Publications by authors named "Ethel Ciampi"

23 Publications

  • Page 1 of 1

Coronavirus disease 2019 in Latin American patients with multiple sclerosis.

Mult Scler Relat Disord 2021 Jul 25;55:103173. Epub 2021 Jul 25.

Section of Biostatistics, Department of Health Sciences, University of Genoa, Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

Patients with multiple sclerosis (MS) who present coronavirus disease 2019 (COVID-19) are of particular interest to neurologists. These patients have a neuroimmune disease and receive immunomodulatory or immunosuppressive therapies in the long-term. We present here data from 73 patients with MS and a confirmed diagnosis of COVID-19 from five Latin American countries. Fifteen patients (20.5%) were hospitalized and two patients died. The use of anti-CD20 therapies was the only risk factor associated to hospitalization and death. Despite the small sample size, this study highlights the awareness regarding therapeutic options for MS during the pandemic.
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http://dx.doi.org/10.1016/j.msard.2021.103173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310568PMC
July 2021

Status of the neuromyelitis optica spectrum disorder in Latin America.

Mult Scler Relat Disord 2021 Aug 15;53:103083. Epub 2021 Jun 15.

Hospital Universitario de Maracaibo y Policlínica Maracaibo, Maracaibo, Venezuela.

Background: Neuromyelitis optica spectrum disorders (NMOSD) is an increasing diagnostic and therapeutic challenge in Latin America (LATAM). Despite the heterogeneity of this population, ethnic and socioeconomic commonalities exist, and epidemiologic studies from the region have had a limited geographic and population outreach. Identification of some aspects from the entire region are lacking.

Objectives: To determine ethnic, clinical characteristics, and utilization of diagnostic tools and types of therapy for patients with NMOSD in the entire Latin American region.

Methods: The Latin American Committee for Treatment and Research in MS (LACTRIMS) created an exploratory investigational survey addressed by Invitation to NMOSD Latin American experts identified through diverse sources. Data input closed after 30 days from the initial invitation. The questionnaire allowed use of absolute numbers or percentages. Multiple option responses covering 25 themes included definition of type of practice; number of NMOSD cases; ethnicity; utilization of the 2015 International Panel criteria for the diagnosis of Neuromyelitis optica (IPDN); clinical phenotypes; methodology utilized for determination of anti-Aquaporin-4 (anti- AQP4) antibodies serological testing, and if this was performed locally or processed abroad; treatment of relapses, and long-term management were surveyed.

Results: We identified 62 investigators from 21 countries reporting information from 2154 patients (utilizing the IPDN criteria in 93.9% of cases), which were categorized in two geographical regions: North-Central, including the Caribbean (NCC), and South America (SA). Ethnic identification disclosed Mestizos 61.4% as the main group. The most common presenting symptoms were concomitant presence of optic neuritis and transverse myelitis in 31.8% (p=0.95); only optic neuritis in 31.4% (more common in SA), p<0.001); involvement of the area postrema occurred in 21.5% and brain stem in 8.3%, both were more frequent in the South American cases (p<0.001). Anti-AQP4 antibodies were positive in 63.9% and anti-Myelin Oligodendrocyte Glycoprotein (MOG) antibodies in 4.8% of total cases. The specific laboratorial method employed was not known by 23.8% of the investigators. Acute relapses were identified in 81.6% of cases, and were treated in 93.9% of them with intravenous steroids (IVS); 62.1% with plasma exchange (PE), and 40.9% with intravenous immunoglobulin-G (IVIG). Therapy was escalated in some cases due to suboptimal initial response. Respondents favored Rituximab as long-term therapy (86.3%), whereas azathioprine was also utilized on 81.8% of the cases, either agent used indistinctly by the investigators according to treatment accessibility or clinical judgement. There were no differences among the geographic regions.

Conclusions: This is the first study including all countries of LATAM and the largest cohort reported from a multinational specific world area. Ethnic distributions and phenotypic features of the disease in the region, challenges in access to diagnostic tools and therapy were identified. The Latin American neurological community should play a determinant role encouraging and advising local institutions and health officials in the availability of more sensitive and modern diagnostic methodology, in facilitating the the access to licensed medications for NMOSD, and addressing concerns on education, diagnosis and management of the disease in the community.
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http://dx.doi.org/10.1016/j.msard.2021.103083DOI Listing
August 2021

Pregnancy outcomes in women with Multiple Sclerosis.

Mult Scler Relat Disord 2021 Feb 9;48:102682. Epub 2020 Dec 9.

Departamento de Neurología, Pontificia Universidad Católica de Chile, Santiago, Chile.

