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

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.

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

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.

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

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.

Patients recovering from COVID-19 who presented with anosmia during their acute episode have behavioral, functional, and structural brain alterations.

Patients recovering from COVID-19 commonly exhibit cognitive and brain alterations, yet the specific neuropathological mechanisms and risk factors underlying these alterations remain elusive. Given the significant global incidence of COVID-19, identifying factors that can distinguish individuals at risk of developing brain alterations is crucial for prioritizing follow-up care. Here, we report findings from a sample of patients consisting of 73 adults with a mild to moderate SARS-CoV-2 infection without signs of respiratory failure and 27 with infections attributed to other agents and no history of COVID-19. The participants underwent cognitive screening, a decision-making task, and MRI evaluations. We assessed for the presence of anosmia and the requirement for hospitalization. Groups did not differ in age or cognitive performance. Patients who presented with anosmia exhibited more impulsive alternative changes after a shift in probabilities (r = - 0.26, p = 0.001), while patients who required hospitalization showed more perseverative choices (r = 0.25, p = 0.003). Anosmia correlated with brain measures, including decreased functional activity during the decision-making task, thinning of cortical thickness in parietal regions, and loss of white matter integrity. Hence, anosmia could be a factor to be considered when identifying at-risk populations for follow-up.

Plasma urate in REM sleep behavior disorder.

BACKGROUND: Rapid eye movement (REM) sleep behavior disorder (RBD) is associated with a high risk of developing Parkinson's disease (PD). Higher urate levels are associated with a lower risk of PD. We conducted a study to evaluate plasma urate levels in patients with RBD and their role in the development of PD. METHODS: We evaluated plasma urate levels in a cohort of 24 patients with idiopathic RBD. Patients were divided into 2 groups according to the presence or absence of PD. Other known markers of the risk of developing PD, such as olfaction testing, and substantia nigra (SN) hyperechogenicity, were evaluated in the 2 groups. RESULTS: No differences were observed regarding age, years of evolution of the RBD, SN hyperechogenicity, or plasma urate levels between the 2 groups. In patients without PD, there was a positive correlation between years of evolution of RBD and the levels of uric acid (R(2) =0.88). Patients without PD and those who had more than 5 years of RBD exhibited higher levels of uric acid than patients with PD (P=0.02). CONCLUSIONS: Higher levels of plasma urate were associated with a longer duration of RBD without converting to PD. Future prospective studies would be needed to confirm this finding. Disorder Society

Frequency of diminished ovarian reserve in women with multiple sclerosis in Chile: An exploratory study.

INTRODUCTION: Multiple Sclerosis (MS) is a chronic disease affecting around 2.8 million people worldwide. Two-thirds are women, and the mean age at diagnosis is about 30 years old. Social trends are moving towards older age at first pregnancy, both in women with and without MS. OBJECTIVES: To determine the frequency of diminished ovarian reserve (DOR) through anti-Mullerian Hormone (AMH) measurement in women with MS at fertile age and Healthy Females (HF) in Chile. METHODS: Case-control, multicentric, cross-sectional study including relapsing-remitting people with MS (pwMS) between 18 and 40 years and sex and age-matched HF. We obtained a blood sample to determine AMH levels. We defined DOR as AMH <1.5 ng/mL and very-low AMH levels as <0.5 ng/mL. Also, we performed questions regarding reproductive decision-making. RESULTS: We included 79 sex and age-matched HF and 92 pwMS, median age 32(19-40) years, median disease duration 6 (1-17)years, median EDSS 1.0 (0-6), 95% were receiving disease-modifying therapy (DMT), 70% high-efficacy DMT and 37% with a treatment that contraindicates pregnancy. DOR was observed in 24% (n = 22) of the pwMS, compared to 14% (n = 11) of the HF (p = 0.09), while very-low AMH levels were observed in 7.6% (n = 7) of pwMS and none of the HF (p = 0.0166). We observed an inverse correlation between age and AMH levels. Age was the only significant risk factor for low AMH levels in pwMS (OR 1.14 95%CI(1.00-1-31), p = 0.04), including smoking, body mass index (BMI), hormonal contraception, autoimmune comorbidity, high/low-moderate efficacy DMT, and active disease as covariables. We did not find statistically significant differences in age at diagnosis, BMI, disease duration, EDSS, autoimmune comorbidity, use of hormonal contraception, or percentage of active disease between MS women with normal vs DOR. Over 70% of pwMS desired to become pregnant in the future, while 60% considered that the diagnosis of MS was a limitation for pregnancy planning. CONCLUSIONS: No differences in DOR, measured by levels of AMH, were observed between pwMS MS and HF in Chile. As expected, AMH levels were correlated only with ageing. This information may be evaluated early during the disease course to help patients and neurologists with fertility counselling and family planning considerations regarding DMT use.

Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD) in Chile: lessons learned from challenging cases.

BACKGROUND: Anti-Myelin Oligodendrocyte Glycoprotein (MOG) Antibody Associated Disease (MOGAD) is an emerging disorder recognized as a clinical entity distinct from Multiple Sclerosis and Aquaporin-4-positive Neuromyelitis Optica Spectrum Disorders (NMOSD-AQP4+), and its phenotypic spectrum continues to expand. Most information about its clinical course has emerged from retrospective studies, and treatment response both in acute and chronic-relapsing disease is still limited. We aimed to describe the clinical and paraclinical characteristics of monophasic and relapsing, paediatric and adult patients with MOGAD under regular clinical care in Chile, highlighting some challenging cases that are far from being considered benign. METHODS: Observational, retrospective, and prospective longitudinal multicentre study including patients with positive serum MOG-IgG assessed by cell-based assay. RESULTS: We include 35 patients, 71% women, median age at onset 30 years (range 1-68), 23% had paediatric onset, with a median disease-duration 24 months (range 12-348). In the whole cohort, the most frequent symptoms at onset were isolated optic neuritis (ON) (34%) and myelitis (22%). Encephalitis with seizures or encephalomyelitis was the most common presentation in paediatric-onset patients 75% (n = 6), compared to 11% (n = 3) of the adult-onset patients (p < 0.001). A relapsing course was observed in 34%, these patients were younger (25 vs. 34 years, p = 0.004) and with a longer disease duration (64 vs. 6 months, p = 0.004) compared to monophasic patients. Two patients developed encephalitis with seizures/status epilepticus, with concomitant positive CSF anti-NMDAR-IgG. Chronic immunotherapy was ever prescribed in 77%, the most frequent was rituximab (35%). Relapses under chronic immunotherapy occurred in 5/27 patients (18.5%), two of them under rituximab, one paediatric patient who started combined therapy with monthly IVIG and one adult patient that switched to satralizumab plus mycophenolate. The median EDSS at the last follow-up was 1.5 (range 0-6.0). CONCLUSION: In Chile, patients with MOGAD exhibit a wide spectrum of clinical presentations at disease onset and during relapses. Close monitoring is needed, particularly in younger patients with short follow-up periods.

Acute to Chronic Electro-Clinical Manifestations of Neuro-COVID and the Long-Haul Consequences in People With Epilepsy: A Review.

Severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection can involve the central nervous system (CNS). Acute symptomatic seizures or epileptiform discharges have not been commonly reported in patients with altered mental status related to coronavirus disease 2019 (COVID-19) infection. However, long-term neurological symptoms have been reported after COVID-19 infection (i.e., brain fog, cognitive complaints, and confusion), suggesting chronic encephalopathy. People with epilepsy (PWE) have been specifically affected by the COVID-19 pandemic, with changes in their seizure frequency, quality of life, health care accessibility, and medication interactions. This narrative review highlights possible pathophysiological mechanisms of COVID-19 on the brain, related to short- and long-term epileptiform activity and the impact of this infection on PWE.

Safety and humoral response rate of inactivated and mRNA vaccines against SARS-CoV-2 in patients with Multiple Sclerosis.

BACKGROUND: Safety and effectiveness outcomes in Multiple Sclerosis (MS) patients receiving different disease-modifying therapies (DMT) and different types of vaccines against SARS-CoV-2 are limited. Growing evidence coming mainly from Israel, Europe and North America using mRNA and adenoviral vector vaccines has been published. OBJECTIVES: To assess the safety and humoral response of inactivated virus and mRNA vaccines against SARS-CoV-2 in patients with MS. METHODS: Ongoing, multicentric, prospective, observational study performed between February and September 2021. Humoral response (antibodies against spike-1 protein) was determined at least 4 weeks after the complete schedule of anti-SARS-CoV-2 vaccines. Categorical outcome (positive/negative) and total antibody titres were recorded. Adverse events supposedly attributable to vaccination (AESAV) were collected. RESULTS: 178 patients, 68% women, mean age 39.7 ± 11.2 years, 123 received inactivated (Coronavac-Sinovac), 51 mRNA (Pfizer-BioNtech), and 4 adenoviral vector vaccines (CanSino n = 2, Jonhson&Johnson-Jannsen n = 1, Oxford-AstraZeneca n = 1). Six patients had a history of COVID-19 before vaccination. Overall humoral response was observed in 66.9% (62.6% inactivated vs. 78.4% mRNA, p = 0.04). Positive anti-S1-antibodies were observed in 100% of patients with no DMT (n = 3), 100% with interferon/glatiramer-acetate (n = 11), 100% with teriflunomide/dimethyl-fumarate (n = 16), 100% with natalizumab (n = 10), 100% with alemtuzumab (n = 8), 90% with cladribine (n = 10), and 88% with fingolimod (n = 17), while 43% of patients receiving antiCD20 (n = 99) were positive (38% inactivated vaccine vs. 59% mRNA vaccine, p = 0.05). In the multivariate analysis including antiCD20 patients, the predictors for a positive humoral response were receiving the mRNA vaccine (OR 8.11 (1.79-36.8), p = 0.007) and a lower number of total infusions (OR 0.44 (0.27-0.74) p = 0.002. The most frequent AESAV was local pain (14%), with 4 (2.2%) patients experiencing mild-moderate relapses within 8 weeks of first vaccination compared to 11 relapses (6.2%) within the 8 weeks before vaccination (Chi-squared 3.41, p = 0.06). DISCUSSION: A higher humoral response rate was observed using the mRNA compared to the inactivated vaccine, while patients using antiCD20 had a significantly lower response rate, and patients using antiCD20 and fingolimod had lower antibody titres. In this MS patient cohort, inactivated and mRNA vaccines against SARS-CoV-2 appear to be safe, with no increase in relapse rate. This information may help guidelines including booster shots and types of vaccines in selected populations.

