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Stefano MELETTI

Professore Associato
Dipartimento di Scienze Biomediche, Metaboliche e Neuroscienze sede ex-Neuroscienze

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Pubblicazioni

2024 - Intraoperative ECoG in bottom-of-the-sulcus syndrome using a novel flexible strip electrode [Articolo su rivista]
Biagioli, N.; Morandi, S.; Vaudano, A. E.; Pugnaghi, M.; Moriconi, E.; Pavesi, G.; Tramontano, V.; Meletti, S.
abstract

The recording of epileptiform discharges from bottom-of-sulcus focal cortical dysplasia (BOSD) is often difficult during intraoperative electrocorticography (ECoG) due to the deep localization. We describe the use in this scenario of a new-generation electrode strip with high flexibility, easily adapted to cortical gyri and sulci. A right-handed 20-year-old male with drug-resistant focal epilepsy due to BOSD of the inferior frontal gyrus and daily focal aware seizures was evaluated for epilepsy surgery. Based on electroclinical and neuroimaging results, a focal cortectomy guided by ECoG was proposed. ECoG recordings were performed with new-generation cortical strips (Wise Cortical Strip; WCS (R)) and standard cortical strips. ECoG, performed on the convexity of the frontal cortical surface, recorded only sporadic spikes with both types of strips. Then, after microsurgical trans-sulcal dissection, WCS was molded along the sulcal surface of the suspected BOSD based on 3D-imaging reconstruction, showing continuous/subcontinuous 3-4-Hz rhythmic spike activity from the deepest electrode. Registration after resection of the BOSD did not show any epileptiform activity. Pathology showed dysmorphic neurons and gliosis. No surgical complications occurred. The patient is seizure-free after 12 months. This single case experience shows that highly flexible electrode strips with adaptability to cortical gyrations can identify IEDs originating from deep location and could therefore be useful in cases of bottom of the sulcus dysplasia.

2024 - Patterns of subregional cerebellar atrophy across epilepsy syndromes: An ENIGMA-Epilepsy study [Articolo su rivista]
Kerestes, R.; Perry, A.; Vivash, L.; O'Brien, T. J.; Alvim, M. K. M.; Arienzo, D.; Aventurato, I. K.; Ballerini, A.; Baltazar, G. F.; Bargallo, N.; Bender, B.; Brioschi, R.; Burkle, E.; Caligiuri, M. E.; Cendes, F.; de Tisi, J.; Duncan, J. S.; Engel, J. P.; Foley, S.; Fortunato, F.; Gambardella, A.; Giacomini, T.; Guerrini, R.; Hall, G.; Hamandi, K.; Ives-Deliperi, V.; Joao, R. B.; Keller, S. S.; Kleiser, B.; Labate, A.; Lenge, M.; Marotta, C.; Martin, P.; Mascalchi, M.; Meletti, S.; Owens-Walton, C.; Parodi, C. B.; Pascual-Diaz, S.; Powell, D.; Rao, J.; Rebsamen, M.; Reiter, J.; Riva, A.; Ruber, T.; Rummel, C.; Scheffler, F.; Severino, M.; Silva, L. S.; Staba, R. J.; Stein, D. J.; Striano, P.; Taylor, P. N.; Thomopoulos, S. I.; Thompson, P. M.; Tortora, D.; Vaudano, A. E.; Weber, B.; Wiest, R.; Winston, G. P.; Yasuda, C. L.; Zheng, H.; Mcdonald, C. R.; Sisodiya, S. M.; Harding, I. H.
abstract

Objective: The intricate neuroanatomical structure of the cerebellum is of longstanding interest in epilepsy, but has been poorly characterized within the current corticocentric models of this disease. We quantified cross-sectional regional cerebellar lobule volumes using structural magnetic resonance imaging in 1602 adults with epilepsy and 1022 healthy controls across 22 sites from the global ENIGMA-Epilepsy working group. Methods: A state-of-the-art deep learning-based approach was employed that parcellates the cerebellum into 28 neuroanatomical subregions. Linear mixed models compared total and regional cerebellar volume in (1) all epilepsies, (2) temporal lobe epilepsy with hippocampal sclerosis (TLE-HS), (3) nonlesional temporal lobe epilepsy, (4) genetic generalized epilepsy, and (5) extratemporal focal epilepsy (ETLE). Relationships were examined for cerebellar volume versus age at seizure onset, duration of epilepsy, phenytoin treatment, and cerebral cortical thickness. Results: Across all epilepsies, reduced total cerebellar volume was observed (d =.42). Maximum volume loss was observed in the corpus medullare (dmax =.49) and posterior lobe gray matter regions, including bilateral lobules VIIB (dmax =.47), crus I/II (dmax =.39), VIIIA (dmax =.45), and VIIIB (dmax =.40). Earlier age at seizure onset ((Formula presented.) =.05) and longer epilepsy duration ((Formula presented.) =.06) correlated with reduced volume in these regions. Findings were most pronounced in TLE-HS and ETLE, with distinct neuroanatomical profiles observed in the posterior lobe. Phenytoin treatment was associated with reduced posterior lobe volume. Cerebellum volume correlated with cerebral cortical thinning more strongly in the epilepsy cohort than in controls. Significance: We provide robust evidence of deep cerebellar and posterior lobe subregional gray matter volume loss in patients with chronic epilepsy. Volume loss was maximal for posterior subregions implicated in nonmotor functions, relative to motor regions of both the anterior and posterior lobe. Associations between cerebral and cerebellar changes, and variability of neuroanatomical profiles across epilepsy syndromes argue for more precise incorporation of cerebellar subregional damage into neurobiological models of epilepsy.