Introduction: Women represent two-thirds of the MS population and are usually diagnosed during childbearing age. Collection of local information about pregnancy outcomes is fundamental to support individual decision-making.

Objective: To explore the trends in pregnancy decision making and pregnancy outcomes before (PreMS) and after (PostMS) MS diagnosis.

Methods: We developed a questionnaire for retrospective assessment of pregnancy outcomes in PreMS and PostMS patients under regular care at the Programa de Esclerosis Multiple UC in Chile.

Results: From the 218 women who responded to the questionnaire, 67 women did not have pregnancies. The total number of pregnancies registered was 299, 223 were PreMS (97 women, mean 2.5 ± 1.3 per/woman), and 76 PostMS (59 women, mean 1.9 ± 1.1 per/woman, p = 0.003). Mean age at first pregnancy was 27.6 ± 6.2 in PreMS, and 32.6 ± 4.6 years in PostMS women (p < 0.001). Significant differences between PreMS and PostMS pregnancy outcomes were cesarean section (37% vs. 66%; OR 2.74 95%CI(1.5-52), p=0.002), suspected relapse during 6 months after birth (7% vs. 18%, p<0.001), and breastfeeding (83% vs 67%, p=0.005). Gestational age, weight/size at birth, were not different between groups. Major malformations were observed similarly in both groups.

Conclusions: Changes in pregnancy decision-making after MS diagnosis occur, having fewer children and at an older age. It also changes obstetrician decisions for cesarean sections, with a 3 fold increase. Regarding newborn outcomes, there were no differences between groups.
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http://dx.doi.org/10.1016/j.msard.2020.102682DOI Listing
February 2021

Prevalence of comorbidities in Multiple Sclerosis and impact on physical disability according to disease phenotypes.

Mult Scler Relat Disord 2020 Nov 5;46:102565. Epub 2020 Oct 5.

Neurology, Pontificia Universidad Católica de Chile, Santiago, Chile; Neurosurgery, Pontificia Universidad Católica de Chile and Hospital Dr. Sótero del Río, Santiago, Chile.

Background: Comorbidities are prevalent among Multiple Sclerosis (MS) patients. Few studies have characterized their prevalence and impact in Latin American populations.

Objective: We aim to assess the prevalence of comorbidities and their impact on the risk of physical disability across different MS phenotypes.

Methods: Cross-sectional multicenter study of patients under regular clinical care at the Programa de Esclerosis Múltiple UC and Hospital Dr. Sótero del Río in Chile. Prevalence of comorbidities was estimated from the retrospective assessment of electronic medical charts. Disease phenotypes were categorized into two groups: clinically isolated syndrome/relapsing-remitting (inflammatory group) and primary/secondary progressive MS patients (progressive group). A multivariable analysis using binary logistic regression for assessing the risk of EDSS ≥ 6.0 in each group was performed.

Results: A total of 453 patients was included, 71% female, mean age at onset 31 years, mean disease duration 10 years, and median EDSS 2.0 (range 0-10). In the whole sample, most prevalent comorbidities were ever-smoking (42.2%), depression/anxiety (34.9%), thyroid disease (15.7%), hypertension (11.3%) and insulin resistance/type 2 diabetes mellitus (11.0%). When assessing the risk of EDSS ≥ 6, in the inflammatory group (N = 366), age at onset (OR 1.06, 95%CI(1.02-1.11), p = 0.008), disease duration (OR 1.06, 95%CI(1.00-1.12), p = 0.039) and epilepsy comorbidity (OR 5.36, 95%CI(1.33-21.5), p = 0.018) were associated with a higher risk of disability. In the progressive group (N = 87), disease duration was a risk factor (OR 1.08 95%CI(1.02-1.16), p = 0.014), while shorter diagnostic delay (OR 0.91 95%CI(0.85-0.99), p = 0.025) and insulin resistance/type 2 diabetes mellitus comorbidity were protective factors (OR 0.18 95%CI(0.04-0.83), p = 0.028), 72% of these patients were receiving metformin.

Conclusions: Comorbidities are common across different MS disease phenotypes. Epilepsy seems particularly related with a higher risk of physical disability in relapsing-remitting patients, while the role of insulin resistance/type 2 diabetes mellitus or the impact of metformin use as a protective factor should be further studied. Prospective and larger studies are still needed in order to assess the real impact of comorbidities and their management in MS outcomes.
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http://dx.doi.org/10.1016/j.msard.2020.102565DOI Listing
November 2020

Forecasting Seizure Freedom After Epilepsy Surgery Assessing Concordance Between Noninvasive and StereoEEG Findings.

