Publications by authors named "Mar Carreño"

74 Publications

Psychotic symptoms in drug resistant epilepsy patients after cortical stimulation.

Epilepsy Res 2021 Apr 2;173:106630. Epub 2021 Apr 2.

Epilepsy Program, Neurology Department, Hospital Clinic of Barcelona, Barcelona, 08036, Spain; Clinical Institute of Neurosciences, Hospital Clinic of Barcelona, Barcelona, 08036, Spain; Biomedical Research Institute August Pi i Sunyer (IDIBAPS), Hospital Clinic of Barcelona, Barcelona, 08036, Spain.

Purpose: The use of invasive EEG (iEEG) recordings before epilepsy surgery has increased as more complex focal epilepsies are evaluated. Psychotic symptoms (PS) during iEEG have been scarcely reviewed. We aim to report our series of patients with psychotic symptoms (PS) brought about by cortical stimulation (CS) and to identify triggers.

Methods: Retrospective cohort of patients who underwent iEEG and CS. We report patients who developed delusional thinking and/or disorganized behaviour within 24 h after CS. Exclusion criteria were primary psychiatric disorders or absence of CS.

Results: We evaluated 32 (SEEG 23; subdural 9) patients with a median age of 38 years, 6 with PS. Patients underwent 2586 stimulations over 1130 contacts. Age at CS was significantly higher in patients with PS. Temporal lobe epilepsy was significantly more often documented in patients with PS (χ: 3.94; p< 0.05). We found no correlation between stimulation of the limbic system and development of psychosis. Four (66.7 %) patients were stimulated in the non-dominant limbic system and developed psychosis compared to 7 (27 %) who did not [χ2: 3.41; p= 0.06].Epilepsy duration was significantly higher in PS patients (p=0.002). Patients with history of postictal psychosis were twice more likely to experience PS(p=0.04).

Conclusions: PS may arise more frequently in patients with PIP history, older age and longer epilepsy duration. The neurobiology and physiology of psychosis, that may share common mechanisms with epilepsy, is yet to be identified but we hypothesize that it may be triggered by CS due to alteration of brain networks dynamics.
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http://dx.doi.org/10.1016/j.eplepsyres.2021.106630DOI Listing
April 2021

Psychiatric disorders in patients with resistant temporal lobe epilepsy two years after undergoing elective surgery. A longitudinal study.

Epilepsy Behav 2021 May 5;118:107921. Epub 2021 Apr 5.

Department of Psychiatry, Hospital Clinic of Barcelona, Barcelona 08036, Spain; Clinical Institute of Neurosciences, Hospital Clinic of Barcelona, Barcelona 08036, Spain; Epilepsy Unit, Neurology Department, Hospital Clinic of Barcelona, Barcelona 08036, Spain; Biomedical Research Institute August Pi i Sunyer (IDIBAPS), Hospital Clinic of Barcelona, Barcelona, 08036, Spain. Electronic address:

Purpose: Psychiatric morbidity in temporal lobe epilepsy (TLE) is frequent and negatively affects patients' life quality. Surgery is the procedure of choice when treating seizures, although the effects on psychiatric disorders remain unclear. We evaluate the effect of surgery on psychiatric disorders in patients with TLE two years after the intervention, to then shed light on how these are related to anxiety and depression symptoms, and Interictal Dysphoric Disorder (IDD).

Methods: We included data from 65 patients with TLE whose psychiatric evaluations were performed according to DSM-IV criteria. Anxiety and depression symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS) test.

Results: At 2-year follow-up, anxiety and depressive disorders decreased, and psychotic disorders augmented without statistical significance. Baseline psychiatric disorders predisposed to psychiatric pathology at 2-year follow-up and did not correlate with epilepsy outcome after surgery. Postoperative psychiatric disorders correlated with the seizure incidence two years after the intervention, suggesting that epilepsy and psychiatric disorders were associated in processes such as surgery. De novo psychiatric disorders represented 52% of postoperative psychiatric pathology, 62% being psychotic disorders. De novo psychiatric disorders became more frequent from the first year of surgery, occurring mainly in patients free of seizures. The HADS test scores and IDD correlated with psychiatric disorders at 2-year follow-up.

Conclusions: Baseline psychiatric disorders did not influence surgery outcome, but correlated with psychiatric disorders' prevalence two years after surgery. Despite not finding statistical significance, surgery reduced the prevalence of psychiatric disorders, and de novo psychiatric disorders were associated with an improvement in the epilepsy course at 2-year follow-up.
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http://dx.doi.org/10.1016/j.yebeh.2021.107921DOI Listing
May 2021

A survey of the European Reference Network EpiCARE on clinical practice for selected rare epilepsies.

Epilepsia Open 2021 03 13;6(1):160-170. Epub 2021 Jan 13.

IRCCS Mondino Foundation Pavia Italy.

Objective: Clinical care of rare and complex epilepsies is challenging, because evidence-based treatment guidelines are scarce, the experience of many physicians is limited, and interdisciplinary treatment of comorbidities is required. The pathomechanisms of rare epilepsies are, however, increasingly understood, which potentially fosters novel targeted therapies. The objectives of our survey were to obtain an overview of the clinical practice in European tertiary epilepsy centers treating patients with 5 arbitrarily selected rare epilepsies and to get an estimate of potentially available patients for future studies.

Methods: Members of the ( were invited to participate in a web-based survey on clinical practice of patients with Dravet syndrome, tuberous sclerosis complex (TSC), autoimmune encephalitis, and progressive myoclonic epilepsies including Unverricht Lundborg and Unverricht-like diseases. A consensus-based questionnaire was generated for each disease.

Results: Twenty-six of 30 invited epilepsy centers participated. Cohorts were present in most responding centers for TSC (87%), Dravet syndrome (85%), and autoimmune encephalitis (71%). Patients with TSC and Dravet syndrome represented the largest cohorts in these centers. The antiseizure drug treatments were rather consistent across the centers especially with regard to Dravet syndrome, infantile spasms in TSC, and Unverricht Lundborg / Unverricht-like disease. Available, widely used targeted therapies included everolimus in TSC and immunosuppressive therapies in autoimmune encephalitis. Screening for comorbidities was routinely done, but specific treatment protocols were lacking in most centers.

Significance: The survey summarizes the current clinical practice for selected rare epilepsies in tertiary European epilepsy centers and demonstrates consistency as well as heterogeneity in the treatment, underscoring the need for controlled trials and recommendations. The survey also provides estimates for potential participants of clinical trials recruited via EpiCARE, emphasizing the great potential of Reference Networks for future studies to evaluate new targeted therapies and to identify novel biomarkers.
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http://dx.doi.org/10.1002/epi4.12459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918306PMC
March 2021

The emerging role of the advanced practice epilepsy nurse: A comparative study between two countries.

J Clin Nurs 2021 May 2;30(9-10):1263-1272. Epub 2021 Mar 2.

Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Aims And Objectives: The aim of the study was to compare advanced practice in epilepsy nurses in Spain and United Kingdom, identifying differences in the domains of standard advanced practice.

