Georgina Arrambide

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.

Antibodies to MOG and AQP4 in adults with neuromyelitis optica and suspected limited forms of the disease

Objective: We aimed to report the frequency and implications of antibodies to myelin oligodendrocyte glycoprotein (MOG-ab) in adults with demyelinating syndromes suspicious for neuromyelitis optica (NMO). Methods: Samples from 174 patients (48 NMO, 84 longitudinally extensive myelitis (LETM), 39 optic neuritis (ON), and three acute disseminated encephalomyelitis (ADEM) who presented initially with isolated LETM) were retrospectively examined for AQP4-ab and MOG-ab using cell-based assays. Results: MOG-ab were found in 17 (9.8%) patients, AQP4-ab in 59 (34%), and both antibodies in two (1.1%). Among the 17 patients with MOG-ab alone, seven (41%) had ON, five (29%) LETM, four (24%) NMO, and one (6%) ADEM. Compared with patients with AQP4-ab, those with MOG-ab were significantly younger (median: 27 vs. 40.5 years), without female predominance (53% vs. 90%), and the clinical course was more frequently monophasic (41% vs. 7%) with a benign outcome (median Expanded Disability Status Scale: 1.5 vs. 4.0). In eight patients with paired serum-cerebrospinal fluid (CSF) samples, five had MOG-ab in both samples and three only in serum. Antibody titres did not differ among clinical phenotypes or disease course. MOG-ab remained detectable in 12/14 patients (median follow-up: 23 months) without correlation between titres’ evolution and outcome. Conclusion: MOG-ab identify a subgroup of adult patients with NMO, LETM and ON that have better outcome than those associated with AQP4-ab. MOG-ab are more frequently detected in serum than CSF and the follow-up of titres does not correlate with outcome.

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.

Chitinase 3-like 1: prognostic biomarker in clinically isolated syndromes.

Chitinase 3-like 1 (CHI3L1) has been proposed as a biomarker associated with the conversion to clinically definite multiple sclerosis in patients with clinically isolated syndromes, based on the finding of increased cerebrospinal fluid CHI3L1 levels in clinically isolated syndrome patients who later converted to multiple sclerosis compared to those who remained as clinically isolated syndrome. Here, we aimed to validate CHI3L1 as a prognostic biomarker in a large cohort of patients with clinically isolated syndrome. This is a longitudinal cohort study of clinically isolated syndrome patients with clinical, magnetic resonance imaging, and cerebrospinal fluid data prospectively acquired. A total of 813 cerebrospinal fluid samples from patients with clinically isolated syndrome were recruited from 15 European multiple sclerosis centres. Cerebrospinal fluid CHI3L1 levels were measured by enzyme-linked immunosorbent assay. Multivariable Cox regression models were used to investigate the association between cerebrospinal fluid CHI3L1 levels and time to conversion to multiple sclerosis and time to reach Expanded Disability Status Scale 3.0. CHI3L1 levels were higher in patients who converted to clinically definite multiple sclerosis compared to patients who continued as clinically isolated syndrome (P = 8.1 × 10(-11)). In the Cox regression analysis, CHI3L1 levels were a risk factor for conversion to multiple sclerosis (hazard ratio = 1.7; P = 1.1 × 10(-5) using Poser criteria; hazard ratio = 1.6; P = 3.7 × 10(-6) for McDonald criteria) independent of other covariates such as brain magnetic resonance imaging abnormalities and presence of cerebrospinal fluid oligoclonal bands, and were the only significant independent risk factor associated with the development of disability (hazard ratio = 3.8; P = 2.5 × 10(-8)). High CHI3L1 levels were associated with shorter time to multiple sclerosis (P = 3.2 × 10(-9) using Poser criteria; P = 5.6 × 10(-11) for McDonald criteria) and more rapid development of disability (P = 1.8 × 10(-10)). These findings validate cerebrospinal fluid CHI3L1 as a biomarker associated with the conversion to multiple sclerosis and development of disability and reinforce the prognostic role of CHI3L1 in patients with clinically isolated syndrome. We propose that determining cerebrospinal fluid chitinase 3-like 1 levels at the time of a clinically isolated syndrome event will help identify those patients with worse disease prognosis.