Neurosurgery 2020 12;88(1):113-121

"Claudio Munari" Epilepsy Surgery Centre, Niguarda Hospital, Piazza Ospedale Maggiore 3, 20162 Milan, Italy.

Background: Accurate localization of the probable Epileptogenic Zone (EZ) from presurgical studies is crucial for achieving good prognosis in epilepsy surgery.

Objective: To evaluate the degree of concordance at a sublobar localization derived from noninvasive studies (video electroencephalography, EEG; magnetic resonance imaging, MRI; 18-fluorodeoxyglucose positron emission tomography FDG-PET, FDG-PET) and EZ estimated by stereoEEG, in forecasting seizure recurrence in a long-term cohort of patients with focal drug-resistant epilepsy.

Methods: We selected patients with a full presurgical evaluation and with postsurgical outcome at least 1 yr after surgery. Multivariate Cox regression analysis for seizure freedom (Engel Ia) was performed.

Results: A total of 74 patients were included, 62.2% were in Engel class Ia with a mean follow-up of 2.8 + 2.4 yr after surgery. In the multivariate analysis for Engel Ia vs >Ib, complete resection of the EZ found in stereoEEG (hazard ratio, HR: 0.24, 95%CI: 0.09-0.63, P = .004) and full concordance between FDG-PET and stereoEEG (HR: 0.11, 95%CI: 0.02-0.65, P = .015) portended a more favorable outcome. Most of our results were maintained when analyzing subgroups of patients.

Conclusion: The degree of concordance between noninvasive studies and stereoEEG may help to forecast the likelihood of cure before performing resective surgery, particularly using a sublobar classification and comparing the affected areas in the FDG-PET with EZ identified with stereoEEG.
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http://dx.doi.org/10.1093/neuros/nyaa322DOI Listing
December 2020

Multiple sclerosis and related disorders: Short report peripheral vascular events in a real-world cohort of multiple sclerosis patients using Fingolimod.

Mult Scler Relat Disord 2020 Oct 17;45:102411. Epub 2020 Jul 17.

Neurology Department, Pontificia Universidad Católica de Chile, Chile.

Background: Fingolimod is a high-efficacy disease-modifying therapy for multiple sclerosis (MS) and was the first oral treatment approved for the disease. Adverse events include bradyarrhythmia, hypertension, macular oedema and increased risk of infections, mainly due to its main mechanism of action, the non-selective modulation of sphingosine-1-phosphate receptor.

Methods And Results: We report the baseline characteristics, effectiveness outcomes and adverse events of a prospective cohort of 177 patients with a median treatment duration of 24 months, in which four patients (2.3%) presented with otherwise non-provoked peripheral vascular events (PVE).

Conclusions: Further studies are still needed to evaluate the frequency and severity of PVE in fingolimod patients.
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http://dx.doi.org/10.1016/j.msard.2020.102411DOI Listing
October 2020

Social cognition in Multiple Sclerosis is associated to changes in brain connectivity: A resting-state fMRI study.

Mult Scler Relat Disord 2020 Oct 24;45:102333. Epub 2020 Jun 24.

Neurology Department, School of Medicine, Pontificia Universidad Católica de Chile, Chile. Electronic address:

Background: Multiple Sclerosis produces changes in the functional connectivity of the brain. Resting-State fMRI is a useful tool for the study of functional changes in the human brain, and its metrics can be related to clinical findings involved in clinical decline. Social cognition has focused increasing interest because patients are exposed to experiencing social disorganization during the progression of the disease. fMRI has proved to be a useful tool for studying brain connectivity and its relation with social cognition both in resting-state and during socio-cognitive tasks.

Objective: to identify functional changes during rest in Relapsing-Remitting Multiple Sclerosis patients and look for a correlation with social cognition.

Methods: 45 patients with Relapsing-Remitting Multiple Sclerosis and 47 control subjects were recruited to perform a neuropsychological evaluation of the social cognition performance and to acquire resting-state fMRI.

Results: Patients exhibited lower performance in social cognition tasks, mostly related to face emotion recognition. Decreased functional connectivity in patients is seen concerning the right anterior insula, middle frontal, and occipital regions while increased connectivity is mostly related to the occipital and visual areas. The connectivity of the fusiform cortex and the amygdala is related to the performance in emotion recognition and Theory of Mind tasks respectively.

Conclusion: Social cognition compromise was found in this sample. Functional connectivity changes during rest were detected and correlated with social cognition changes in patients.
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http://dx.doi.org/10.1016/j.msard.2020.102333DOI Listing
October 2020

COVID-19 pandemic: The experience of a multiple sclerosis centre in Chile.