Background: Europe has recently faced the challenge of providing high-quality care for patients with epilepsy, a disease that generates many health demands. In some countries, such as the United Kingdom, advanced practice nursing is well established and could serve as a guide for implantation in countries where it is still in development, as is the case of Spain.

Design: A multicentre cross-sectional descriptive cohort study compared differences in the roles of advanced practice nurses in Spain and the United Kingdom.

Methods: The Advanced Practice Role Delineation Tool and its validated Spanish version were administered using an online questionnaire in a cohort of advanced practice epilepsy nurses in both countries. A convenience sample was recruited between January to December 2019. The study complied with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist.

Results: Most United Kingdom nurses in our sample came from community environments, in contrast to Spanish nurses who worked in hospital. All domains analysed in the survey had significantly higher scores in the United Kingdom than in the Spanish cohort, especially in the research and leadership domains.

Conclusions: The advanced practice role in Spain is underdeveloped compared with the United Kingdom. Differences in the settings of advanced roles in epilepsy nurses may be explained by greater community practice in the United Kingdom and differences in organisational and health systems.

Relevance To Clinical Practice: Our study showed the need to implement specific policies to develop advance practice nurse roles in Spain to improve the quality of care of patients with epilepsy.
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http://dx.doi.org/10.1111/jocn.15669DOI Listing
May 2021

Comparative analysis of the safety and tolerability of eslicarbazepine acetate in older (≥60 years) and younger (18-59 years) adults.

Epilepsy Res 2021 Jan 10;169:106478. Epub 2020 Oct 10.

Sunovion Pharmaceuticals Inc., Marlborough, MA, USA. Electronic address:

Objective: To investigate the safety and tolerability of eslicarbazepine acetate (ESL), a once-daily oral anti-seizure drug (ASD), in older and younger adult patient populations.

Methods: Two post-hoc pooled data analyses were performed: one from three Phase III studies in patients with focal (partial-onset) seizures who were taking 1-3 concomitant ASDs; the other from five Phase II studies in patients from non-epilepsy populations not taking other ASDs chronically and/or at a clinically-effective anti-seizure dose. The frequencies of treatment-emergent adverse events (TEAEs) were calculated for the older (≥60 years) and younger (18-59 years) adults separately.

Results: In the focal seizures study pool, 4.1 % of patients (58/1431) were aged ≥60 years. The overall frequency of TEAEs was 77.5 % in older ESL-treated patients and 72.6 % in younger ESL-treated patients (p = 0.495). For patients who received placebo, the overall frequency of TEAEs was 50.0 % in the older adults and 57.5 % in the younger adults (p = 0.531). The overall placebo-adjusted frequency of TEAEs was 27.5 % in older adults and 15.1 % in younger adults. The placebo-adjusted frequencies of the TEAEs dizziness, somnolence, headache, nausea, diplopia, blurred vision, and ataxia were ≥5 % higher, and frequencies of vomiting and vertigo were ≥2 % higher in older than younger adults. The overall frequency of TEAEs leading to discontinuation was 15.0 % in older ESL-treated patients and 17.6 % in younger ESL-treated patients (p = 0.647); the frequency increased with increasing ESL dose. For patients who received placebo, the overall frequency of TEAEs leading to discontinuation was 5.6 % in older adults and 6.6 % in younger adults (p = 0.847). In the non-epilepsy study pool, 30.2 % of patients (515/1705) were aged ≥60 years. The overall frequency of TEAEs was 56.9 % in older ESL-treated patients and 58.8 % in younger ESL-treated patients. The placebo-adjusted frequencies were 14.9 % in older and 15.1 % in younger ESL-treated patients. The placebo-adjusted frequencies of the TEAEs nausea, vomiting, fatigue, and vertigo were ≥2 % higher in older adults, whereas somnolence was ≥2 % higher in younger adults. The overall frequency of TEAEs leading to discontinuation was 18.3 % in older ESL-treated patients and 12.1 % in younger ESL-treated patients (p = 0.003); frequencies were not related to ESL dose. For patients who received placebo, the overall frequency of TEAEs leading to discontinuation was 8.0 % in older adults and 5.6 % in younger adults (p = 0.407).

Conclusion: Analyses of adverse event data support the safety and tolerability of ESL in adults aged ≥60 years. In the limited number of older patients with focal seizures taking ESL plus concomitant ASDs (n = 40), the frequency of TEAEs was generally higher than in younger adults. However, in the non-epilepsy patient group (in which the number of older patients was ten times larger; 427 patients taking ESL without concomitant ASDs), no marked age-related TEAE differences were observed, suggesting that increased ASD load associated with adjunctive therapy may complicate treatment selection in older patients, due to risk of increased adverse events. As is common practice for all ASDs, balancing clinical response and tolerability is needed in this vulnerable group of patients.
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http://dx.doi.org/10.1016/j.eplepsyres.2020.106478DOI Listing
January 2021

Initiating antiepilepsy treatment: An update of expert consensus in Spain.

Epilepsy Behav 2021 01 24;114(Pt A):107540. Epub 2020 Nov 24.

Programa de Epilepsia, Hospital Ruber Internacional, Madrid, Spain.

Following publication in 2014 of the International League Against Epilepsy (ILAE) official report changing the definition of epilepsy, a number of questions remain unresolved in regard to deciding when to start treatment and to the choice of a particular antiseizure medication (ASM). This study uses a Delphi method to update consensus among a panel of experts on the initiation of epilepsy treatment in order to provide insight regarding those questions. The study was undertaken in four phases. Firstly, a multi-center steering committee met to review relevant bibliography and to draft a questionnaire. Secondly, a panel of neurologists specialized in epilepsy was selected and convened. Thirdly, an online survey was carried out in two rounds. Fourthly, the final results were discussed at a face-to-face meeting of the steering committee to draw conclusions. The final questionnaire focused on three independent sections: the decision to commence ASM in different clinical situations, the choice of initial monotherapy depending on the type of epilepsy and the patient's age/sex (including childbearing potential), and the choice of initial monotherapy depending on comorbidity. In these two latter sections, fourteen ASMs approved for monotherapy use by the EMA and available in Spain were considered. Regarding the decision as to when to commence treatment, the results show agreement exists to initiate treatment following a first generalized tonic-clonic seizure or a focal seizure if the electroencephalography (EEG) reveals epileptiform activity, if the MRI reveals a lesion, or when it occurs in elderly patients. With respect to the choice of initial monotherapy depending on the type of epilepsy and the patient's age/sex profile, it is agreed to avoid valproic acid (VPA) in women with childbearing potential, with levetiracetam (LEV) and lamotrigine (LTG) being the preferable options in generalized epilepsy. In focal epilepsy, the options are broader, particularly in men, and include the most recent ASMs approved for monotherapy. In the elderly, LEV, lacosamide (LCM), eslicarbazepine acetate (ESL) and LTG are considered the most suitable drugs for initiating treatment. With regard to comorbidities, the recommendation is to avoid enzyme inducing ASMs, with LEV, the most recent ASMs approved for monotherapy and LTG being the preferred options. In conclusion, as the ILAE definition states, there are different situations that lead to treatment initiation after a first seizure. When choosing the first ASM, the type of epilepsy, childbearing potential and drug-drug interaction are key factors.
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http://dx.doi.org/10.1016/j.yebeh.2020.107540DOI Listing
January 2021

Epilepsy and lockdown: A survey of patients normally attending a Spanish centre.

