostic value for identifying patients with disease activity in the second and third year of therapy.

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.

Plasma exchange for acute attacks of CNS demyelination Predictors of improvement at 6 months

Background: Plasma exchange (PE) is used to treat severe episodes of CNS demyelination unresponsive to corticosteroids. Predictors of long-term response are not well known. Methods: We retrospectively reviewed the medical records of 41 patients consecutively treated by PE between January 1995 and July 2007. The primary outcome was improvement at 6 months after PE defined as decrease of ≥1 point in the Expanded Disability Status Scale (EDSS) score for patients with EDSS ≤7.5 or 1.5 points with EDSS ≥8.0 or improvement of more than 2 lines in the visual acuity chart for patients with optic neuritis (ON). Results: Twenty-five patients (61%) were women, and the median age was 33 years (range 14–57 years). Twenty-three (56%) had multiple sclerosis, 2 (5%) had clinically isolated syndrome, 2 (5%) had Marburg disease, 7 (17%) had acute disseminated encephalomyelitis, 4 (10%) had neuromyelitis optica, 2 (5%) had idiopathic ON, and 1 (2%) had idiopathic transverse myelitis. The median EDSS score before the attack was 1.0 (range 0–6.5). At PE onset, the median EDSS score was 7.0 (range 3.0–9.5). Sixteen patients (39%) improved at discharge, and 26 (63%) improved at 6 months. In the multivariate analysis, early initiation of PE (odds ratio [OR] 6.29, 95% confidence interval [CI] 1.18–52.96) and improvement at discharge (OR 7.32, 95% CI 1.21–44.38) were significantly associated with response at 6 months. Conclusions: Plasma exchange (PE) was associated with clinical improvement in 63% of patients at 6 months. Early initiation of PE and improvement at discharge were predictors of this response. Twelve patients (48%) who did not improve early did so during follow-up.

Brainstem lesions in clinically isolated syndromes

Background: Number of baseline lesions has been shown to predict future attacks and disability in clinically isolated syndromes (CIS). Objective: To investigate the role of baseline infratentorial lesions in long-term prognosis. Methods: Subjects were included in a prospective cohort of patients with CIS. Patients underwent brain MRI within 3 months after CIS onset. Number and location of lesions at baseline were prospectively studied. Retrospective scan analysis was conducted to specifically look at number and location of infratentorial lesions. We analyzed the time to a second attack and to reach EDSS 3.0. Results: We included 246 patients with CIS followed for a median of 7.7 years. Patients with infratentorial lesions had both a higher risk of conversion (71.4% vs 29.6%; hazard ratio [HR] 3.3; 95% confidence interval [CI] 2.2–4.8; p < 0.001) and of developing disability (32.5% vs 12.4%; HR 2.4; 95% CI 1.3–4.3; p = 0.003). Presence of at least one cerebellar lesion was associated with an increased risk of conversion (HR 2.4; 95% CI 1.3–4.5; p = 0.007). Presence of at least one brainstem lesion increased both the risk of conversion (HR 2.9; 95% CI 1.7–5.0; p < 0.001) and disability (HR 2.5; 95% CI 1.1–5.4; p = 0.026). Broken down into number of lesions, the presence of infratentorial lesions increased both the risk of conversion (83% vs 61%) (HR 22.3; 95% CI 9.7–51.1; p < 0.001) and of reaching EDSS 3.0 (40% vs 19%) (HR 3.2; 95% CI 1.3–7.4; p = 0.008) only in patients with 9 or more lesions. Conclusions: Presence of infratentorial lesions increases the risk for disability. Brainstem rather than cerebellar lesions may be responsible for poor prognosis.

Clinical impact of early brain atrophy in clinically isolated syndromes.

Background: The impact of global and tissue-specific brain atrophy on conversion to multiple sclerosis (MS) after a clinically isolated syndrome (CIS) is not fully gauged. Objectives: We aimed to determine the magnitude and clinical relevance of brain volume dynamics in the first year after a CIS. Methods: We assessed 176 patients with CIS within 3 months of onset, clinically and by conventional magnetic resonance imaging (MRI) scans, at baseline and 1 year after clinical onset. We determined the percentage of brain volume change (PBVC) and the brain parenchymal (BPF), grey matter (GMF) and white matter (WMF) fractions. Results: The mean follow-up time was 53 months (SD = 16.8): 76 patients (43%) experienced a second attack, 32 (18%) fulfilled MRI-only 2005 McDonald criteria and 68 (39%) remained as CIS. Statistically significant decreases in the volume measures tested were observed in patients with a second attack, for BPF and PBVC; in both MS groups for GMF; whereas in all groups, the WMF was unchanged. Patients with a second attack had larger PBVC decreases (− 0.65% versus + 0.059%; p < 0.001). PBVC decreases below − 0.817% independently predicted shorter times to a second attack. Conclusions: Global brain and grey matter volume loss occurred within the first year after a CIS; brain volume loss predicted conversion to MS.