Mult Scler Relat Disord 2020 07 16;42:102204. Epub 2020 May 16.

Neurology, Pontificia Universidad Católica de Chile, Santiago, Chile. Electronic address:

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http://dx.doi.org/10.1016/j.msard.2020.102204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229721PMC
July 2020

Frontoparietal connectivity correlates with working memory performance in multiple sclerosis.

Sci Rep 2020 06 9;10(1):9310. Epub 2020 Jun 9.

Laboratorio de Neurociencia Social y Neuromodulación, Centro de Investigación en Complejidad Social (neuroCICS), Facultad de Gobierno, Universidad del Desarrollo, Santiago de Chile, Chile.

Working Memory (WM) impairment is the most common cognitive deficit of patients with Multiple Sclerosis (MS). However, evidence of its neurobiological mechanisms is scarce. Here we recorded electroencephalographic activity of twenty patients with relapsing-remitting MS and minimal cognitive deficit, and 20 healthy control (HC) subjects while they solved a WM task. In spite of similar performance, the HC group demonstrated both a correlation between temporoparietal theta activity and memory load, and a correlation between medial frontal theta activity and successful memory performances. MS patients did not show theses correlations leading significant differences between groups. Moreover, cortical connectivity analyses using granger causality and phase-amplitude coupling between theta and gamma revealed that HC group, but not MS group, presented a load-modulated progression of the frontal-to-parietal connectivity. This connectivity correlated with working memory capacity in MS groups. This early alterations in the oscillatory dynamics underlaying working memory could be useful for plan therapeutic interventions.
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http://dx.doi.org/10.1038/s41598-020-66279-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283327PMC
June 2020

Efficacy of andrographolide in not active progressive multiple sclerosis: a prospective exploratory double-blind, parallel-group, randomized, placebo-controlled trial.

BMC Neurol 2020 May 7;20(1):173. Epub 2020 May 7.

Pharmacology and Morphophysiology, Faculty of Veterinary Sciences, Universidad Austral de Chile, Independencia, 613, Valdivia, Chile.

Background: Multiple sclerosis (MS) is a chronic immune mediated disease and the progressive phase appears to have significant neurodegenerative mechanisms. The classification of the course of progressive MS (PMS) has been re-organized into categories of active vs. not active inflammatory disease and the presence vs. absence of gradual disease progression. Clinical trial experience to date in PMS with anti-inflammatory medications has shown limited effect. Andrographolide is a new class of anti-inflammatory agent, that has been proposed as a potential drug for autoimmune disorders, including MS. In the present trial, we perform an exploratory pilot study on the efficacy and safety of andrographolide (AP) compared to placebo in not active PMS.

Methods: A pilot clinical trial using 140 mg oral AP or placebo twice daily for 24 months in patients with not active primary or secondary progressive MS was conducted. The primary efficacy endpoint was the mean percentage brain volume change (mPBVC). Secondary efficacy endpoints included 3-month confirmed disability progression (3-CDP) and mean EDSS change.

Results: Forty-four patients were randomized: 23 were assigned to the AP group, and 21 were assigned to the placebo group. The median baseline EDSS of both groups was 6.0. Annualized mPBVC was - 0.679% for the AP group and - 1.069% for the placebo group (mean difference: -0.39; 95% CI [- 0.836-0.055], p = 0.08, relative reduction: 36.5%). In the AP group, 30% had 3-CDP compared to 41% in the placebo group (HR: 0.596; 95% CI [0.200-1.777], p = 0.06). The mean EDSS change was - 0.025 in the AP group and + 0.352 in the placebo group (mean difference: 0.63, p = 0.042). Adverse events related to AP were mild rash and dysgeusia.

Conclusions: AP was well tolerated and showed a potential effect in reducing brain atrophy and disability progression, that need to be further evaluated in a larger clinical trial.

Trial Registration: ClinicalTrials.gov NCT02273635 retrospectively registered on October 24th, 2014.
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http://dx.doi.org/10.1186/s12883-020-01745-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203851PMC
May 2020

Practical Issues Concerning the Approval and Use of Biosimilar Drugs for the Treatment of Multiple Sclerosis in Latin America.

Neurol Ther 2019 Dec 24;8(2):207-214. Epub 2019 May 24.

MS Section, Hospital Británico de CABA, Buenos Aires, Argentina.