2024 - Predictors of respiratory failure in Guillain−Barré syndrome: a 22 year cohort study from a single Italian centre [Articolo su rivista]
Galassi, G.; Mazzoli, M.; Ariatti, A.; Bedin, R.; Marzullo, D.; Bastia, E.; Agnoletto, V.; Gozzi, M.; Valzania, F.; Meletti, S.; Marchioni, A.
abstract

Background and purpose: The study aimed to identify predictors of respiratory failure leading to mechanical ventilation (MV) and tracheostomy in Guillain−Barré syndrome (GBS). Methods: Two hundred and thirty adult cases admitted to the Neurology Unit of Modena, Italy, between January 2000 and December 2021 were studied. A cut-off of MV starting within 8 weeks from onset of weakness was used. Univariable, multivariable logistic and Cox regression analyses were used to determine which pre-specified clinical and diagnostic characteristics were capable of predicting MV and tracheostomy, due to weaning failure. The model was internally validated within the full cohort. The Erasmus GBS Respiratory Insufficiency Score was retrospectively applied. Results: One hundred and seventy-six cases (76.5%) were classified as classical sensorimotor GBS and 54 (23.4%) as variants. Thirty-two patients (13.9%) needed MV: 84.3% required respiratory support within 7 days. Independent predictors of respiratory failure and MV were older age, facial, bulbar, neck flexor weakness, dysautonomia, axonal electrophysiological subtype, cardiovascular comorbidities and higher disability score at entry. There was no association with abnormal spinal fluid parameters nor with positive serology for recent infections. Twenty-two patients (68.7%) were ventilated for more than 7 days; 4.7% died within 8 weeks. The patients who required MV were treated more often with plasma exchange. Independent predictors of tracheostomy due to weaning trial failure were facial, bulbar, neck flexor weakness, autonomic dysfunction, associated cardiovascular morbidities and axonal electrophysiological subtype on nerve conduction study. Conclusions: Our study indicates distinct predictors of MV and tracheostomy in GBS patients.

2024 - Refractory status epilepticus: Is there room for grading refractoriness? [Articolo su rivista]
Lattanzi, S.; Meletti, S.
abstract

2024 - The Epilepsy Surgery Satisfaction Questionnaire (ESSQ-19): Italian language translation and validation [Articolo su rivista]
Burani, M.; Giovannini, G.; Pugnaghi, M.; Orlandi, N.; Cioclu, M. C.; Vaudano, A. E.; Moriconi, E.; Pavesi, G.; Meletti, S.
abstract

ObjectiveEpilepsy surgery can be proposed as a treatment option in people with focal epilepsy, however satisfaction with epilepsy surgery in Italy remains unknown. We aimed to validate in Italy an instrument to measure patient satisfaction with epilepsy surgery, the 19-item Epilepsy Surgery Satisfaction Questionnaire (ESSQ-19).MethodsConsecutive patients with epilepsy who received epilepsy surgery between the years 2018-2021 at Modena Academic Hospital were recruited and provided clinical and demographic data. The Italian version of the ESSQ-19 and other three questionnaires were completed to assess construct validity. To evaluate the validity and reliability of the tool Spearman's rank correlation, and internal consistency analysis were performed.Results66 out of 79 eligible patients participated in the study (22 females; median age 37 years). The mean values of satisfaction for each domain of the IT-ESSQ-19 were: seizure control 83.4; (SD 16.7), psychosocial functioning 79.3 (SD 17.1), surgical complications 90.8 (SD 14.9), and recovery from surgery 81.4 (SD 16.9). The mean summary score was 83.7 (SD 13.3). The questionnaire was shown to have high internal consistency in the four domains (Cronbach's alpha = 0.82-0.93), and no significant floor/ceiling effects of the summary score. The ESSQ-19 scores significantly correlated with other instruments to support construct validity. It also demonstrated good discriminant validity for being seizure free [AUC 0.72; 95% CI = 0.56-0.88], and to endorse depression [AUC 0.76, 95% CI = 0.56-0.96].SignificanceThe Italian version of the ESSQ-19 is a reliable and valid self-reported questionnaire for assessing patient satisfaction with epilepsy surgery.

2024 - The Role of Early Intubation in Status Epilepticus with Out-of-Hospital Onset: A Large Prospective Observational Study [Articolo su rivista]
Turcato, G.; Giovannini, G.; Lattanzi, S.; Orlandi, N.; Turchi, G.; Zaboli, A.; Brigo, F.; Meletti, S.
abstract

Background: this study aimed to evaluate the role of early airway management and intubation in status epilepticus (SE) with out-of-hospital onset. Methods: We included all patients with out-of-hospital SE onset referred to the emergency department of the Academic Hospital of Modena between 2013 and 2021. Patients were compared according to out-of-hospital airway management (intubation versus non-intubation) and a propensity score was performed for clinical variables unevenly distributed between the two groups. Results: We evaluated 711 patients with SE. A total of 397 patients with out-of-hospital SE onset were eventually included; of these, 20.4% (81/397) were intubated before arrival at the hospital. No difference was found in the clinical characteristics of patients after propensity score matching. The 30-day mortality in the propensity group was 19.4% (14/72), and no difference was found between intubated (7/36, 19.4%) and non-intubated (7/36, 19.4%) patients. No difference was found in SE cessation. Compared to non-intubated patients, those who underwent out-of-hospital intubation had a higher risk of progression to refractory or super-refractory SE, greater worsening of mRS values between hospital discharge and admission, and lower probability of returning to baseline condition at 30 days after SE onset. Conclusions: Early intubation for out-of-hospital SE onset is not associated with improved patient survival even after balancing for possible confounders. Further studies should evaluate the timing of intubation and its association with first-line treatments for SE and their efficacy. In addition, they should focus on the settings and the exact reasons leading to intubation to better inform early management of SE with out-of-hospital onset.