Acta Neurol Scand 2021 Feb 17;143(2):206-209. Epub 2020 Nov 17.

Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS). EpiCARE Network, Barcelona, Spain.

Background: Lockdown due to the SARS-CoV-2 pandemic became a challenge to maintain care for patients with epilepsy; we aimed to find out how the pandemic affected them.

Methods: We sent an online 22-item questionnaire to patients from our outpatient clinic, a reference centre in Spain for drug-resistant epilepsy, inquiring about the effects of lockdown, from March to May 2020.

Results: We sent the survey to 627 patients; 312 (58% women) sent a complete response and were included. Of all respondents, 57% took >2 antiseizure medications. One-third of respondents (29%) declared an associated cognitive or motor disability. A minority had confirmed infection with SARS-CoV-2 (1.92%). Seizure frequency remained like usual in 56% of patients, while 31.2% reported an increase. Less than 10% needed emergent assistance. Almost half reported anxiety or depression, and 25% increased behavioural disorders. Mood (F: 5.40; p: 0.002) and sleep disorders (F = 2.67; p: 0.05) were associated with increase in seizure frequency. Patients were able to contact their physicians when needed and were open to a future telematic approach to follow-up visits.

Conclusions: Seizure frequency and severity remained unchanged in most patients during the lockdown. Mood and sleep disorders were common and associated with seizure worsening. Patients were open to telematic care in the future.
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http://dx.doi.org/10.1111/ane.13354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646661PMC
February 2021

Seizures and epilepsy of autoimmune origin: A long-term prospective study.

Seizure 2020 Oct 25;81:157-165. Epub 2020 Jul 25.

Epilepsy Unit, Department of Neurology, Hospital Clinic i Provincial, Barcelona, Spain.

Objective: To follow prospectively a group of patients with seizures or epilepsy and suggestive clinical features of autoimmune aetiology and find out how many are finally diagnosed with acute symptomatic seizures (ASS) secondary to autoimmune encephalitis or autoimmune-related epilepsy, and how many develop epilepsy.

Methods: Consecutive patients meeting the inclusion criteria from 2010 to 2018 were identified. Patients were classified as confirmed, probable autoimmune, non-autoimmune, or unknown.

Results: One-hundred and nine patients were included, 64 (48.7 %) women, mean age 55.2 years (SD 17.9). ASS were reported by 61 patients (56 %), while 48 presented epilepsy (44 %). During follow-up 18 patients died (16.5 %). Final diagnosis was autoimmune-relatedepilepsy (confirmed + probable) in 22 cases and ASS secondary to autoimmune encephalitis (confirmed or probable) in 27, non-autoimmune aetiologies or other diagnosis in 49 (44 %), and unknown aetiology in 11 (10.2 %). Neuronal antibodies (ab) were found in 27 patients (24.7 %). T-lymphocyte infiltration in temporal lobes was observed in 2/8 patients (20 %). Neuronal ab were more frequent in the autoimmune groups: 17 patients (29.8 %) vs 1(2.3 %), p:0.001, and they suffered more autoimmune diseases: 37 (75.5 %) vs 12 (24.48 %), p:0.0001, and 34 (69 %) vs 22 (44.9 %) p:0.027, respectively. All patients with GAD ab 17/17 (100 %) evolved to chronic disease. Four patients (29 %) with ASS secondary to autoimmune encephalitis developed epilepsy.

Significance: ASS secondary to autoimmune encephalitis or autoimmune-related epilepsy will be diagnosed in nearly half of patients who have been suspected of it. The only diagnostic clue is neuronal ab. Patients who have suffered ASS secondary to autoimmune encephalitis may develop epilepsy over time.
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http://dx.doi.org/10.1016/j.seizure.2020.07.019DOI Listing
October 2020

Emergency implementation of telemedicine for epilepsy in Spain: Results of a survey during SARS-CoV-2 pandemic.

Epilepsy Behav 2020 10 5;111:107211. Epub 2020 Jun 5.

Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Epilepsy Study Group of the Catalan Neurological Society, Spanish Epilepsy Society, European Reference Network (ERN), Spain. Electronic address:

Teleneurology in Spain had not been implemented so far in clinical practice, except in urgent patients with stroke. Telemedicine was hardly used in epilepsy, and patients and neurologists usually preferred onsite visits. Our goal was to study impressions of adult and pediatric epileptologists about the use of telemedicine after emergent implementation during the new coronavirus 2019 (COVID-19) pandemic.

Methods: An online survey was sent to the members of the Spanish Epilepsy Society and the members of the Epilepsy Study Group of the Catalan Neurological Society, inquiring about different aspects of telemedicine in epilepsy during the pandemic lockdown.

Results: A total of 66 neurologists responded, mostly adult neurologists (80.3%), the majority with a monographic epilepsy clinic (4 out of 5). Of all respondents, 59.1% reported to attend more than 20 patients with epilepsy (PWE) a week. During the pandemic, respondents handled their epilepsy clinics mainly with telephone calls (88%); only 4.5% used videoconference. Changes in antiseizure medications were performed less frequently than during onsite visits by 66.6% of the epileptologists. Scales were not administered during these visits, and certain types of information such as sudden expected unrelated death in epilepsy (SUDEP) were felt to be more appropriate to discuss in person. More than 4 out of 5 of the neurologists (84.8%) stated that they would be open to perform some telematic visits in the future.

Conclusions: In Spain, emergent implantation of teleneurology has shown to be appropriate for the care of many PWE. Technical improvements, extended use of videoconference and patient selection may improve results and patient and physician satisfaction.
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http://dx.doi.org/10.1016/j.yebeh.2020.107211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274642PMC
October 2020

External trigeminal nerve stimulation for drug resistant epilepsy: A randomized controlled trial.

Brain Stimul 2020 Sep - Oct;13(5):1245-1253. Epub 2020 Jun 10.

Epilepsy Unit, Department of Neurology, Hospital Clínic de Barcelona, Barcelona, Spain, Institut D'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Barcelona, Spain.

Background: External trigeminal nerve stimulation (ETNS) is an emergent, non-invasive neurostimulation therapy delivered bilaterally with adhesive skin electrodes. In previous studies, ETNS was associated to a decrease in seizure frequency in patients with focal drug-resistant epilepsy (DRE).

Objective: To determine the long-term efficacy and tolerability of ETNS in patients with focal DRE. Moreover, to explore whether its efficacy depends on the epileptogenic zone (frontal or temporal), and its impact on mood, cognitive function, quality of life, and trigeminal nerve excitability.

Methods: Forty consecutive patients with frontal or temporal DRE, unsuitable for surgery, were randomized to ETNS or usual medical treatment. Participants were evaluated at 3, 6 and 12 months for efficacy, side effects, mood scales, neuropsychological tests and trigeminal nerve excitability.