The use of biosimilar drugs for multiple sclerosis (MS) has become widespread in Latin America, with the goal of reducing costs of treatments, promoting the sustainability of healthcare systems, and improving patient access to these therapies. There is currently a need to define and comply with requirements to guarantee the efficacy, safety, and quality of these drugs. Thus, the objective of the present study was to compile up-to-date information from each Latin American country assessed on (a) approval of biosimilar drugs by regulatory agencies; (b) use of biosimilar drugs, pharmacovigilance plans, risk management; and (c) update in the knowledge on different molecules. To do so, a group of experts from Argentina, Bolivia, Brazil, Chile, Colombia, Costa Rica, Ecuador, Mexico, Panama, Peru, Uruguay, and Venezuela met to discuss the current situation regarding good practices and risks associated with the use of biosimilar drugs in their respective countries. Regulation, risk management plans, and pharmacovigilance in the whole continent must guide the strategies on the commercialization and access of biosimilar drugs and copies of complex molecules. Current regulations must be implemented for the registration of biosimilar drug products and complex molecules. It is paramount to ensure that new products follow the best quality standards at all stages beyond being safe and efficient. Uncontrolled interchangeability between original biological and biosimilar should be avoided. Latin America requires the implementation and full use of strong pharmacovigilance programs. National and multinational clinical studies are required to demonstrate the similarity in safety, efficacy, and immunogenicity profiles of complex molecules, as well as biological and biosimilar products. Plain language summary available for this article.
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http://dx.doi.org/10.1007/s40120-019-0139-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858893PMC
December 2019

Assessment and Impact of Cognitive Impairment in Multiple Sclerosis: An Overview.

Biomedicines 2019 Mar 19;7(1). Epub 2019 Mar 19.

Neurology, Pontificia Universidad Católica de Chile, Neurology, Hospital Dr. Sótero del Río, Santiago 8320000, Chile.

Cognitive impairment affects 40⁻60% of patients with multiple sclerosis. It may be present early in the course of the disease and has an impact on a patient's employability, social interactions, and quality of life. In the last three decades, an increasing interest in diagnosis and management of cognitive impairment has arisen. Neuropsychological assessment and neuroimaging studies focusing on cognitive impairment are now being incorporated as primary outcomes in clinical trials. However, there are still key uncertainties concerning the underlying mechanisms of damage, neural basis, sensitivity and validity of neuropsychological tests, and efficacy of pharmacological and non-pharmacological interventions. The present article aimed to present an overview of the assessment, neural correlates, and impact of cognitive impairment in multiple sclerosis.
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http://dx.doi.org/10.3390/biomedicines7010022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466345PMC
March 2019

Characterization of relapsing-remitting multiple sclerosis patients using support vector machine classifications of functional and diffusion MRI data.

Neuroimage Clin 2018 4;20:724-730. Epub 2018 Sep 4.

Biomedical Imaging Center, Pontificia Universidad Católica de Chile, Santiago, Chile; Radiology Department, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile; Millennium Nucleus for Cardiovascular Magnetic Resonance, Santiago, Chile. Electronic address:

Multiple Sclerosis patients' clinical symptoms do not correlate strongly with structural assessment done with traditional magnetic resonance images. However, its diagnosis and evaluation of the disease's progression are based on a combination of this imaging analysis complemented with clinical examination. Therefore, other biomarkers are necessary to better understand the disease. In this paper, we capitalize on machine learning techniques to classify relapsing-remitting multiple sclerosis patients and healthy volunteers based on machine learning techniques, and to identify relevant brain areas and connectivity measures for characterizing patients. To this end, we acquired magnetic resonance imaging data from relapsing-remitting multiple sclerosis patients and healthy subjects. Fractional anisotropy maps, structural and functional connectivity were extracted from the scans. Each of them were used as separate input features to construct support vector machine classifiers. A fourth input feature was created by combining structural and functional connectivity. Patients were divided in two groups according to their degree of disability and, together with the control group, three group pairs were formed for comparison. Twelve separate classifiers were built from the combination of these four input features and three group pairs. The classifiers were able to distinguish between patients and healthy subjects, reaching accuracy levels as high as 89% ± 2%. In contrast, the performance was noticeably lower when comparing the two groups of patients with different levels of disability, reaching levels below 63% ± 5%. The brain regions that contributed the most to the classification were the right occipital, left frontal orbital, medial frontal cortices and lingual gyrus. The developed classifiers based on MRI data were able to distinguish multiple sclerosis patients and healthy subjects reliably. Moreover, the resulting classification models identified brain regions, and functional and structural connections relevant for better understanding of the disease.
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http://dx.doi.org/10.1016/j.nicl.2018.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148733PMC
January 2019

Corpus callosum atrophy and post-surgical seizures in temporal lobe epilepsy associated with hippocampal sclerosis.