Early brain pseudoatrophy while on natalizumab therapy is due to white matter volume changes

Background: Investigation of atrophy data from a pivotal natalizumab trial has demonstrated an increased rate of volume loss, compared to placebo, after the first year of therapy. It was considered to be probably due to a pseudoatrophy effect. Objective: To assess grey and white matter volume changes and their relation to global brain volume changes and to baseline inflammation, for patients under natalizumab therapy. Methods: We selected 45 patients on natalizumab therapy for at least 24 months, with magnetic resonance imaging (MRI) scans at baseline, 12 and 24 months. We calculated the percentage brain volume change (PBVC) for the first and second year, using SIENA software. Grey and white matter fractions (GMF and WMF, respectively) for the first year were calculated with SPM5, using lesion masks. After quality checks, six patients were excluded. We studied the predictive variables of change in brain volumes. Results: The PBVC decrease was faster during the first year (−1.10% ± 1.43%), as compared to the second (−0.51% ± 0.96%) (p = 0.037). These differences were more marked in patients with baseline gadolinium-enhancing lesions (p = 0.005). Mean GMF and WMF changes during the first year of treatment were +1.15% (n.s.) and −1.72% (p = 0.017), respectively. The presence of active lesions at baseline MRI predicted PBVC (p = 0.022) and WMF change (p = 0.026) during the first year of treatment, after adjusting for age and corticosteroid treatment. No predictors were found for GMF volume changes. Conclusion: Early brain volume loss during natalizumab therapy is mainly due to WMF volume loss and it is related to the inflammatory activity present at the onset of therapy. We found that the pseudoatrophy effect is mostly due to white matter volume changes.

Change in the clinical activity of multiple sclerosis after treatment switch for suboptimal response

Background:  Therapy for multiple sclerosis (MS) has a partial efficacy, and a significant proportion of treated patients will develop a suboptimal response with first‐line disease‐modifying drugs (DMD). Therapy switch in patients with MS can be a strategy after a treatment failure. We studied the change in clinical activity after switching of first‐line DMD because of a treatment failure.

Do multimodal evoked potentials add information to MRI in clinically isolated syndromes

The role of multimodal evoked potentials (MMEPs) in establishing multiple sclerosis (MS) diagnosis and prognosis has diminished nowadays. The objective of this article is to evaluate whether MMEPs add information to MRI in identifying patients with higher risk of relapse or development of disability after a clinically isolated syndrome (CIS). Patients who underwent visual, somato-sensory and brainstem auditory evoked potentials (EPs) were identified from a cohort of consecutive CIS. Patients also underwent brain MRI within 3 months of first attack. We analysed time to second attack and to Expanded Disability Status Scale (EDSS) score of 3.0 according to number of Barkhof criteria and number of abnormal MMEPs. A complete study was performed in 245 patients who were followed for a mean of 76.4 months (interquartile range: 61 to 96). Seventy-one patients (29%) had the three EPs normal, 115 patients (47%) had one abnormal EP; 40 patients (16%) had two; and 19 patients (8%) had three abnormal EPs. Baseline MRI determined the risk for converting to clinically definite MS and correlated with disability according to previous studies. EPs individually did not modify the risk of conversion or disability. However, the presence of three abnormal EPs increased the risk of reaching moderate disability (hazard ratio 7.0; 1.4—34.9) independently of baseline MRI. In conclusion, in the presence of three abnormal EPs could help identify CIS patients with a higher risk of developing disability, independently of MRI findings. However, the utility of MMEPs is limited by the low percentage of CIS patients having the three abnormal at baseline.

Analysis of prognostic factors associated with longitudinally extensive transverse myelitis

Objective: The aim of this study is to report the clinical profile and outcome of longitudinally extensive transverse myelitis (LETM). Methods: We prospectively studied adult patients who presented with LETM from January 2008 to December 2011. Information on demographic, clinical course, magnetic resonance imaging (MRI) and outcome was collected. HLA-DRB1 genotype was compared with those of 225 normal controls and patients with MS (228) and neuromyelitis optica (NMO) (22). Results: In total, 23 patients (16 female) with a median age of 44.5 years (range: 20–77 years) were included. Most (74%) had moderate–severe disability at nadir (48% non-ambulatory), normal/non-multiple sclerosis (MS) brain MRI (96%) and a median MRI cord lesion of 5 vertebral segments (range: 3–19). Laboratory analysis showed cerebrospinal fluid pleocytosis (45%), NMO-IgG (9%), antinuclear antibodies (70%), and genotype HLA-DRB1*13 (57%). The frequency of DRB1*13 genotype was higher compared with controls (p=0.002), MS (p=0.001) and NMO (p= 0.003) patients. After a median follow-up of 32 months, one patient converted to MS, two had relapsing LETM with NMO-IgG, and 20 remained as idiopathic with recurrences in four (20%). Twelve (52%) patients recovered with minimal disability (Expanded Disability Status Scale (EDSS) <2.5) and three (13%) remained wheelchair dependent. Disability at nadir was associated with the final outcome and extension of the spinal cord lesion with risk of recurrence. Recurrence was not associated with worse outcome. Conclusions: Inflammatory LETM is mostly idiopathic with a good outcome. It includes a relatively homogenous group of patients with an overrepresentation of the HLA-DRB1*13 genotype. EDSS at nadir is a predictor of the final outcome and extension of the myelitis of the recurrence risk.

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.