Neuromyelitis optica spectrum disorders Comparison according to the phenotype and serostatus

Objective: To (1) determine the value of the recently proposed criteria of neuromyelitis optica (NMO) spectrum disorder (NMOSD) that unify patients with NMO and those with limited forms (NMO/LF) with aquaporin-4 immunoglobulin G (AQP4-IgG) antibodies; and (2) investigate the clinical significance of the serologic status in patients with NMO. Methods: This was a retrospective, multicenter study of 181 patients fulfilling the 2006 NMO criteria (n = 127) or NMO/LF criteria with AQP4-IgG (n = 54). AQP4-IgG and myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) antibodies were tested using cell-based assays. Results: Patients were mainly white (86%) and female (ratio 6.5:1) with median age at onset 39 years (range 10–77). Compared to patients with NMO and AQP4-IgG (n = 94), those with NMO/LF presented more often with longitudinally extensive transverse myelitis (LETM) (p < 0.001), and had lower relapse rates (p = 0.015), but similar disability outcomes. Nonwhite ethnicity and optic neuritis presentation doubled the risk for developing NMO compared with white race (p = 0.008) or LETM presentation (p = 0.008). Nonwhite race (hazard ratio [HR] 4.3, 95% confidence interval [CI] 1.4–13.6) and older age at onset were associated with worse outcome (for every 10-year increase, HR 1.7, 95% CI 1.3–2.2). Patients with NMO and MOG-IgG (n = 9) had lower female:male ratio (0.8:1) and better disability outcome than AQP4-IgG-seropositive or double-seronegative patients (p < 0.001). Conclusions: In patients with AQP4-IgG, the similar outcomes regardless of the clinical phenotype support the unified term NMOSD; nonwhite ethnicity and older age at onset are associated with worse outcome. Double-seronegative and AQP4-IgG-seropositive NMO have a similar clinical outcome. The better prognosis of patients with MOG-IgG and NMO suggests that phenotypic and serologic classification is useful.

Early predictors of multiple sclerosis after a typical clinically isolated syndrome

Background: The 2010 McDonald criteria allow diagnosing multiple sclerosis (MS) with one magnetic resonance imaging (MRI) scan. Nevertheless, not all patients at risk fulfil criteria at baseline. Other predictive factors (PFs) are: age ≤40 years, positive oligoclonal bands (OBs), and ≥3 periventricular lesions. Objective: The purpose of this study was to evaluate the 2010 McDonald criteria performance and to assess other PFs in patients without dissemination in space (DIS). Methods: Patients with clinically isolated syndrome (CIS) underwent baseline MRI and OB determination with clinical and radiological follow-up. Adjusted hazard ratios (aHRs) for clinically definite MS were estimated for DIS, dissemination in time (DIT), and DIS+DIT. Diagnostic properties at two years were calculated. In cases without DIS, combinations of ≥2 PFs were assessed. Results: A total of 652 patients were recruited; aHRs were 3.8 (2.5–5.8) for DIS, 4.2 (1.9–9.2) for DIT, and 8.6 (5.4–13.8) for DIS+DIT. Sensitivities were 69.6%, 42.3%, and 36.4%, and specificities were 67.3%, 87.9%, and 90.2%, respectively. In patients without DIS, aHRs varied between 2.7–5.5 and specificities ranged from 73.5–89.7% for PF combinations. Conclusion: The high specificity of the 2010 McDonald criteria is confirmed. In patients without DIS, PF combinations could be helpful in identifying those at risk for MS.

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.

Early onset multiple sclerosis: the role of gender.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), predominantly affecting young females. A review of the role of gender and early age of onset of this disease will be presented. MS can be difficult to differentiate from other demyelinating diseases when it presents before the adult age, particularly from acute disseminated encephalomyelitis (ADEM). Several working definitions and diagnostic criteria have been proposed to differentiate pediatric MS from ADEM. A male predominance seems to occur in the latter, whereas a female predominance is seen in MS patients from puberty; however, a 1:1 ratio has been observed before the age of 12. Neuromyelitis optica (NMO) in children and adolescents shows a clear female predominance. Some cohort studies have suggested that in the last decades, MS tends to initiate at an older age and that the female:male ratio is increasing. Sex hormones may have immunologic implications, but more data are needed to explain the female predominance and its changes over time.

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.