Epilepsy Res 2018 05 3;142:29-35. Epub 2018 Mar 3.

"Claudio Munari" Epilepsy Surgery Centre, Niguarda Hospital, Milano, Italy.

Objective: Our aim in this retrospective study was to explore whether corpus callosum atrophy could predict the post-surgical seizure control in patients with temporal lobe epilepsy associated with Hippocampal Sclerosis (HS).

Methods: We used the Corpus Callosum Index (CCI) obtained from best mid-sagittal T2/FLAIR or T1-weighted MRI at two time-points, more than one year apart. CCI has been mainly used in Multiple Sclerosis (MS), but not in epilepsy, so we tested the validity of our results performing a proof of concept cohort, incorporating MS patients with and without epilepsy. Then, we explored this measurement in a well-characterized and long-term cohort of patients with temporal lobe epilepsy associated with HS.

Results: In the proof of concept cohort (MS without epilepsy n:40, and MS with epilepsy, n:15), we found a larger CCI atrophy rate in MS patients with poor epilepsy control vs. MS without epilepsy (p:0.01). Then, in HS patients (n:74), annualized CCI atrophy rate was correlated with the long-term Engel scale (Rho:0.31, p:0.007). In patients with post-surgical seizure recurrence, a larger CCI atrophy rate was found one year before any seizure relapse. Univariate analysis showed an increased risk of seizure recurrence in males, higher pre-surgical seizure frequency, necessity of invasive EEG monitoring, and higher CCI atrophy rate. Two of these variables were independent predictors in the multivariate analysis, male gender (HR:4.87, p:0.002) and CCI atrophy rate (HR:1.21, p:0.001).

Conclusion: We demonstrated that atrophy of the corpus callosum, using the CCI, is related with poor seizure control in two different neurological disorders presenting with epilepsy, which might suggest that corpus callosum atrophy obtained in early post-surgical follow-up, could be a biomarker for predicting recurrences and guiding treatment plans.
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http://dx.doi.org/10.1016/j.eplepsyres.2018.03.001DOI Listing
May 2018

Risk factors of early adverse drug reactions with phenytoin: A prospective inpatient cohort.

Epilepsy Behav 2017 11 15;76:139-144. Epub 2017 Sep 15.

Neurology Department, School of Medicine, Pontifical Catholic University of Chile, Santiago, Chile.

Introduction: Phenytoin (PHT) is an effective and inexpensive antiepileptic drug (AED). However, its use has been limited for fear of adverse drug reactions (ADRs) and is being replaced by newer AED, increasing the costs and causing major budget problems, particularly for developing countries.

Objective: The objective of this study was to determine ADR frequency, explore, and establish related risk factors.

Methods: Prospective data were collected from a cohort of inpatients using PHT for the first time. Pharmacovigilance was performed during hospitalization and after one month from the discharge. Clinical variables, plasma levels, and concomitant medications were collected and their association with the occurrence of different ADRs was explored.

Results: One hundred patients were included: 59 were women, and mean age was 59±21years. Thirty-three patients presented ADR, all moderate and idiosyncratic. The most frequent were rash (17%), fever (10%), and elevated transaminases (10%). Female gender (85% vs 52%, p=0.029), younger age (mean age: 49 vs 62years, p=0.032), and higher PHT plasmatic levels after IV-PO load (mean plasmatic levels: 18.6 vs 13.9μg/mL, p=0.040) were found to be associated with rash. A higher number of concomitant medications were also found to be associated with the risk for developing any ADR. The multivariate analysis revealed an association between rash and younger age (cut-off: 35years old; relative risk (RR)=11.7; p=0.026), and higher PHT plasmatic levels (cut-off: 16μg/mL; RR=12.5; p=0.021); and increased risk of elevated transaminases with use of PHT inductors (RR=18; p=0.006). A longer hospital stay was found in patients who developed fever (mean: 43days, p<0.0001) and elevated transaminases (mean: 26days, p=0.041) compared with patients without ADR (mean: 17days).

Conclusions: Phenytoin is a widely used AED associated with easily detectable ADR through structured pharmacovigilance. The development of ADR is associated with longer hospital stays. Recognition of local risk factors may lead to ADR prevention in a near future. Larger studies are needed to better define PHT-related ADR risk profile and to individualize treatment regimens.
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http://dx.doi.org/10.1016/j.yebeh.2017.08.032DOI Listing
November 2017

Th1 and Th17 Cells and Associated Cytokines Discriminate among Clinically Isolated Syndrome and Multiple Sclerosis Phenotypes.