2024 - The risk of unprovoked seizure occurrence after status epilepticus in adults [Articolo su rivista]
Lattanzi, S.; Orlandi, N.; Giovannini, G.; Brigo, F.; Trinka, E.; Meletti, S.
abstract

Objective: Status epilepticus (SE) may lead to long-term consequences. This study evaluated the risk and predictors of seizure occurrence after SE, with a focus on SE due to acute symptomatic etiologies. Methods: Prospectively collected data about adults surviving a first non-hypoxic SE were reviewed. The outcome was the occurrence of unprovoked seizures during the follow-up. Kaplan–Meier survival curve analysis and log-rank test were used to analyze the time to seizure occurrence and determine the statistical significance between etiological groups. Three subcategories within acute etiology were considered according to the presence of the following: (1) structural lesion (acute-primary); (2) brain involvement during systemic disorders (acute-secondary); and (3) drug or alcohol intoxication/withdrawal (acute-toxic). Cox proportional hazards model was adopted to estimate hazard ratios (HRs) with the 95% confidence intervals (CIs). Results: Two hundreds fifty-seven individuals were included. Fifty-four subjects (21.0%) developed seizures after a median of 9.9 (interquartile range 4.3–21.7) months after SE. The estimated 1-, 2-, and 5-year rates of seizure occurrence according to acute SE etiologies were 19.4%, 23.4%, and 30.1%, respectively, for acute-primary central nervous system (CNS) pathology; 2.2%, 2.2%, and 8.7%, respectively, for acute-secondary CNS pathology; and 0%, 9.1%, and 9.1%, respectively, for acute-toxic causes. Five-year rates of seizure occurrence for non-acute SE causes were 33.9% for remote, 65.7% for progressive, and 25.9% for unknown etiologies. In multivariate Cox regression model, progressive etiology (adjusted HR [adjHR] 2.27, 95% CI 1.12–4.58), SE with prominent motor phenomena evolving in non-convulsive SE (adjHR 3.17, 95% CI 1.38–7.25), and non-convulsive SE (adjHR 2.38, 95% CI 1.16–4.90) were independently associated with higher hazards of unprovoked seizures. Older people (adjHR.98, 95% CI.96–.99) and people with SE due to acute-secondary CNS pathology (adjHR.18, 95% CI.04–.82) were at decreased risk of seizure occurrence. Significance: SE carries a risk of subsequent seizures. Both the underlying cause and epileptogenic effects of SE are likely to contribute.

2024 - Use, experience and perspectives of high-density EEG among Italian epilepsy centers: a national survey [Articolo su rivista]
Nucera, B.; Perulli, M.; Alvisi, L.; Bisulli, F.; Bonanni, P.; Canafoglia, L.; Cantalupo, G.; Ferlazzo, E.; Granvillano, A.; Mecarelli, O.; Meletti, S.; Strigaro, G.; Tartara, E.; Assenza, G.
abstract

Introduction: High-density EEG (hdEEG) is a validated tool in presurgical evaluation of people with epilepsy. The aim of this national survey is to estimate diffusion and knowledge of hdEEG to develop a network among Italian epilepsy centers. Methods: A survey of 16 items (and 15 additional items) was distributed nationwide by email to all members of the Italian League Against Epilepsy and the Italian Society of Clinical Neurophysiology. The data obtained were analyzed using descriptive statistics. Results: A total of 104 respondents were collected from 85 centers, 82% from the Centre-North of Italy; 27% of the respondents had a hdEEG. The main applications were for epileptogenic focus characterization in the pre-surgical evaluation (35%), biomarker research (35%) and scientific activity (30%). The greatest obstacles to hdEEG were economic resources (35%), acquisition of dedicated personnel (30%) and finding expertise (17%). Dissemination was limited by difficulties in finding expertise and dedicated personnel (74%) more than buying devices (9%); 43% of the respondents have already published hdEEG data, and 91% of centers were available to participate in multicenter hdEEG studies, helping in both pre-processing and analysis. Eighty-nine percent of respondents would be interested in referring patients to centers with established experience for clinical and research purposes. Conclusions: In Italy, hdEEG is mainly used in third-level epilepsy centers for research and clinical purposes. HdEEG diffusion is limited not only by costs but also by lack of trained personnel. Italian centers demonstrated a high interest in educational initiatives on hdEEG as well as in clinical and research collaborations.

2024 - When the brain moves away: a case of sphenoidal sinus encephalocele [Articolo su rivista]
Scolastico, S.; Pugnaghi, M.; Meletti, S.
abstract

2023 - A retrospective multicentric study on the effectiveness of intravenous brivaracetam in seizure clusters: Data from the Italian experience [Articolo su rivista]
Orlandi, N.; D'Orsi, G.; Pauletto, G.; Nilo, A.; Sicurella, L.; Pescini, F.; Giglia, F.; Labate, A.; Lagana, A.; Renna, R.; Cavalli, S. M.; Zummo, L.; Coletti Moja, M.; Vollono, C.; Sabetta, A.; Ranzato, F.; Zappulla, S.; Audenino, D.; Miniello, S.; Nazerian, P.; Marino, D.; Lattanzi, S.; Piccioli, M.; Estraneo, A.; Zini, A.; Servo, S.; Giovannini, G.; Meletti, S.; Bianchini, D.; Contardi, S.; Fasolino, A.; Fiore, G. M.; Foschi, N.; Giordano, A.; Laisa, P.; Lo Coco, D.; Maccora, S.; Magaudda, A.; Panebianco, M.; Merli, E.; Piccirillo, G.; Pugnaghi, M.; Ramacciotti, L.; Vaudano, A. E.; Vitale, G.; Zaniboni, A.
abstract

Objective: Nearly half of people with epilepsy (PWE) are expected to develop seizure clusters (SC), with the subsequent risk of hospitalization. The aim of the present study was to evaluate the use, effectiveness and safety of intravenous (IV) brivaracetam (BRV) in the treatment of SC. Methods: Retrospective multicentric study of patients with SC (≥ 2 seizures/24 h) who received IV BRV. Data collection occurred from January 2019 to April 2022 in 25 Italian neurology units. Primary efficacy outcome was seizure freedom up to 24 h from BRV administration. We also evaluated the risk of evolution into Status Epilepticus (SE) at 6, 12 and 24 h after treatment initiation. A Cox regression model was used to identify outcome predictors. Results: 97 patients were included (mean age 62 years), 74 (76%) of whom had a history of epilepsy (with drug resistant seizures in 49% of cases). BRV was administered as first line treatment in 16% of the episodes, while it was used as first or second drug after benzodiazepines failure in 49% and 35% of episodes, respectively. On the one hand, 58% patients were seizure free at 24 h after BRV administration and no other rescue medications were used in 75 out of 97 cases (77%) On the other hand, SC evolved into SE in 17% of cases. A higher probability of seizure relapse and/or evolution into SE was observed in patients without a prior history of epilepsy (HR 2.0; 95% CI 1.03 – 4.1) and in case of BRV administration as second/third line drug (HR 3.2; 95% CI 1.1 – 9.7). No severe treatment emergent adverse events were observed. Significance: In our cohort, IV BRV resulted to be well tolerated for the treatment of SC and it could be considered as a treatment option, particularly in case of in-hospital onset. However, the underlying etiology seems to be the main outcome predictor.