Results: Subjects had a median of 15 seizures per month and had tried a median of 12.5 antiepileptic drugs. At 12 months, percentage of responders was 50% in ETNS group and 0% in control group. Seizure frequency in ETNS group decreased by -43.5% from baseline. Temporal epilepsy subgroup responded better than frontal epilepsy subgroup (55.56% vs. 45.45%, respectively). Median stimulation intensity was 6.2 mA. ETNS improved quality of life, but not anxiety or depression. Long-term ETNS affected neither neuropsychological function, nor trigeminal nerve excitability. No relevant adverse events were observed.

Conclusions: ETNS is an effective and well-tolerated therapy for focal DRE. Patients with temporal epilepsy showed a better response than those with frontal epilepsy. Future studies with larger populations may define its role compared to other neurostimulation techniques.

Classification Of Evidence: This study provides Class II evidence that ETNS reduces seizure frequency in patients with focal DRE.
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http://dx.doi.org/10.1016/j.brs.2020.06.005DOI Listing
March 2021

Could the 2017 ILAE and the four-dimensional epilepsy classifications be merged to a new "Integrated Epilepsy Classification"?

Seizure 2020 May 5;78:31-37. Epub 2020 Mar 5.

Neurocenter Bellevue, Zurich, Switzerland.

Over the last few decades the ILAE classifications for seizures and epilepsies (ILAE-EC) have been updated repeatedly to reflect the substantial progress that has been made in diagnosis and understanding of the etiology of epilepsies and seizures and to correct some of the shortcomings of the terminology used by the original taxonomy from the 1980s. However, these proposals have not been universally accepted or used in routine clinical practice. During the same period, a separate classification known as the "Four-dimensional epilepsy classification" (4D-EC) was developed which includes a seizure classification based exclusively on ictal symptomatology, which has been tested and adapted over the years. The extensive arguments for and against these two classification systems made in the past have mainly focused on the shortcomings of each system, presuming that they are incompatible. As a further more detailed discussion of the differences seemed relatively unproductive, we here review and assess the concordance between these two approaches that has evolved over time, to consider whether a classification incorporating the best aspects of the two approaches is feasible. To facilitate further discussion in this direction we outline a concrete proposal showing how such a compromise could be accomplished, the "Integrated Epilepsy Classification". This consists of five categories derived to different degrees from both of the classification systems: 1) a "Headline" summarizing localization and etiology for the less specialized users, 2) "Seizure type(s)", 3) "Epilepsy type" (focal, generalized or unknown allowing to add the epilepsy syndrome if available), 4) "Etiology", and 5) "Comorbidities & patient preferences".
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http://dx.doi.org/10.1016/j.seizure.2020.02.018DOI Listing
May 2020

Beyond the Epileptic Focus: Functional Epileptic Networks in Focal Epilepsy.

Cereb Cortex 2020 04;30(4):2338-2357

Epilepsy Program, Department of Neurology, Hospital Clínic, Neuroscience Institute, CP 08036, Barcelona, Spain.

Focal epilepsy can be conceptualized as a network disorder, and the functional epileptic network can be described as a complex system of multiple brain areas that interact dynamically to generate epileptic activity. However, we still do not fully understand the functional architecture of epileptic networks. We studied a cohort of 21 patients with extratemporal focal epilepsy. We used independent component analysis of functional magnetic resonance imaging (fMRI) data. In order to identify the epilepsy-related components, we examined the general linear model-derived electroencephalography-fMRI (EEG-fMRI) time courses associated with interictal epileptic activity as intrinsic hemodynamic epileptic biomarkers. Independent component analysis revealed components related to the epileptic time courses in all 21 patients. Each epilepsy-related component described a network of spatially distributed brain areas that corresponded to the specific epileptic network in each patient. We also provided evidence for the interaction between the epileptic activity generated at the epileptic network and the physiological resting state networks. Our findings suggest that independent component analysis, guided by EEG-fMRI epileptic time courses, have the potential to define the functional architecture of the epileptic network in a noninvasive way. These data could be useful in planning invasive EEG electrode placement, guiding surgical resections, and more effective therapeutic interventions.
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http://dx.doi.org/10.1093/cercor/bhz243DOI Listing
April 2020

Spanish version of the Satisfaction with Epilepsy Care questionnaire: Adaptation and psychometric properties.

Epilepsy Behav 2020 01 9;102:106812. Epub 2019 Dec 9.

Epilepsy Unit, Department of Neurology, Hospital Clínic de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Objective: The objective of this study was to perform a cross-cultural adaption and psychometric evaluation of the Spanish version of the Satisfaction with Epilepsy Care (SEC) questionnaire and analyze patient satisfaction with epilepsy care.

Methods: Transcultural adaptation and validation of the SEC were carried out using translation and back-translation with pilot testing and an expert panel. The SEC-E (Spanish) was analyzed in 213 patients with epilepsy to examine construct and criterion validity and internal consistency.

Results: The SEC-E achieved conceptual, semantic, and content equivalence with the original version. For content validity, one question was eliminated from the original questionnaire as it has little relevance in our cultural setting. Positive correlations for criterion validity were obtained using the gold standard measure (Satisfaction in Hospitalized Patients scale). Construct validity replicated the three dimensions of the original questionnaire. The scale showed adequate reliability through internal consistency (Cronbach's α of 0.94) and temporal stability on retest (n = 85). Patients scored (0 to 100) 77.5 [standard deviation (SD): 19.9] for satisfaction with communication, 76.9 (SD: 17) for organization, and 67.2 (SD: 22.1) for information.

Significance: The SEC-E is a valid and reliable tool for the assessment of educational interventions aiming to improve the quality of care in patients with epilepsy in Spanish clinical practice. The results showed a good level of patient satisfaction with epilepsy care.
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http://dx.doi.org/10.1016/j.yebeh.2019.106812DOI Listing
January 2020

Hypothalamic hamartomas in adulthood: Clinical spectrum and treatment outcome-A unicenter experience.

Brain Behav 2019 11 2;9(11):e01412. Epub 2019 Oct 2.

Epilepsy Unit, Department of Neurology, Hospital Clinic, Barcelona, Spain.

Introduction: Clinical manifestations of the hypothalamic hamartoma-epilepsy syndrome (HH-ES) in adulthood are variable. Efficacy of therapeutic options and outcome are diverse.

Methods: Retrospective study of adult patients diagnosed with a HH in magnetic resonance imaging and epilepsy who attended our tertiary Epilepsy Unit between 2003 and 2018. We report the clinical and electroencephalographic features of a series of adult patients with HH and related epilepsy seen in our center together with the treatments and seizure outcome.

