The long-term outcomes of CIS patients in the Barcelona inception cohort: Looking back to recognize aggressive MS.

OBJECTIVE: To explore the long-term outcomes of patients with clinically isolated syndromes from the Barcelona cohort. METHODS: We selected patients with a follow-up longer than 10 years to (1) estimate the risks of multiple sclerosis (MS) and disability accumulation according to the baseline number of T2 lesions and to compare treated versus untreated patients and early versus delayed treatment, and (2) to study baseline features of patients with aggressive MS (Expanded Disability Status Scale (EDSS) ⩾6.0 at 10 years). RESULTS: In all, 401 patients were included (mean follow-up of 14.4 (standard deviation of 2.9) years). A higher number of T2 lesions was associated with an earlier MS diagnosis and an earlier risk of irreversible disability. Early treatment was associated with a decreased risk of EDSS of 3.0: adjusted hazard ratio = 0.4, 95% confidence interval = (0.2, 0.7). Patients with aggressive MS differed in their baseline brain magnetic resonance images: The median (interquartile range) number of T2 lesions and contrast-enhancing lesions (CEL) was 71 (28-95) versus 7 (1-19) and 3 (1-24) versus 0 (0-1), respectively. The cut-offs that better classified patients with aggressive MS were 20 for T2 lesions and 2 for CEL. CONCLUSION: Although MS natural history is changing, a high lesion load at onset is helpful to identify patients at risk of presenting an aggressive MS.

The value of oligoclonal bands in the multiple sclerosis diagnostic criteria.

The presence of oligoclonal bands in clinically isolated syndromes is an independent risk factor for developing multiple sclerosis and has been largely excluded from the more recent multiple sclerosis diagnostic criteria. Therefore, our objective was to explore the value of oligoclonal bands in the context of the 2010 McDonald criteria, especially in patients fulfilling exclusively dissemination in space at baseline. For this purpose, we selected 566 patients from a clinically isolated syndrome inception cohort who had IgG oligoclonal bands determination and sufficient data on baseline brain MRI to assess dissemination in space and time. We excluded the cases already fulfilling both dissemination in space and time and divided the remaining 398 into 'no dissemination in space and time' (n = 218), 'dissemination in space' (n = 164) and 'dissemination in time' (n = 16). We assessed Cox proportional hazards regression models with 2010 McDonald as the outcome, using 'no dissemination in space and time' with 0 lesions and negative oligoclonal bands as the reference for different subgroups according to oligoclonal bands status (positive/negative). To assess the diagnostic properties, we selected cases with a follow-up ≥3 years or fulfilling 2010 McDonald within 3 years of the clinically isolated syndrome (n = 314), and compared the performance of all 'dissemination in space' cases (n = 137) versus patients with 'dissemination in space' and positive oligoclonal bands (n = 101). The remaining patients classified as fulfilling 'dissemination in time' or 'no dissemination in space and time' were taken into account to calculate the diagnostic properties. The respective adjusted hazard ratios (95% confidence interval) were 1.5 (0.4-5.7) for 'no dissemination in space and time' with 0 lesions and positive oligoclonal bands, 3.1 (1.4-7.2) for 'no dissemination in space and time' with ≥1 lesions and negative oligoclonal bands, 7.4 (3.5-15.7) for 'no dissemination in space and time' with ≥1 lesions and positive oligoclonal bands, 10.4 (4.8-22.6) for 'dissemination in space' with negative oligoclonal bands, 15.3 (7.5-31.3) for 'dissemination in space' with positive oligoclonal bands, and 9.1 (3.5-23.4) for 'dissemination in time' (not subdivided due to the sample size). The specificity for all cases with 'dissemination in space' was 80.6 and increased to 88.1 after selecting those with positive oligoclonal bands. According to these results, we propose radiological dissemination in space at any time plus positive oligoclonal bands as an additional criterion for diagnosing multiple sclerosis.

Brain atrophy 15 years after CIS: Baseline and follow-up clinico-radiological correlations.