2023 - Acute symptomatic status epilepticus: Splitting or lumping? A proposal of classification based on real-world data [Articolo su rivista]
Lattanzi, S.; Giovannini, G.; Brigo, F.; Orlandi, N.; Trinka, E.; Meletti, S.
abstract

This study aimed to group acute symptomatic etiologies of consecutive episodes of status epilepticus (SE) into different subcategories and explore their associations with clinical outcome. Etiologies were first categorized as “acute,” “remote,” “progressive,” “SE in defined electroclinical syndromes,” and “unknown.” Four subcategories of acute etiologies were then defined: (1) withdrawal, low levels, or inappropriate prescription of antiseizure medications, or sleep deprivation in patients with pre-existing epilepsy; (2) acute insults to central nervous system (CNS; “acute-primary CNS”); (3) CNS pathology secondary to metabolic disturbances, systemic infection, or fever (“acute-secondary CNS”); and (4) drug/alcohol intoxication or withdrawal. Poor outcome at discharge, defined as worsening of clinical conditions (modified Rankin Scale [mRS] at discharge higher than mRS at baseline), was reported in 55.6% of cases. The etiological categories of acute-primary CNS (odds ratio [OR] = 3.61, 95% confidence interval [CI] = 2.11–6.18), acute-secondary CNS (OR = 1.80, 95% CI = 1.11–2.91), and progressive SE (OR = 2.65, 95% CI = 1.57–4.47), age (OR = 1.05, 95% CI = 1.04–1.06), nonconvulsive semiology with coma (OR = 3.06, 95% CI = 1.52–6.17), and refractoriness (OR = 4.31, 95% CI = 2.39–7.77) and superrefractoriness to treatment (OR = 8.24, 95% CI = 3.51–19.36) increased the odds of poor outcome. Heterogeneity exists within the spectrum of acute symptomatic causes of SE, and distinct etiological subcategories may inform about the clinical outcome.

2023 - Clinical scores and clusters for prediction of outcomes in status epilepticus [Articolo su rivista]
Lattanzi, Simona; Trinka, Eugen; Brigo, Francesco; Meletti, Stefano
abstract

Status epilepticus (SE) is a life-threatening condition and may have long-term negative sequelae. Short -and long-term outcomes encompass mortality, deterioration of functional status compared to baseline, refractoriness to treatment, recurrence of SE, and development of epilepsy, cognitive impairment, and behavioral disturbances. So far, the greatest amount of evidence is available for the prediction of short-term mortality. Conversely, the knowledge regarding long-term consequences among SE survivors is still scarce and several issues have not yet been resolved. The heterogeneity of SE renders the prognos-tication of outcomes challenging. Although aetiology is the main determinant of the outcome, different prognostic predictors have been identified. In this regard, data on group effects need to be integrated into prognostic scores to allow individual risk stratification. Importantly, many of the present scores are not designed to enable repetition to follow patient evolution. A new paradigm for the assessment of SE out-comes should consider variables that become available and/or can be retested during the course of SE. Neuroimaging findings, serum biomarkers, treatment characteristics, complications during SE, peri-ictal and postictal characteristics after SE cessation look as promising determinants of outcome and are suitable for inclusion in future models to enhance the quality and increase the reliability of predic-tion. This paper was presented at the 8th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures held in September 2022.(c) 2023 Elsevier Inc. All rights reserved.

2023 - Comparison of the status epilepticus severity score and the epidemiology-based mortality score in predicting 30-day mortality and status epilepticus cessation [Articolo su rivista]
Brigo, F.; Zaboli, A.; Giovannini, G.; Lattanzi, S.; Orlandi, N.; Turcato, G.; Meletti, S.
abstract

Objective: To evaluate the role of the Status Epilepticus Severity Score (STESS) and the Epidemiology-based Mortality score (EMSE) in predicting 30-day mortality and SE (Status epilepticus) cessation, and their prognostic performance in subgroups of patients with specific characteristics. Methods: We reviewed consecutive episodes of SE occurring in patients aged ≥14 years at Baggiovara Civil Hospital (Modena, Italy) from 2013 to 2021. We evaluated the predictive accuracy of EMSE and STESS for 30-day mortality and SE cessation through stepwise regression binary logistic models adjusted for possible univariate clinical confounders. Results: Seven hundred and eleven patients were enrolled. The mean value of STESS was 3.2 (SD 1.7) and of EMSE was 80.1 (SD 52.6). Within 30 days of the onset of SE, 28.4% of patients (202/711) died. EMSE had higher discriminatory ability for 30-day mortality compared with STESS (AUROC: 0.799; 95% CI: 0.765–0.832 versus 0.727; 95% CI: 0.686–0.766, respectively; p = 0.014). SE cessation within 1 h for convulsive SE and within 12 h for nonconvulsive SE was achieved in 35.3% (251/711) of patients. No significant difference was found between EMSE and STESS in discriminatory ability for SE cessation (AUROC: 0.516; 95% CI: 0.488–0.561 and 0.518; 95% CI: 0.473–0.563, respectively; p = 0.929). EMSE was superior to STESS in predicting 30-day mortality in patients with specific characteristics. No difference between the two scores was found in predicting SE cessation in subgroups of patients with specific characteristics. Conclusions: EMSE seems superior to STESS in predicting 30-day mortality, particularly in specific patient categories. Conversely, there is no difference in the ability of these scores in predicting SE cessation, which is overall rather low.