Results: We describe a series of eight patients. Five males (62.5%), median age at evaluation was 28.5 years (IQR: 15.5). Clinical manifestations included focal with preserved and impaired awareness emotional seizures (gelastic seizures [GS]) in six patients (75%), focal tonic, atonic with impaired awareness and focal to bilateral tonic-clonic seizures. Mild GS were the only symptom in one patient. Three patients (37.5%) had endocrinological disturbances such as obesity and hypothyroidism. Fifty percent of the patients showed psychiatric comorbidity such as anxiety disorder and aggressiveness, and two patients had psychomotor delay. Seven patients (87.7%) had drug-resistant seizures and three of them were treated with radiosurgery. Out of the treated group, only one (33.3%) became seizure-free 2 years after surgery but developed psychiatric problems. The other two patients had an Engel IV outcome and received a vagal nerve stimulation (VNS) implant. VNS did not lead to changes either in intensity nor in seizure frequency.

Conclusions: Hypothalamic hamartoma-epilepsy syndrome clinical manifestations in adult patients are as variable as at pediatric age. Outcome of therapeutic options such as radiosurgery or VNS may be poorer at this stage.
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http://dx.doi.org/10.1002/brb3.1412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851795PMC
November 2019

Consensus statement for the management of generalized tonic-clonic seizures in Spain.

Acta Neurol Scand 2020 Jan 21;141(1):22-32. Epub 2019 Oct 21.

Hospital del Mar de Barcelona, Barcelona, Spain.

Objective: To develop recommendations for the management of patients with primary or secondary generalized tonic-clonic seizures (GTCS) based on best evidence and experience.

Methods: The Delphi methodology was followed. A multidisciplinary panel of 10 experts was established, who defined the scope, users and preliminary recommendations. Systematic and narrative reviews of the current literature were performed to assess data on the risk of sudden unexpected death in epilepsy and the efficacy and safety of add-on therapy in patients with GTCS. Twenty-five definitive recommendations were generated which were then graded on a scale of 1 (totally disagree) to 10 (totally agree) by the experts and 45 neurologists. Consensus was reached if at least 70% of the participants applied a score of ≥7. Each recommendation was then assigned a level of evidence, a grade of agreement and a grade of recommendation. The entire process was supervised by an expert methodologist.

Results: Overall, 24 out of 25 recommendations achieved consensus. These included specific recommendations on diagnosis, evaluation and treatment. The recommendations also emphasized the importance of proper psychological evaluation and effective communication between patients and health professionals, and the importance of patient and family education and support.

Significance: The recommendations generated by this consensus can be used as a guide for the diagnosis and management of patients with GTCS.
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http://dx.doi.org/10.1111/ane.13169DOI Listing
January 2020

Epileptogenic Zone Localization With FDG PET Using a New Dynamic Parametric Analysis.

Front Neurol 2019 17;10:380. Epub 2019 Apr 17.

Nuclear Medicine Department, Hospital Clínic, Barcelona, Spain.

[F]fluorodeoxyglucose (F-FDG) positron emission tomography (PET) is part of the regular preoperative work-up in medically refractory epilepsy. As a complement to visual evaluation of PET, statistical parametric maps can help in the detection of the epileptogenic zone (EZ). However, software packages currently available are time-consuming and little intuitive for physicians. We develop a user-friendly software (referred as PET-analysis) for EZ localization in PET studies that allows dynamic real-time statistical parametric analysis. To evaluate its performance, the outcome of PET-analysis was compared with the results obtained by visual assessment and Statistical Parametric Mapping (SPM). Thirty patients with medically refractory epilepsy who underwent presurgical F-FDG PET with good post-operative outcomes were included. The F-FDG PET studies were evaluated by visual assessment, with SPM8 and PET-analysis. In SPM, parametric T-maps were thresholded at corrected < 0.05 and cluster size k = 50 and at uncorrected < 0.001 and k = 100 (the most used parameters in the literature). Since PET-analysis rapidly processes different threshold combinations, T-maps were thresholded with multiple -value and different clusters sizes. The presurgical EZ identified by visual assessment, SPM and PET-analysis was compared to the confirmed EZ according to post-surgical follow-up. PET-analysis obtained 66.7% (20/30) of correctly localizing studies, comparable to the 70.0% (21/30) achieved by visual assessment and significantly higher ( < 0.05) than that obtained with the SPM threshold < 0.001/k = 100, of 36.7% (11/30). Only one study was positive, albeit non-localizing, with the SPM threshold corrected < 0.05/k = 50. Concordance was substantial for PET-analysis (κ = 0.643) and visual interpretation (κ = 0.622), being fair for SPM (κ = 0.242). Compared to SPM with the fixed standard parameters, PET-analysis may be superior in EZ localization with its easy and rapid processing of different threshold combinations. The results of this initial proof-of-concept study validate the clinical use of PET-analysis as a robust objective complementary tool to visual assessment for EZ localization.
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http://dx.doi.org/10.3389/fneur.2019.00380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478660PMC
April 2019

Critique of the 2017 epileptic seizure and epilepsy classifications.

Epilepsia 2019 06 28;60(6):1032-1039. Epub 2019 Mar 28.

Department of Neurology, University Hospitals Cleveland Medical Center, Cleveland, Ohio.

This article critiques the International League Against Epilepsy (ILAE) 2015-2017 classifications of epilepsy, epileptic seizures, and status epilepticus. It points out the following shortcomings of the ILAE classifications: (1) they mix semiological terms with epileptogenic zone terminology; (2) simple and widely accepted terminology has been replaced by complex terminology containing less information; (3) seizure evolution cannot be described in any detail; (4) in the four-level epilepsy classification, level two (epilepsy category) overlaps almost 100% with diagnostic level one (seizure type); and (5) the design of different classifications with distinct frameworks for newborns, adults, and patients in status epilepticus is confusing. The authors stress the importance of validating the new ILAE classifications and feel that the decision of Epilepsia to accept only manuscripts that use the ILAE classifications is premature and regrettable.
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http://dx.doi.org/10.1111/epi.14699DOI Listing
June 2019

Classification of paroxysmal events and the four-dimensional epilepsy classification system.

Epileptic Disord 2019 02;21(1):1-29

Case Medical Center - Pediatrics, Cleveland, Ohio, USA.

This educational review describes the classification of paroxysmal events and a four-dimensional epilepsy classification system. Paroxysmal events are classified as epileptic and non-epileptic paroxysmal events. Non-epileptic events are, in turn, classified as psychogenic and organic paroxysmal events. The following four dimensions are used to classify epileptic paroxysmal events: ictal semiology, the epileptogenic zone, etiology, and comorbidities. Efforts are made to keep these four dimensions as independent as possible. The review also includes 12 educational vignettes and three more detailed case reports classified using the 2017 classification of the ILAE and the four-dimensional epilepsy classification. In addition, a case is described which is classified using the four-dimensional epilepsy classification with different degrees of precision by an emergency department physician, a neurologist, and an epileptologist. [Published with video sequences on www.epilepticdisorders.com].
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http://dx.doi.org/10.1684/epd.2019.1033DOI Listing
February 2019

Autoimmune seizures and epilepsy.

J Clin Invest 2019 03 4;129(3):926-940. Epub 2019 Feb 4.

Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and.