Front Immunol 2017 30;8:753. Epub 2017 Jun 30.

School of Medicine, Institute of Biomedical Sciences (ICBM), Universidad de Chile, Santiago, Chile.

Multiple sclerosis (MS) is a chronic, inflammatory, and demyelinating disease of the central nervous system. It is a heterogeneous pathology that can follow different clinical courses, and the mechanisms that underlie the progression of the immune response across MS subtypes remain incompletely understood. Here, we aimed to determine differences in the immunological status among different MS clinical subtypes. Blood samples from untreated patients diagnosed with clinically isolated syndrome (CIS) ( = 21), different clinical forms of MS ( = 62) [relapsing-remitting (RRMS), secondary progressive, and primary progressive], and healthy controls (HCs) ( = 17) were tested for plasma levels of interferon (IFN)-γ, IL-10, TGF-β, IL-17A, and IL-17F by immunoanalysis. Th1 and Th17 lymphocyte frequencies were determined by flow cytometry. Our results showed that IFN-γ levels and the IFN-γ/IL-10 ratio were higher in CIS patients than in RRMS patients and HC. Th1 cell frequencies were higher in CIS and RRMS than in progressive MS, and RRMS had a higher Th17 frequency than CIS. The Th1/Th17 cell ratio was skewed toward Th1 in CIS compared to MS phenotypes and HC. Receiver operating characteristic statistical analysis determined that IFN-γ, the IFN-γ/IL-10 ratio, Th1 cell frequency, and the Th1/Th17 cell ratio discriminated among CIS and MS subtypes. A subanalysis among patients expressing high IL-17F levels showed that IL-17F and the IFN-γ/IL-17F ratio discriminated between disease subtypes. Overall, our data showed that CIS and MS phenotypes displayed distinct Th1- and Th17-related cytokines and cell profiles and that these immune parameters discriminated between clinical forms. Upon validation, these parameters might be useful as biomarkers to predict disease progression.
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http://dx.doi.org/10.3389/fimmu.2017.00753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491887PMC
June 2017

Galectin-8 as an immunosuppressor in experimental autoimmune encephalomyelitis and a target of human early prognostic antibodies in multiple sclerosis.

PLoS One 2017 26;12(6):e0177472. Epub 2017 Jun 26.

Center for Aging and Regeneration (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.

Galectin-8 (Gal-8) is a member of a glycan-binding protein family that regulates the immune system, among other functions, and is a target of antibodies in autoimmune disorders. However, its role in multiple sclerosis (MS), an autoimmune inflammatory disease of the central nervous system (CNS), remains unknown. We study the consequences of Gal-8 silencing on lymphocyte subpopulations and the development of experimental autoimmune encephalitis (EAE), to then assess the presence and clinical meaning of anti-Gal-8 antibodies in MS patients. Lgals8/Lac-Z knock-in mice lacking Gal-8 expression have higher polarization toward Th17 cells accompanied with decreased CCR6+ and higher CXCR3+ regulatory T cells (Tregs) frequency. These conditions result in exacerbated MOG35-55 peptide-induced EAE. Gal-8 eliminates activated Th17 but not Th1 cells by apoptosis and ameliorates EAE in C57BL/6 wild-type mice. β-gal histochemistry reflecting the activity of the Gal-8 promoter revealed Gal-8 expression in a wide range of CNS regions, including high expression in the choroid-plexus. Accordingly, we detected Gal-8 in human cerebrospinal fluid, suggesting a role in the CNS immune-surveillance circuit. In addition, we show that MS patients generate function-blocking anti-Gal-8 antibodies with pathogenic potential. Such antibodies block cell adhesion and Gal-8-induced Th17 apoptosis. Furthermore, circulating anti-Gal-8 antibodies associate with relapsing-remitting MS (RRMS), and not with progressive MS phenotypes, predicting clinical disability at diagnosis within the first year of follow-up. Our results reveal that Gal-8 has an immunosuppressive protective role against autoimmune CNS inflammation, modulating the balance of Th17 and Th1 polarization and their respective Tregs. Such a role can be counteracted during RRMS by anti-Gal-8 antibodies, worsening disease prognosis. Even though anti-Gal-8 antibodies are not specific for MS, our results suggest that they could be a potential early severity biomarker in RRMS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0177472PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5484466PMC
September 2017

Secondary paroxysmal dyskinesia in multiple sclerosis: Clinical-radiological features and treatment. Case report of seven patients.

Mult Scler 2017 Nov 11;23(13):1791-1795. Epub 2017 Apr 11.