BACKGROUND: Brain atrophy in multiple sclerosis (MS) patients is present since the very early stages of the disease and it has been related to long-term disability. OBJECTIVE: To estimate brain volume (BV) at 15 years after a clinically isolated syndrome (CIS) and to evaluate its relationship with disease outcomes. METHODS: From a prospective cohort including patients presenting with a CIS, 54 patients with a brain magnetic resonance imaging (MRI) performed 15 years after CIS were included. Brain parenchymal fraction (BPF), grey matter fraction (GMF) and white matter fraction (WMF) at 15-year follow-up were obtained. Regression analyses were conducted to predict BV loss and reaching an Expanded Disability Status Scale (EDSS) of 3.0 in that 15-year period. RESULTS: In multivariable analyses, lower values of BPF and WMF were significantly associated with being male, presenting 3-4 Barkhof criteria at baseline, presenting a second relapse, and with a decision to start treatment. In the multivariable logistic regression analysis, only lower GMF was associated with a greater risk of reaching EDSS 3.0 (odds ratio (OR) = 0.24, p = 0.028). CONCLUSION: Lower BPF and WMF 15 years after CIS are associated with previous markers of inflammatory disease. Lower GMF 15 years after a CIS is associated with an increased risk of reaching an EDSS of 3.0.

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.

Should we systematically test patients with clinically isolated syndrome for auto-antibodies?

BACKGROUND: Several autoimmune diseases (ADs) can mimic multiple sclerosis (MS). For this reason, testing for auto-antibodies (auto-Abs) is often included in the diagnostic work-up of patients with a clinically isolated syndrome (CIS). OBJECTIVE: The purpose was to study how useful it was to systematically determine antinuclear-antibodies, anti-SSA and anti-SSB in a non-selected cohort of CIS patients, regarding the identification of other ADs that could represent an alternative diagnosis. METHODS: From a prospective CIS cohort, we selected 772 patients in which auto-Ab levels were tested within the first year from CIS. Baseline characteristics of auto-Ab positive and negative patients were compared. A retrospective revision of clinical records was then performed in the auto-Ab positive patients to identify those who developed ADs during follow-up. RESULTS: One or more auto-Ab were present in 29.4% of patients. Only 1.8% of patients developed other ADs during a mean follow-up of 6.6 years. In none of these cases the concurrent AD was considered the cause of the CIS. In all cases the diagnosis of the AD resulted from the development of signs and/or symptoms suggestive of each disease. CONCLUSION: Antinuclear-antibodies, anti-SSA and anti-SSB should not be routinely determined in CIS patients but only in those presenting symptoms suggestive of other ADs.

Diagnostic value of brain chronic black holes on T1-weighted MR images in clinically isolated syndromes.

BACKGROUND: Non-enhancing black holes (neBHs) are more common in multiple sclerosis (MS) patients with longer disease durations and progressive disease subtypes. OBJECTIVE: Our aim was to analyse the added value of neBHs in patients with clinically isolated syndromes (CISs) for predicting conversion to clinically definite MS (CDMS). METHODS: Patients were classified based on the presence or absence of neBHs and on the number of Barkhof-Tintoré (B-T) criteria fulfilled. Dissemination in space (DIS) was defined as the presence of at least three of the four B-T criteria. Dissemination in time (DIT)1 was defined by simultaneous presence of enhancing and non-enhancing lesions. DIT2 was defined by simultaneous presence of neBHs and T2 lesions not apparent on T1-weighted images. RESULTS: Focal T2-hyperintense brain lesions were identified in 87.7% of the 520 CIS patients, and 41.4% of them presented at least one neBH. Patients meeting DIS, DIT1, and DIT2 had a significantly higher rate of conversion to CDMS. After adjusting for DIS, only patients who fulfilled DIT1 preserved a significant increase in CDMS conversion. CONCLUSIONS: Non-enhancing black holes in CIS patients are associated with a higher risk of conversion to CDMS. However, the predictive value of this finding is lost when added to the DIS criteria.

Menarche, pregnancies, and breastfeeding do not modify long-term prognosis in multiple sclerosis.