The rapid expansion in the number of encephalitis disorders associated with autoantibodies against neuronal proteins has led to an incremental increase in use of the term "autoimmune epilepsy," yet has occurred with limited attention to the physiopathology of each disease and genuine propensity to develop epilepsy. Indeed, most autoimmune encephalitides present with seizures, but the probability of evolving to epilepsy is relatively small. The risk of epilepsy is higher for disorders in which the antigens are intracellular (often T cell-mediated) compared with disorders in which the antigens are on the cell surface (antibody-mediated). Most autoantibodies against neuronal surface antigens show robust effects on the target proteins, resulting in hyperexcitability and impairment of synaptic function and plasticity. Here, we trace the evolution of the concept of autoimmune epilepsy and examine common inflammatory pathways that might lead to epilepsy. Then, we focus on several antibody-mediated encephalitis disorders that associate with seizures and review the synaptic alterations caused by patients' antibodies, with emphasis on those that have been modeled in animals (e.g., antibodies against NMDA, AMPA receptors, LGI1 protein) or in cultured neurons (e.g., antibodies against the GABAb receptor).
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http://dx.doi.org/10.1172/JCI125178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391086PMC
March 2019

Hippocampus and Insula Are Targets in Epileptic Patients With Glutamic Acid Decarboxylase Antibodies.

Front Neurol 2018 9;9:1143. Epub 2019 Jan 9.

Epilepsy Unit, Department of Neurology, Hospital Clinic i Provincial, Barcelona, Spain.

Antibodies to glutamic acid decarboxylase (GAD ab) have been found in patients with limbic encephalitis (LE) and chronic pharmacoresistant focal epilepsy (FE). The objectives of the study were to: (1) analyze the clinical and neuroimaging course of patients with FE+GAD ab, (2) compare these characteristics with a control group, and (3) describe the most affected cerebral areas with structural and functional imaging. Patients with FE + high titers of GAD ab and a follow-up of at least 5 years were selected. Titers of serum GAD ab exceeding 2,000 UI/ml were considered high. Evolutive clinical and radiological characteristics were studied in comparison to two different control groups: patients with bilateral or with unilateral mesial temporal sclerosis (BMTS or UMTS) of a non-autoimmune origin. A group of 13 patients and 17 controls were included (8 BMTS, 9 UMTS). The most frequent focal aware seizures (FAS) reported by patients were psychic (5/13: 33%). Somatosensorial, motor, and visual FAS (4/13:32%) (: 0.045), musicogenic reflex seizures (MRS), and a previous history of cardiac syncope were reported only patients (2/13:16% each) (: NS). Comparing EEG characteristics between patients and controls, a more widespread distribution of interictal epileptiform discharges (IED) was observed in FE+ GAD ab patients than in controls (:0.01). Rhythmic delta activity was observed in all controls in anterior temporal lobes while in patients this was less frequent (: 0.001). No IED, even in 24 h cVEEG, was seen in 6 patients (46%).First MRI was normal in 4/5 (75%) patients. During the follow-up mesial temporal lobe (MTsL) sclerosis was observed in 5/8 (62%) of patients. All patients had abnormal FDG-PET study. MTL hypometabolism was observed in 10/11 (91%) patients, being bilateral in 7/11 (63%). In controls, this was observed in 16/17 (94%), and it was bilateral in 8/17 (47%) (: NS). Insular hypometabolism was observed in 5/11 (45%) patients (:0.002). Clinical, EEG, and FDG-PET findings in FE+GAD ab suggest a widespread disease not restricted to the temporal lobe. Progressive MTL sclerosis may be observed during follow-up. In comparison to what is found in patients with non-autoimmune MTL epilepsy, insular hypometabolism is observed only in patients with GAD ab, so it may be an important diagnostic clue.
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http://dx.doi.org/10.3389/fneur.2018.01143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334555PMC
January 2019

Typical asymmetry in the hemispheric activation during an fMRI verbal comprehension paradigm is related to better performance in verbal and non-verbal tasks in patients with epilepsy.

Neuroimage Clin 2018 15;20:742-752. Epub 2018 Sep 15.

IDIBAPS (Institut d'Investigacions Biomèdiques August Pi i Sunyer), Barcelona, Spain; Epilepsy Unit, Department of Radiology, Hospital Clínic, Barcelona, Spain.

Chronic exposure to seizures in patients with left hemisphere (LH) epileptic focus could favor higher activation in the contralateral hemisphere during language processing, but the cognitive effects of this remain unclear. This study assesses the relationship between asymmetry in hemispheric activation during language fMRI and performance in verbal and non-verbal tasks. Whereas prior studies primarily used fMRI paradigms that favor frontal lobe activation and less prominent activation of the medial or superior temporal lobes, we used a verbal comprehension paradigm previously demonstrated to activate reliably receptive language areas. Forty-seven patients with drug-resistant epilepsy candidates for surgery underwent a multidisciplinary assessment, including a comprehensive neuropsychological evaluation and an fMRI verbal comprehension paradigm. Patients were distributed in two groups depending on laterality indexes (LI): typical hemispheric asymmetry (unilateral left activation preponderance; n = 23) and atypical hemispheric asymmetry (bilateral or unilateral right preponderance; n = 24). Right-handedness and right hemisphere (RH) focus were significant predictors of typical asymmetry. Patients with typical activation pattern presented better performance intelligence quotient and verbal learning than patients with atypical hemispheric asymmetry (for all, p < 0.014). Patients with LH focus had more frequently atypical hemispheric asymmetry than patients with RH focus (p = 0.05). Specifically, they showed lower LI and this was related to worse performance in verbal and non-verbal tasks. In conclusion, an increased activation of homologous RH areas for verbal comprehension processing could imply a competition of cognitive resources in the performance of the same task, disrupting cognitive performance.
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http://dx.doi.org/10.1016/j.nicl.2018.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6154460PMC
January 2019

PISCOM: a new procedure for epilepsy combining ictal SPECT and interictal PET.

Eur J Nucl Med Mol Imaging 2018 12 1;45(13):2358-2367. Epub 2018 Aug 1.

Department of Nuclear Medicine, Hospital Clínic, C/Villarroel 170, 08036, Barcelona, Spain.

Purpose: We present a modified version of the SISCOM procedure that uses interictal PET instead of interictal SPECT for seizure onset zone localization. We called this new nuclear imaging processing technique PISCOM (PET interictal subtracted ictal SPECT coregistered with MRI).

Methods: We retrospectively studied 23 patients (age range 4-61 years) with medically refractory epilepsy who had undergone MRI, ictal SPECT, interictal SPECT and interictal FDG PET and who had been seizure-free for at least 2 years after surgical treatment. FDG PET images were reprocessed (rFDG PET) to assimilate SPECT features for image subtraction. Interictal SPECT and rFDG PET were compared using statistical parametric mapping (SPM). PISCOM and SISCOM images were evaluated visually and using an automated volume of interest-based analysis. The results of the two studies were compared with each other and with the known surgical resection site.