Pregnancy outcomes in women with Multiple Sclerosis.

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.

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

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.

EEG findings and clinical prognostic factors associated with mortality in a prospective cohort of inpatients with COVID-19.

PURPOSE: Our objective is to describe the most prevalent electroencephalographic findings in COVID-19 hospitalized patients, and to determine possible predictors of mortality including EEG and clinical variables. METHODS: A multicentric prospective observational study in patients with COVID-19 requiring EEG during hospitalization. RESULTS: We found 94 EEG from 62 patients (55 % men, mean age 59.7 ± 17.8 years) were analyzed. Most frequent comorbidity was cardiac (52 %), followed by metabolic (45 %) and CNS disease (39 %). Patients required ICU management by 60 %, with a mortality of 27 % in the whole cohort. The most frequent EEG finding was generalized continuous slow-wave activity (66 %). Epileptic activity was observed in 19 % including non-convulsive status epilepticus, seizures and interictal epileptiform discharges. Periodic patterns were observed in 3 patients (3.2 %). Multivariate analysis found that cancer comorbidity and requiring an EEG during the third week of evolution portended a higher risk of mortality CONCLUSION: We observed that the most prevalent EEG finding in this cohort was generalized continuous slow-wave activity, while epileptic activity was observed in less than 20 % of the cases. Mortality risk factors were comorbidity with cancer and requiring an EEG during the third week of evolution, possibly related to the hyperinflammatory state.

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

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.

Frontoparietal connectivity correlates with working memory performance in multiple sclerosis.

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.

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

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.

Stereo-EEG ictal/interictal patterns and underlying pathologies.

PURPOSE: To define Stereo-EEG (SEEG) ictal and interictal patterns associated with different pathologies in a cohort of patients with drug-resistant focal epilepsy. METHODS: We retrospectively analyzed findings from 102 patient with epilepsy due to Polymicrogyria (PMG), Periventricular Nodular Heterotopia (PNH), Focal Cortical Dysplasia (FCD) type I, IIa, IIb and Hippocampal Sclerosis (HS). Ictal and interictal SEEG recordings were reviewed to describe Seizure Onset Zone (SEEG-SOZ) patterns and to define the Lesional and Irritative Zones. RESULTS: Five SEEG-SOZ patterns were identified: significant associations were found between low-voltage fast activity and PMG and between repetitive fast spikes bursts and FCD type IIa. A trend was found between fast activity and PNH, rhythmic sharp activity and FCD type I, repetitive fast spikes bursts and FCD type IIb, slow burst and HS. In 62 of the 102 patients, a complete surgical resection of the SEEG-SOZ was performed, and in 12 patients a partial resection was carried out to preserve eloquent areas. In 18 patients (15 with PNH) the SEEG-SOZ was thermo-coagulated. Seizure freedom was achieved in 58% of surgically treated patients and in 72% of those treated with thermocoagulation (mean ±â€¯SD follow-up 5.9 ±â€¯2.3 years). Seizure freedom after surgery was achieved in 84% of the patients with PMG, FCD I, IIa and IIb presenting with characteristic SEEG-SOZ patterns. With the exception of FCD type II, interictal activity was not sufficient to identify SEEG-SOZ boundaries. CONCLUSION: The study demonstrates that specific histopathologies correlate with particular neurophysiological patterns, reflecting lesion-specific seizure patterns in focal epilepsies.

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

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.

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

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) (n = 21), different clinical forms of MS (n = 62) [relapsing-remitting (RRMS), secondary progressive, and primary progressive], and healthy controls (HCs) (n = 17) were tested for plasma levels of interferon (IFN)-γ, IL-10, TGF-ß, 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.

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

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. ß-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.