2023 - Dissecting the genetics of spectrum of Epilepsies with Eyelid Myoclonia by exome sequencing [Articolo su rivista]
Coppola, Antonietta; Krithika, S; Iacomino, Michele; Bobbili, Dheeraj; Balestrini, Simona; Bagnasco, Irene; Bilo, Leonilda; Buti, Daniela; Casellato, Susanna; Cuccurullo, Claudia; Ferlazzo, Edoardo; Leu, Costin; Giordano, Lucio; Gobbi, Giuseppe; Hernandez-Hernandez, Laura; Lench, Nick; Martins, Helena; Meletti, Stefano; Messana, Tullio; Nigro, Vincenzo; Pinelli, Michele; Pippucci, Tommaso; Bellampalli, Ravishankara; Salis, Barbara; Sofia, Vito; Striano, Pasquale; Striano, Salvatore; Tassi, Laura; Vignoli, Aglaia; Vaudano, Anna Elisabetta; Viri, Maurizio; Scheffer, Ingrid E; May, Patrick; Zara, Federico; Sisodiya, Sanjay M
abstract

Objectives: Epilepsy with Eyelid Myoclonia (EEM) spectrum, is a generalized form of epilepsy characterized by eyelid myoclonia with or without absences, eye closure-induced seizures with EEG paroxysms, and photosensitivity. Based on the specific clinical features, age of onset and familial occurrence, a genetic cause has been postulated. Pathogenic variants in CHD2, SYNGAP1, NEXMIF and RORB and GABRA1 have been reported in individuals with photosensitivity and eyelid myoclonia, but whether other genes are also involved, or a single gene is uniquely linked with EEM, or its subtypes, is not yet known. We aimed to dissect the genetic aetiology of EEM. Methods: we studied a cohort of 105 individuals by using whole-exome sequencing. Individuals were divided into two groups: EEM- (isolated EEM) and EEM+ (EEM accompanied by intellectual disability, ID, or any other neurodevelopmental/psychiatric disorder) RESULTS: We identified nine variants classified as pathogenic/likely pathogenic in the entire cohort (8.57%); among these eight (five in CHD2, one in NEXMIF, one in SYNGAP1 and one in TRIM8) were found in the EEM+ sub-cohort (28.57%). Only one variant (IFIH1) was found in the EEM- sub-cohort (1.29%); however, since the phenotype of the proband did not fit with published data, additional evidence is needed before considering IFIH1 variants and EEM- an established association. Burden analysis did not identify any single burdened gene or gene set. Significance: Our results suggest that for EEM, as for many other epilepsies, the identification of a genetic cause is more likely with co-morbid ID and/or other neurodevelopmental disorders. Pathogenic variants were mostly found in CHD2 and the association of CHD2-EEM+ can now be considered a reasonable gene-disease association. We provide further evidence to strengthen the association of EEM+ with NEXMIF and SYNGAP1. Possible new associations between EEM+ and TRIM8, and EEM- and IFIH1, are also reported. While we provided robust evidence for gene variants associated with EEM+, the core genetic aetiology of EEM- remains to be elucidated.

2023 - EEG Glossary App: A first bilingual app for EEG terms [Articolo su rivista]
Strigaro, G.; Meletti, S.; Mecarelli, O.; Tassi, L.; Strigaro, D.; Bisulli, F.
abstract

2023 - Efficacy and Safety of Fenfluramine in Epilepsy: A Systematic Review and Meta-analysis [Articolo su rivista]
Tabaee Damavandi, P.; Fabin, N.; Giossi, R.; Matricardi, S.; Del Giovane, C.; Striano, P.; Meletti, S.; Brigo, F.; Trinka, E.; Lattanzi, S.
abstract

Introduction: Fenfluramine (FFA) is an amphetamine derivative that promotes the release and blocks the neuronal reuptake of serotonin. Initially introduced as an appetite suppressant, FFA also showed antiseizure properties. This systematic review aimed to assess the efficacy and safety of FFA for the treatment of seizures in patients with epilepsy. Methods: We systematically searched (in week 3 of June 2022) MEDLINE, the Cochrane Central Register of Controlled Trials, and the US National Institutes of Health Clinical Trials Registry. Randomized, double- or single-blinded, placebo-controlled studies of FFA in patients with epilepsy and uncontrolled seizures were identified. Efficacy outcomes included the proportions of patients with ≥ 50% and 100% reductions in baseline seizure frequency during the treatment period. Tolerability outcomes included the proportions of patients who withdrew from treatment for any reason and suffered adverse events (AEs). The risk of bias in the included studies was assessed according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions. The risk ratio (RR) along with the 95% confidence interval (CI) were estimated for each outcome. Results: Three trials were identified and a total of 469 Dravet syndrome (DS) and Lennox–Gastaut syndrome (LGS) subjects were randomized. All three trials were judged to be at low risk of biases. In patients with DS, the RRs for ≥ 50% and 100% reductions in convulsive seizure frequency for the FFA group compared to placebo were 5.61 (95% CI 2.73–11.54) and 4.71 (95% CI 0.57–39.30), respectively. In patients with LGS, the corresponding RRs for ≥ 50% and 100% reductions in drop seizure frequency were 2.58 (95% CI 1.33–5.02) and 0.50 (95% CI 0.031–7.81), respectively. The drug was withdrawn for any reason in 10.1% and 5.8% of patients receiving FFA and placebo, respectively (RR 1.79, 95% CI 0.89–3.59). Treatment discontinuation due to AEs occurred in 5.4% and 1.2% of FFA- and placebo-treated patients, respectively (RR 3.63, 95% CI 0.93–14.16). Decreased appetite, diarrhoea, fatigue, and weight loss were AEs associated with FFA treatment. Conclusion: Fenfluramine reduces the frequency of seizures in patients with DS and LGS. Decreased appetite, diarrhoea, fatigue, and weight loss are non-cardiovascular AEs associated with FFA.