OBJECTIVE: To investigate the effect of menarche, pregnancies, and breastfeeding on the risk of developing multiple sclerosis (MS) and disability accrual using a multivariate approach based on a large prospective cohort of patients with clinically isolated syndrome (CIS). METHODS: A cross-sectional survey of the reproductive information of female participants in a CIS cohort was performed. We examined the relationship of age at menarche with the risk of clinically definite MS (CDMS), McDonald 2010 MS, and Expanded Disability Status Scale (EDSS) 3.0 and 6.0. The effect of pregnancy (before and after CIS) and breastfeeding in the risk of CDMS, McDonald 2010 MS, and EDSS 3.0 was also examined. Univariate and multivariate analyses were performed and findings were confirmed using sensitivity analyses and a propensity score model. RESULTS: The data of 501 female participants were collected. Age at menarche did not correlate with age at CIS and was not associated with the risk of CDMS or EDSS 3.0 or 6.0. Pregnancy before CIS was protective for CDMS in the univariate analysis, but the effect was lost in the multivariate model and did not modify the risk of EDSS 3.0. Pregnancy after CIS was protective for both outcomes in univariate and multivariate analyses when pregnancy was considered a baseline variable, but the protective effect disappeared when analyzed as a time-dependent event. Breastfeeding did not modify the risk for the 3 outcomes. CONCLUSIONS: These results demonstrate that menarche, pregnancies, and breastfeeding did not substantially modify the risk of CDMS or disability accrual using a multivariable and time-dependent approach.

Lesion topographies in multiple sclerosis diagnosis: A reappraisal.

OBJECTIVES: To assess the contributions of cortico-juxtacortical and corpus callosum lesions to multiple sclerosis diagnosis and to compare the value of ≥1 vs ≥3 periventricular lesions in clinically isolated syndromes (CIS). METHODS: Step 1: We evaluated lesion topography classifications in 657 patients with CIS with stepwise Cox proportional hazards regression models considering second attack as the outcome. Step 2: We established 2 dissemination in space (DIS) versions according to the periventricular lesion cutoffs of ≥1 and ≥3 and assessed their performance at 10 years with second attack as the outcome, first individually and then combined with dissemination in time (DIT) in all cases (n = 326), by age, and by CIS topography. RESULTS: Step 1: The models (hazard ratios [95% confidence interval]) favored ≥1 over ≥3 periventricular lesions (2.5 [1.7-3.6]) and cortico-juxtacortical over juxtacortical lesions (1.4 [1.0-1.8]). Callosal lesions were not selected. Step 2: DIS specificity with ≥1 periventricular lesions was slightly lower than with ≥3 (59.1 vs 61.4) and the same after adding DIT (88.6). Regarding age, ≥3 periventricular lesions improved DIS specificity over ≥1 lesions in the 40-49 years of age bracket (66.7 vs 58.3). This difference disappeared when adding DIT (83.3). Optic neuritis had a similar pattern when evaluating CIS topographies. CONCLUSIONS: Our results comply with the Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) consensus recommendation of combining cortical and juxtacortical lesions into a single term when possible. Concerning periventricular lesions, maintaining the current ≥1 cutoff in the McDonald criteria does not compromise specificity in typical CIS cases, but attention should be paid to older patients or optic neuritis cases.

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.

[Demyelinating lesions as incidental findings in magnetic resonance imaging: a study of 11 cases with clinico-radiological follow-up and a review of the literature]. / Lesiones incidentales desmielinizantes en resonancia magnetica: estudio de 11 casos con seguimiento clinicorradiologico y revision de la bibliografia.

INTRODUCTION: The widespread application of magnetic resonance imaging (MRI) has brought with it an increase in the detection of alterations in the white matter of the central nervous system. AIM. To investigate the evolution of patients with no previous neurological symptoms, but in whom MRI findings are highly suggestive of multiple sclerosis (MS). PATIENTS AND METHODS: We conducted a descriptive study of 11 patients with MRI findings suggesting MS. A longitudinal follow-up was used to determine the radiological progression and conversion into an isolated neurological syndrome and clinically defined MS. RESULTS: Eleven patients (seven females and four males) were identified, with a mean age of 36 years (range: 28-48 years), who had been submitted to an MRI scan due to headache (n = 2), radiculalgia (n = 3), traumatic brain injury (n = 1), syncope (n = 1), peripheral nervous pathology (n = 1) and epileptic seizures (n = 1). The mean number of Barkhof-Tintore criteria in the initial MRI scan was three. The oligoclonal band study was positive in six cases and in nine patients visual evoked potentials were performed (three pathological). The mean follow-up time was 2.9 years (range: 2 months-11.9 years). The mean amount of time elapsed between the first and the second MRI scan was 2.03 years. A radiological progression was identified in seven cases (five of them with gadolinium uptake). Five patients became cases of isolated neurological syndrome, with a mean amount of time since the initial MRI scan of 4.13 years. Of these, three patients presented conversion into clinically defined MS, two into the relapsing-remitting form (after an average of 8.54 years since the initial MRI scan) and another into the primary progressive form. CONCLUSIONS: The identification of incidental lesions that are highly suggestive of MS could help to constitute a group of subjects with an increased risk of developing MS.