Department of Neurology, Pontificia Universidad Católica de Chile, Hospital Sótero del Río, Santiago, Chile.

Secondary paroxysmal dyskinesias (SPDs) are short, episodic, and recurrent movement disorders, classically related to multiple sclerosis (MS). Carbamazepine is effective, but with risk of adverse reactions. We identified 7 patients with SPD among 457 MS patients (1.53%). SPD occurred in face ( n = 1), leg ( n = 2), or arm +leg ( n = 4) several times during the day. Magnetic resonance imaging (MRI) showed new or enhancing lesions in thalamus ( n = 1), mesencephalic tegmentum ( n = 1), and cerebellar peduncles ( n = 5). Patients were treated with clonazepam and then acetazolamide ( n = 1), acetazolamide ( n = 5), or levetiracetam ( n = 1) with response within hours (acetazolamide) to days (levetiracetam). No recurrences or adverse events were reported after a median follow-up of 33 months.
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http://dx.doi.org/10.1177/1352458517702968DOI Listing
November 2017

Grey matter atrophy is associated with disability increase in natalizumab-treated patients.

Mult Scler 2017 Apr 11;23(4):556-566. Epub 2016 Jul 11.

Servei de Neurologia/Neuroimmunologia, Multiple Sclerosis Centre of Catalonia (Cemcat), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.

Background: Brain volume loss (BVL) is a key outcome in multiple sclerosis (MS) trials. Natalizumab is highly effective on inflammation with moderate impact on atrophy.

Objective: To explore BVL in patients receiving natalizumab with an emphasis on grey matter (GM).

Methods: We performed a retrospective post hoc analysis of BVL in 38 patients receiving natalizumab for 3 years using longitudinal voxel-based morphometry (VBM) and FreeSurfer.

Results: Significant BVL was observed during first year: brain parenchymal fraction (BPF): -1.12% ( p < 0.001); white matter fraction (WMF): -0.9% ( p = 0.001); grey matter fraction (GMF): -1.28% ( p = 0.002). GM loss was found using VBM in bilateral cerebellum, cingulum, left > right fronto-parietal cortex, right > left hippocampus and left caudate. FreeSurfer showed significant volume losses in subcortical GM, brainstem and cerebellum, and cortical thinning in the left insula. In the second year, only WMF decrease (-0.6%; p = 0.015) was observed with no VBM changes, although FreeSurfer detected significant volume loss in thalamus, hippocampus and cerebellum. Baseline gadolinium enhancement influenced WMF and BPF changes during the first year, but not GMF. Patients with confirmed Expanded Disability Status Scale (EDSS) worsening at 3 years had lower baseline GMF and left thalamus volume and greater BVL over follow-up.

Conclusion: BVL develops mainly during the first year of natalizumab therapy. GM changes are independent of baseline inflammation and correlate with disability.
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http://dx.doi.org/10.1177/1352458516656808DOI Listing
April 2017

Commentary on Pique et al.'s paper entitled: Peripheral late reactivation of a previously typical monofocal Balo's concentric sclerosis lesion.

Mult Scler 2015 Jul 26;21(8):1084-6. Epub 2015 May 26.

Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Department of Neurology/Neuroimmunology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Spain

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http://dx.doi.org/10.1177/1352458515586090DOI Listing
July 2015

Gelastic epilepsy: Beyond hypothalamic hamartomas.

Epilepsy Behav Case Rep 2015 16;4:70-3. Epub 2015 Aug 16.

Department of Neurology, Pontificia Universidad Católica de Chile, Chile.

Gelastic epilepsy or laughing seizures have been historically related to children with hypothalamic hamartomas. We report three adult patients who had gelastic epilepsy, defined as the presence of seizures with a prominent laugh component, including brain imaging, surface/invasive electroencephalography, positron emission tomography, and medical/surgical outcomes. None of the patients had hamartoma or other hypothalamic lesion. Two patients were classified as having refractory epilepsy (one had biopsy-proven neurocysticercosis and the other one hippocampal sclerosis and temporal cortical dysplasia). The third patient had no lesion on MRI and had complete control with carbamazepine. Both lesional patients underwent resective surgery, one with complete seizure control and the other one with poor outcome. Although hypothalamic hamartomas should always be ruled out in patients with gelastic epilepsy, laughing seizures can also arise from frontal and temporal lobe foci, which can be surgically removed. In addition, we present the first case of gelastic epilepsy due to neurocysticercosis.
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http://dx.doi.org/10.1016/j.ebcr.2015.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4544395PMC
May 2016
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