2023 - Electrographic seizure duration and inter-seizure intervals in focal status epilepticus [Articolo su rivista]
Meletti, S.; Turchi, G.; Orlandi, N.; Vaudano, A. E.; Cioclu, M. C.; Pugnaghi, M.; Giovannini, G.
abstract

Objective: To characterize the duration of seizures and inter-seizure intervals in focal status epilepticus (SE). Methods: We reviewed consecutive scalp EEG recordings from adult patients who were admitted for a first episode of focal status epilepticus. We identified electrographic seizure duration and inter-seizure intervals in the first diagnostic pretreatment EEG. We also reviewed isolated focal self-limiting seizures in epilepsy patients, as a comparison group for seizure duration. Results: We recorded 307 focal seizures in 100 consecutive focal SE episodes, with a median seizure duration of 107 s (IQR: 54–186), and 134 isolated focal self-limiting seizures in 42 epilepsy patients, with a median duration of 59 s (IQR: 30–90; p <.001). The only clinical feature of SE that significantly increased seizure duration was acute symptomatic etiology. In SE, 15% and 7% of seizures lasted longer than 300 and 600 s, respectively (t1 of the actual definition for tonic–clonic and focal SE), while only 1% of self-limiting seizures lasted longer than 300 s, and none lasted longer than 600 s. The analysis of inter-seizure intervals in SE with multiple seizures showed that 50% of the inter-seizure periods were shorter than 60 s, and 95% were shorter than 540 s (9 min). Patients who had an increase in seizure duration (last versus first) of at least 1.4 times showed an increased 30-day mortality. Significance: Focal seizures within a SE episode showed a wide range of duration, partly overlapping with the duration of focal self-limiting seizures but with a longer median duration. Inter-seizure intervals within an episode of SE were shorter than 1 min in 50% of the seizures and never lasted more than 10 min. Finally, an increase in seizure duration could represent an “electrophysiological biomarker” of a more severe SE episode, which may require more aggressive and rapid treatment.

2023 - Exploring the relationship between amygdala subnuclei volumes and cognitive performance in left-lateralized temporal lobe epilepsy with and without hippocampal sclerosis [Articolo su rivista]
Ballerini, Alice; Talami, Francesca; Molinari, Maria Angela; Micalizzi, Elisa; Scolastico, Simona; Biagioli, Niccolò; Orlandi, Niccolò; Pugnaghi, Matteo; Giovannini, Giada; Meletti, Stefano; Vaudano, Anna Elisabetta
abstract

Cognitive disruption is a debilitating comorbidity in Temporal Lobe Epilepsy (TLE). Despite recent advances, the amygdala is often neglected in studies that explore cognition in TLE. Amygdala subnuclei are differently engaged in TLE with hippocampal sclerosis (TLE-HS) compared to non-lesional TLE (TLEMRIneg), with predominant atrophy in the first and increased volume in the latter. Herein, we aim to explore the relationship between the volumes of the amygdala and its substructures with respect to cognitive performances in a population of left-lateralized TLE with and without HS. Twenty-nine TLEs were recruited (14 TLE-HS; 15 TLE-MRIneg). After investigating the differences in the subcortical amygdalae and hippocampal volumes compared to a matched healthy control population, we explored the associations between the subnuclei of the amygdala and the hippocampal subfields with the cognitive scores in TLE patients, according to their etiology. In TLE-HS, a reduced volume of the basolateral and cortical amygdala complexes joined with whole hippocampal atrophy, was related to poorer scores in verbal memory tasks, while in TLE-MRIneg, poorer performances in attention and processing speed tasks were associated with a generalized amygdala enlargement, particularly of the basolateral and central complexes. The present findings extend our knowledge of amygdala involvement in cognition and suggest structural amygdala abnormalities as useful disease biomarkers in TLE.(c) 2023 Elsevier Inc. All rights reserved.

2023 - Fluid Biomarkers of Neuro-Glial Injury in Human Status Epilepticus: A Systematic Review [Articolo su rivista]
Giovannini, G.; Meletti, S.
abstract

As per the latest ILAE definition, status epilepticus (SE) may lead to long-term irreversible consequences, such as neuronal death, neuronal injury, and alterations in neuronal networks. Consequently, there is growing interest in identifying biomarkers that can demonstrate and quantify the extent of neuronal and glial injury. Despite numerous studies conducted on animal models of status epilepticus, which clearly indicate seizure-induced neuronal and glial injury, as well as signs of atrophy and gliosis, evidence in humans remains limited to case reports and small case series. The implications of identifying such biomarkers in clinical practice are significant, including improved prognostic stratification of patients and the early identification of those at high risk of developing irreversible complications. Moreover, the clinical validation of these biomarkers could be crucial in promoting neuroprotective strategies in addition to antiseizure medications. In this study, we present a systematic review of research on biomarkers of neuro-glial injury in patients with status epilepticus.

2023 - Hematopoietic Stem Cell Transplantation in People With Active Secondary Progressive Multiple Sclerosis [Articolo su rivista]
Boffa, Giacomo; Signori, Alessio; Massacesi, Luca; Mariottini, Alice; Sbragia, Elvira; Cottone, Salvatore; Amato, Maria Pia; Gasperini, Claudio; Moiola, Lucia; Meletti, Stefano; Repice, Anna Maria; Morra, Vincenzo Brescia; Salemi, Giuseppe; Patti, Francesco; Filippi, Massimo; De Luca, Giovanna; Lus, Giacomo; Zaffaroni, Mauro; Sola, Patrizia; Conte, Antonella; Nistri, Riccardo; Aguglia, Umberto; Granella, Franco; Galgani, Simonetta; Caniatti, Luisa Maria; Lugaresi, Alessandra; Romano, Silvia; Iaffaldano, Pietro; Cocco, Eleonora; Saccardi, Riccardo; Angelucci, Emanuele; Trojano, Maria; Mancardi, Giovanni Luigi; Sormani, Maria Pia; Inglese, Matilde
abstract