Results: SPM showed no significant differences in cortical activity between SPECT and rFDG PET images. PISCOM and SISCOM showed equivalent results in 17 of 23 patients (74%). The seizure onset zone was successfully identified in 19 patients (83%) by PISCOM and in 17 (74%) by SISCOM: in 15 patients (65%) the two techniques showed concordant successful results. The volume of interest-based analysis showed no significant differences between PISCOM and SISCOM in identifying the extension of the seizure onset zone. However, PISCOM showed a lower amount of indeterminate activity due to propagation, background or artefacts.

Conclusion: Preliminary findings of this initial proof-of-concept study suggest that perfusion and glucose metabolism in the cerebral cortex can be correlated and that PISCOM may be a valid technique for identification of the seizure onset zone. However, further studies are needed to validate these results.
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http://dx.doi.org/10.1007/s00259-018-4080-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208811PMC
December 2018

Psychiatric Symptoms in Refractory Epilepsy During the First Year After Surgery.

Neurotherapeutics 2018 10;15(4):1082-1092

Clinical Institute of Neurosciences, Hospital Clinic of Barcelona, Barcelona, 08036, Spain.

Psychiatric morbidity in drug-resistant epilepsy is frequent. Surgery is the best therapeutic alternative for treating seizures, but the current evidence concerning the effects of surgery on psychiatric disorders (PDs) is inconclusive. We aim to clarify surgery's role in long-term PDs. Using a prospective controlled study, we analyzed the psychopathologic outcomes of patients with drug-resistant epilepsy, comparing those who underwent surgery to those who did not due to not being suitable. Surgical candidates were paired (n = 84) with the immediately following nonsurgical candidates (n = 68). Both groups continued their usual medical treatment. We studied psychiatric changes for each group and analyzed de novo and remission cases. The assessments were made during the presurgical evaluation, and at 6 months (6-M) and 12 months (12-M) after surgery. Finally, we determined associated factors for postsurgical PDs. At 12 months, using the Hospital Anxiety and Depression Scale (HADS), anxiety improved in both groups (p = 0.000), while depression improved only in the surgical group (p = 0.016). Moreover, all symptom dimensions on the Symptom Checklist-90-R (SCL-90), as well as severity, distress, and total symptoms, decreased only in the surgical group. These ameliorations reached not only statistical significance but also clinical significance for depression (HADS) (p = 0.014) and the interictal dysphoric disorder (p = 0.013). The main predictors for PDs after surgery were as follows: the presurgical and 6-month psychiatric symptoms, the absence of surgery, seizure outcomes, and some antiepileptic and psychiatric drugs. This study provides evidence that surgery for epilepsy could have a role in improving some symptoms of psychiatric disorders 12-M after the surgery.
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http://dx.doi.org/10.1007/s13311-018-0652-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277301PMC
October 2018

Perampanel in routine clinical use in idiopathic generalized epilepsy: The 12-month GENERAL study.

Epilepsia 2018 09 31;59(9):1740-1752. Epub 2018 Jul 31.

University Hospital Vall d'Hebrón, Barcelona, Spain.

Objective: To analyze the effectiveness and tolerability of perampanel across different seizure types in routine clinical care of patients with idiopathic generalized epilepsy (IGE).

Methods: This multicenter, retrospective, 1-year observational study collected data from patient records at 21 specialist epilepsy units in Spain. All patients who were aged ≥12 years, prescribed perampanel before December 2016, and had a confirmed diagnosis of IGE were included.

Results: The population comprised 149 patients with IGE (60 with juvenile myoclonic epilepsy, 51 generalized tonic-clonic seizures [GTCS] only, 21 juvenile absence epilepsy, 10 childhood absence epilepsy, 6 adulthood absence epilepsy, and one Jeavons syndrome). Mean age was 36 years. The retention rate at 12 months was 83% (124/149), and 4 mg was the most common dose. At 12 months, the seizure-free rate was 59% for all seizures (88/149); 63% for GTCS (72/115), 65% for myoclonic seizures (31/48), and 51% for absence seizures (24/47). Seizure frequency was reduced significantly at 12 months relative to baseline for GTCS (78%), myoclonic (65%), and absence seizures (48%). Increase from baseline seizure frequency was seen in 5.2% of patients with GTCS seizures, 6.3% with myoclonic, and 4.3% with absence seizures. Perampanel was effective regardless of epilepsy syndrome, concomitant antiepileptic drugs (AEDs), and prior AEDs, but retention and seizure freedom were significantly higher when used as early add-on (after ≤2 prior AEDs) than late (≥3 prior AEDs). Adverse events were reported in 50% of patients over 12 months, mostly mild or moderate, and irritability (23%), somnolence (15%), and dizziness (14%) were most frequent.

Significance: In routine clinical care of patients with IGE, perampanel improved seizure outcomes for GTCS, myoclonic seizures, and absence seizures, with few discontinuations due to adverse events. This is the first real-world evidence with perampanel across different seizure types in IGE.
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http://dx.doi.org/10.1111/epi.14522DOI Listing
September 2018

Unilateral pallidal stimulation for disabling dystonia due to Rasmussen's disease.

J Neurol Neurosurg Psychiatry 2019 01 9;90(1):108-110. Epub 2018 Jul 9.

Functional Neurosurgery Unit, Department of Neurosurgery,  Hospital Clínic, Barcelona, Spain.

Objective: To describe an adult patient with Rasmussen's disease with focal dystonia as the most disabling symptom and the good response to unilateral globus pallidus internus (GPi) deep brain stimulation (DBS).

Methods: Retrospective review of clinical records and diagnostic tests.

Results: The patient had displayedmild focal seizures with sensory and motor symptoms on the left arm and hemiface since the age of 22. Ten years later she experienced abrupt onset of focal left dystonia involving mainly the leg. Brain MRI showed progressive right hemisphere atrophy, and   fluorodeoxyglucose-positron emission tomography (FDG-PET) showed right hypometabolism mainly over the frontal and insular regions. Brain biopsy confirmed chronic encephalitis. The dystonia became very severe and made walking extremely difficult. Different treatments including dopaminergic, anticholinergic, immunomodulatory drugs and botulinum toxin were ineffective. Finally the patient was treated with unilateral GPi DBS. Shortly after the onset of the stimulation, the dystonia started to improve. Parameters have been adjusted, and 18 months after surgery the patient is able to walk and run unaided, although a mild left leg dystonia persists.

Conclusion: Rasmussen's disease may be difficult to diagnose in adult patients. Associated movement disorders may be more disabling than seizures. Focal dystonia may be treated successfully with DBS.
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http://dx.doi.org/10.1136/jnnp-2018-318029DOI Listing
January 2019

Psychiatric and cognitive adverse events: A pooled analysis of three phase III trials of adjunctive eslicarbazepine acetate for partial-onset seizures.

Epilepsy Behav 2018 05 28;82:119-127. Epub 2018 Mar 28.

Sunovion Pharmaceuticals Inc., 84 Waterford Dr, Marlborough, MA 01752, USA.

Objective: To evaluate the nature and incidence of psychiatric and cognitive adverse events (AEs) reported with eslicarbazepine acetate (ESL) used as adjunctive treatment for refractory partial-onset seizures (POS) in adults.