Lesiones incidentales desmielinizantes en resonancia magnética: estudio de 11 casos con seguimiento clinicorradiológico y revisión de la bibliografía / Demyelinating lesions as incidental findings in magnetic resonance imaging: a study of 11 cases with clinico-radiological follow-up and a review of the literature

Introducción. La extensa aplicación de estudios de resonancia magnética (RM) conlleva un aumento en la detección de alteraciones de la sustancia blanca del sistema nervioso central. Objetivo. Investigar la evolución de pacientes sin síntomas neurológicos previos, con hallazgos de RM altamente sugestivos de esclerosis múltiple (EM). Pacientes y métodos. Estudio descriptivo de once pacientes con RM sugestiva de EM. Mediante seguimiento longitudinal se determinaron la progresión radiológica y la conversión a síndrome neurológico aislado y EM clínicamente definida. Resultados. Se identificó a 11 pacientes (7 mujeres y 4 varones), con una edad media de 36 años (rango: 28-48 años), sometidos a RM por cefalea (n = 2), prolactinoma (n = 2), radiculalgia (n = 3), traumatismo craneoencefálico (n = 1), síncope (n = 1), patología nerviosa periférica (n = 1) y crisis epiléptica (n = 1). El número medio de criterios Barkhof-Tintoré 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 patológicos). El seguimiento medio fue de 2,9 años (rango: 2 meses-11,9 años). El tiempo medio entre la primera y la segunda RM fue de 2,03 años. Se identificó una progresión radiológica en 7 casos (5 de ellos con captación de gadolinio). Cinco pacientes convirtieron a síndrome neurológico aislado, con un tiempo medio desde la RM inicial de 4,13 años. De ellos, tres pacientes presentaron conversión a EM clínicamente definida, dos en forma recurrenteremitente (tras 8,54 años de media desde la RM inicial) y otro en forma primaria progresiva. Conclusión. La identificación de lesiones incidentales altamente sugestivas de EM podría ayudar a constituir un grupo de sujetos con riesgo aumentado de desarrollar EM (AU)

Introduction. The widespread application of magnetic resonance imaging (MRI) has brought with it an increase in the detection of alterations in the white matter of the central nervous system. Aim. To investhighly suggestive of multiple sclerosis (MS). Patients and methods. We conducted a descriptive studigate the evolution of patients with no previous neurological symptoms, but in whom MRI findings are y of 11 patients with MRI findings suggesting MS. A longitudinal follow-up was used to determine the radiological progression and conversion into an isolated neurological syndrome and clinically defined MS. Results. Eleven patients (seven females and four males) were identified, with a mean age of 36 years (range: 28-48 years), who had been submitted to an MRI scan due to headache (n = 2), radiculalgia (n = 3), traumatic brain injury (n = 1), syncope (n = 1), peripheral nervous pathology (n = 1) and epileptic seizures (n = 1). The mean number of Barkhof-Tintoré criteria in the initial MRI scan was three. The oligoclonal band study was positive in six cases and in nine patients visual evoked potentials were performed (three pathological). The mean follow-up time was 2.9 years (range: 2 months-11.9 years). The mean amount of time elapsed between the first and the second MRI scan was 2.03 years. A radiological progression was identified in seven cases (five of them with gadolinium uptake). Five patients became cases of isolated neurological syndrome, with a mean amount of time since the initial MRI scan of 4.13 years. Of these, three patients presented conversion into clinically defined MS, two into the relapsing-remitting form (after an average of 8.54 years since the initial MRI scan) and another into the primary progressive form (AU)