Background and objectives: Uncontrolled evidence suggests that autologous hematopoietic stem cell transplantation (AHSCT) can be effective in people with active secondary progressive multiple sclerosis (SPMS). In this study we compared the effect of AHSCT with that of other anti-inflammatory disease modifying therapies (DMT) on long-term disability worsening in active SPMS. Methods: We collected data from the Italian-Bone-Marrow-Transplantation-Study-Group and the Italian-Multiple-Sclerosis-Register. Patients were considered eligible if treatment had been started after the diagnosis of SPMS. Disability worsening was assessed by the cumulative proportion of patients with a 6-months confirmed-disability-progression (CDP) according to the Expanded-Disability-Status-Scale (EDSS) score. Key secondary endpoints were the EDSS time-trend after treatment start and the prevalence of disability improvement over time. Time to CDP was assessed by means of proportional hazard Cox regression models. A linear mixed model with a time*treatment group interaction was used to assess the longitudinal EDSS time-trends. Prevalence of improvement was estimated using a modified Kaplan-Meier estimator and compared between groups by bootstrapping the area under the curve. Results: 79 AHSCT-treated patients and 1975 patients treated with other DMT (beta-interferons, azathioprine, glatiramer-acetate, mitoxantrone, fingolimod, natalizumab, methotrexate, teriflunomide, cyclophosphamide, dimethyl fumarate, alemtuzumab) were matched to reduce treatment selection bias using propensity-score and overlap weighting approaches. Time to first CDP was significantly longer in transplanted patients (HR=0.50; 95%CI= 0.31-0.81; p=0.005), with 61.7% of transplanted patients free from CPD at 5 years. Accordingly, EDSS time-trend over 10 years was higher in patients treated with other DMT than in AHSCT-treated patients (+0.157 EDSS points per year compared to -0.013 EDSS points per year; interaction-p<0.001). Patients who underwent AHSCT were more likely to experience a sustained disability improvement: 34.7% of patients maintained an improvement (a lower EDSS than baseline) 3 years after transplant versus 4.6% of patients treated by other DMT (p<0.001). Discussion: The use of AHSCT in people with active SPMS is associated with a slowing of disability progression and a higher likelihood of disability improvement compared to standard immunotherapy. Classification of evidence: This study provides Class III evidence that autologous hematopoietic stem cell transplants prolonged the time to confirmed disability progression compared to other disease modifying therapies.

2023 - How much refractory is ‘refractory status epilepticus’? A retrospective study of treatment strategies and clinical outcomes [Articolo su rivista]
Lattanzi, S.; Giovannini, G.; Orlandi, N.; Brigo, F.; Trinka, E.; Meletti, S.
abstract

Background and purpose: This study aimed to evaluate whether differences in clinical outcomes exist according to treatments received and seizure activity resolution in patients with refractory status epilepticus (RSE). Methods: Consecutive episodes of non-hypoxic status epilepticus (SE) in patients ≥ 14 years old were included. Episodes of RSE were stratified in: (i) SE persistent despite treatment with first‐line therapy with benzodiazepines and one second‐line treatment with antiseizure medications (ASMs), but responsive to successive treatments with ASMs (RSE-rASMs); (ii) SE persistent despite treatment with first‐line therapy with benzodiazepines and successive treatment with one or more second-line ASMs, but responsive to anesthetic drugs [RSE-rGA (general anesthesia)]. Study endpoints were mortality during hospitalization and worsening of modified Rankin Scale (mRS) at discharge. Results: Status epilepticus was responsive in 298 (54.1%), RSE-rASMs in 152 (27.6%), RSE-rGA in 46 (8.3%), and super-refractory (SRSE) in 55 (10.0%) out of 551 included cases. Death during hospitalization occurred in 98 (17.8%) and worsening of mRS at discharge in 287 (52.1%) cases. Multivariable analyses revealed increased odds of in-hospital mortality with RSE-rGA (odds ratio [OR] 3.05, 95% confidence interval [CI] 1.27–7.35) and SRSE (OR 3.83, 95%. CI 1.73–8.47), and increased odds of worsening of mRS with RSE-rASMs (OR 2.06, 95% CI 1.28–3.31), RSE-rGA (OR 4.44, 95% CI 1.97–10.00), and SRSE (OR 13.81, 95% CI 5.34–35.67). Conclusions: In RSE, varying degrees of refractoriness may be defined and suit better the continuum spectrum of disease severity and the heterogeneity of SE burden and prognosis.

2023 - Ictal semiology of gelastic seizures [Articolo su rivista]
Mirandola, Laura; Cantalupo, Gaetano; D'Orsi, Giuseppe; Meletti, Stefano; Vaudano, Anna Elisabetta; Di Vito, Lidia; Vignoli, Aglaia; Tassi, Laura; Pelliccia, Veronica
abstract

: Gelastic seizures are rare epileptic manifestations characterized by laughter or a smile. The main etiology is represented by hypothalamic hamartoma, but also focal localization of the epileptogenic zone is described. We reviewed a group of patients with gelastic seizures to describe the semiology and to establish any difference related to diverse epilepsy etiologies. Thirty-five seizures from 16 patients (6 females) were reviewed. The study confirms that hypothalamic hamartoma is the more frequent etiology associated with gelastic seizures. Laughter represented the majority of gelastic ictal signs, while the ictal smile was less frequent. In 87.5% of patients, the manifestation of laughter or smile was the only ictal phenomenon, or the first and the most important clinical sign. Interestingly, it has been observed that patients with a lesion localized in the hypothalamic region had more frequently laughter with emotional involvement and that laughter was the only manifestation of the seizure. On the contrary, patients with lesions localized outside the hypothalamic region had more often seizures with laugh without emotional involvement, resembling a more mechanical action, and associated with other semeiological signs. It, therefore, seems possible to assume that the emotional involvement and the expression of mirth during the seizure, especially in children, are more frequently associated with hypothalamic hamartoma. On the contrary, when the semiology includes less conveyed emotion similar to a mechanical action and other symptoms, an extra hypothalamic localization should be considered.