Methods: This was a post-hoc analysis of data pooled from three randomized double-blind, placebo-controlled trials (BIA-2093-301, -302, -304). After an 8-week baseline period, patients received placebo or adjunctive ESL 400mg (studies 301 and 302 only), 800mg, or 1200mg once daily (QD) for 14weeks (2-week titration period, 12-week maintenance period). Psychiatric and cognitive AEs were identified from individual patient data. Suicidality was also evaluated using the Columbia-Classification Algorithm of Suicide Assessment (C-CASA), or the Columbia-Suicide Severity Rating Scale (C-SSRS). P-values were obtained using the chi-square test of independence or Fisher's exact test, without correcting for multiplicity.

Results: The analysis population included 1447 patients (ESL, n=1021; placebo, n = 426). Psychiatric treatment-emergent AEs (TEAEs) occurred in 10.8% of patients receiving ESL, and in a comparable proportion (10.3%) of patients receiving placebo (p=0.802). The incidence of depression and suicidality-related TEAEs was higher for ESL (7.4%) vs. placebo (3.8%) (p=0.009). The occurrence of these TEAEs differed between treatment groups (p = 0.010), but there was no notable trend between increasing ESL dose and increasing incidence of depression and suicidality-related TEAEs. Aggression/hostility-related TEAEs occurred in <0.1% of patients taking ESL vs. 0.9% taking placebo. The incidence of cognitive TEAEs was higher for ESL (7.1%) vs. placebo (4.0%) (p=0.023); incidences of memory impairment, attention disturbance, apathy, and aphasia were higher for ESL 1200mg than for other treatment groups. Incidences of psychiatric and cognitive serious AEs (SAEs) were 0.6% and 0.2% with ESL, and 0.5% and 0% with placebo, respectively. Psychiatric and cognitive TEAEs leading to discontinuation occurred in 1.9% and 1.4% of patients taking ESL, and 0.7% and 0.5% taking placebo, respectively.

Conclusions: In phase III clinical trials of adjunctive ESL for treatment-refractory POS, psychiatric and cognitive TEAEs were reported infrequently with ESL and placebo. The incidences of depression and suicidality-related TEAEs and of cognitive TEAEs were higher for patients taking ESL vs. placebo. Incidences of psychiatric and cognitive SAEs, and TEAEs leading to discontinuation, were low with ESL and placebo.
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http://dx.doi.org/10.1016/j.yebeh.2017.12.017DOI Listing
May 2018

Incidence of seizure exacerbation and seizures reported as adverse events during adjunctive treatment with eslicarbazepine acetate: A pooled analysis of three Phase III controlled trials.

Epilepsia Open 2017 12 9;2(4):459-466. Epub 2017 Nov 9.

Sunovion Pharmaceuticals Inc. Marlborough Massachusetts U.S.A.

Objective: To investigate whether adjunctive eslicarbazepine acetate (ESL) could lead to exacerbation of seizures in some patients.

Methods: Post-hoc analysis of data pooled from three Phase III trials of adjunctive ESL (studies 301, 302, and 304) for refractory partial-onset seizures (POS). Following an 8-week baseline period, patients were randomized to receive placebo or ESL 400, 800, or 1,200 mg once daily (2-week titration, 12-week maintenance, 2-4 week tapering-off periods). Patient seizure diary data and seizure treatment-emergent adverse event (TEAE) reports were pooled for analysis.

Results: The modified intent-to-treat and safety populations comprised 1,410 patients and 1,447 patients, respectively. : Compared with placebo (32/21%), significantly smaller proportions of patients taking ESL 800 mg (20/15%) and 1,200 mg (22/12%) had a ≥25/≥50% increase in standardized seizure frequency (SSF) from baseline; there was no significant difference between placebo and ESL 400 mg. : Compared with placebo (20%), significantly smaller proportions of patients taking ESL (400 mg, 12%; 800 mg, 12%; 1,200 mg, 14%) had an increase in SSF ≥25%. When evaluating ≥50% increases in SSF, only ESL 800 mg (7%) was significantly different from placebo (12%). Some patients had no secondarily generalized tonic-clonic (sGTC) seizures during baseline but had ≥1 sGTC seizure during maintenance treatment (placebo, 11%; ESL 400 mg, 5%; 800 mg, 10%; 1,200 mg, 5%). Fewer patients had a ≥25% increase in sGTC seizure frequency with ESL (400 mg, 11%; 800 mg, 9%; 1,200 mg, 14%) versus placebo (19%). The incidence of seizures reported as TEAEs was low in all treatment groups; incidences were generally lower with ESL versus placebo. : Similar proportions of patients taking ESL and placebo had a ≥25/≥50% increase in SSF. Seizure TEAE incidence was numerically higher with ESL versus placebo.

Significance: Treatment with adjunctive ESL does not appear to aggravate POS or sGTC seizures.
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http://dx.doi.org/10.1002/epi4.12083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862126PMC
December 2017

Effects of adjunctive eslicarbazepine acetate on serum lipids in patients with partial-onset seizures: Impact of concomitant statins and enzyme-inducing antiepileptic drugs.

Epilepsy Res 2018 03 9;141:83-89. Epub 2018 Feb 9.

Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, MA 01752, USA. Electronic address:

Purpose: To evaluate the effects of eslicarbazepine acetate (ESL) on lipid metabolism and to determine whether reduced statin exposure during ESL therapy has clinical consequences.

Subjects And Methods: We conducted a post-hoc analysis of pooled data for serum lipids (laboratory values) from three phase III, multicenter, randomized, double-blind, placebo-controlled trials of adjunctive ESL therapy (400, 800, or 1200 mg once daily) in patients with treatment-refractory partial-onset seizures. Changes from baseline in serum lipid levels were analyzed according to use of statins and/or enzyme-inducing antiepileptic drugs (EIAEDs) during the baseline period.

Key Findings: In total, 426 and 1021 placebo- and ESL-treated patients, respectively, were included in the analysis. With regard to the changes from baseline in serum concentrations, there were statistically significant differences between the placebo and ESL 1200 mg QD groups, for both total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C), but the effect sizes were small (+4.1 mg/dL and +1.8 mg/dL, respectively). A small but significant difference in low-density lipoprotein cholesterol (LDL-C; -5.0 mg/dL) was observed between the ESL 400 mg QD group and the placebo group. In patients not taking a concomitant EIAED, there were no changes with ESL 400 mg QD, but modest and statistically significant increases in cholesterol fractions (TC, LDL-C and HDL-C) with ESL 800 mg QD (<6 mg/dL) and ESL 1200 mg QD (<10 mg/dL). ESL had no consistent effect on lipids in patients taking a concomitant EIAED. In patients taking statins during baseline, there were no clinically relevant changes in serum lipids during use of ESL, although the subgroups were small.

Significance: These results suggest that ESL does not appear to have clinically significant effects on serum lipids, nor does the pharmacokinetic interaction between ESL and statins have an impact on serum lipid concentrations.
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http://dx.doi.org/10.1016/j.eplepsyres.2018.02.001DOI Listing
March 2018