2023 - Impact of an optimized epilepsy surgery imaging protocol for focal epilepsy: a monocentric prospective study [Articolo su rivista]
Vaudano, Anna Elisabetta; Ballerini, Alice; Zucchini, Francesca; Micalizzi, Elisa; Scolastico, Simona; Talami, Francesca; Giovannini, Giada; Pugnaghi, Matteo; Orlandi, Niccolò; Biagioli, Niccolò; Cioclu, Maria Cristina; Vallone, Stefano; Genovese, Maurilio; Todeschini, Alessandra; Cavalleri, Francesca; Malagoli, Marcella; Meletti, Stefano
abstract

Objective: To evaluate in a real clinical scenario the impact of the ILAE-recommended "Harmonized neuroimaging of epilepsy structural sequences"- HARNESS protocol in patients affected by focal epilepsy. Methods: We prospectively enrolled focal epilepsy patients who underwent a structural brain MRI between 2020-2021 at Modena University Hospital. For all patients, MRIs were: a) acquired according to the HARNESS-MRI protocol (H-MRI); b) reviewed by the same neuroradiology team. MRI outcomes measures were: the number of positive (diagnostic) and negative MRI; the type of radiological diagnosis classified in: 1. Hippocampal Sclerosis; 2. Malformations of cortical development (MCD); 3. Vascular malformations; 4. Glial scars; 5. Low-grade epilepsy-associated tumours; 6. Dual pathology. For each patient we verified for previous MRI (without HARNESS protocol, noH-MRI) and the presence of clinical information in the MRI request form. Then the measured outcomes were reviewed and compared as appropriate. Results: A total of 131 patients with H-MRI were included in the study. 100 patients out from this cohort had at least one previous noH-MRI scan. Of those, 92/100 were acquired at the same Hospital than H-MRI and 71/92 on a 3T scanner. The HARNESS protocol revealed 81 (62%) positive and 50 (38%) negative MRI, and MCD was the most common diagnosis (60%). Among the entire pool of 100 noH-MRI, 36 resulted positive with a significant difference (p<.001) compared to H-MRI. Similar findings were observed when accounting for the expert radiologists (H-MRI= 57 positive; noH-MRI=33, p<.001) and the scanner field strength (H-MRI 43=positive, noH-MRI=23, p<.001), while clinical information were more present in H-MRI (p<.002). Significance: The adoption of a standardized and optimized MRI acquisition protocol together with adequate clinical information contribute to identify a higher number of potentially epileptogenic lesions (especially FCD) thus impacting concretely on the clinical management of patients with focal epilepsy.

2023 - Incidence and Long-term Functional Outcome of Neurologic Disorders in Hospitalized Patients With COVID-19 Infected With Pre-Omicron Variants [Articolo su rivista]
Beretta, Simone; Cristillo, Viviana; Camera, Giorgia; Morotti Colleoni, Carlo; Pellitteri, Gaia; Viti, Beatrice; Bianchi, Elisa; Gipponi, Stefano; Grimoldi, Maria; Valente, Mariarosaria; Guttmann, Susanna; Cotelli, Maria Sofia; Palumbo, Pasquale; Gelosa, Giorgio; Meletti, Stefano; Schenone, Cristina; Ottaviani, Donatella; Filippi, Massimo; Zini, Andrea; Basilico, Paola; Tancredi, Lucia; Cortelli, Pietro; Braga, Massimiliano; De Giuli, Valeria; Servidei, Serenella; Paolicelli, Damiano; Verde, Federico; Caproni, Stefano; Pisani, Antonio; Lo Re, Vincenzina; Massacesi, Luca; Roccatagliata, Daria Valeria; Manganotti, Paolo; Spitaleri, Daniele; Formenti, Anna; Piccoli, Marta; Marino, Silvia; Polverino, Paola; Aguglia, Umberto; Ornello, Raffaele; Perego, Elisabetta; Siciliano, Gabriele; Merlo, Paola; Capobianco, Marco; Pantoni, Leonardo; Lugaresi, Alessandra; Angelocola, Stefania; De Rosa, Anna; Sessa, Maria; Beghi, Ettore; Agostoni, Elio Clemente; Monaco, Salvatore; Padovani, Alessandro; Priori, Alberto; Silani, Vincenzo; Tedeschi, Gioacchino; Ferrarese, Carlo
abstract

Background and objectives: A variety of neurologic disorders have been reported as presentations or complications of coronavirus disease 2019 (COVID-19) infection. The objective of this study was to determine their incidence dynamics and long-term functional outcome. Methods: The Neuro-COVID Italy study was a multicenter, observational, cohort study with ambispective recruitment and prospective follow-up. Consecutive hospitalized patients presenting new neurologic disorders associated with COVID-19 infection (neuro-COVID), independently from respiratory severity, were systematically screened and actively recruited by neurology specialists in 38 centers in Italy and the Republic of San Marino. The primary outcomes were incidence of neuro-COVID cases during the first 70 weeks of the pandemic (March 2020-June 2021) and long-term functional outcome at 6 months, categorized as full recovery, mild symptoms, disabling symptoms, or death. Results: Among 52,759 hospitalized patients with COVID-19, 1,865 patients presenting 2,881 new neurologic disorders associated with COVID-19 infection (neuro-COVID) were recruited. The incidence of neuro-COVID cases significantly declined over time, comparing the first 3 pandemic waves (8.4%, 95% CI 7.9-8.9; 5.0%, 95% CI 4.7-5.3; 3.3%, 95% CI 3.0-3.6, respectively; p = 0.027). The most frequent neurologic disorders were acute encephalopathy (25.2%), hyposmia-hypogeusia (20.2%), acute ischemic stroke (18.4%), and cognitive impairment (13.7%). The onset of neurologic disorders was more common in the prodromic phase (44.3%) or during the acute respiratory illness (40.9%), except for cognitive impairment whose onset prevailed during recovery (48.4%). A good functional outcome was achieved by most patients with neuro-COVID (64.6%) during follow-up (median 6.7 months), and the proportion of good outcome increased throughout the study period (r = 0.29, 95% CI 0.05-0.50; p = 0.019). Mild residual symptoms were frequently reported (28.1%) while disabling symptoms were common only in stroke survivors (47.6%). Discussion: Incidence of COVID-associated neurologic disorders decreased during the prevaccination phase of the pandemic. Long-term functional outcome was favorable in most neuro-COVID disorders, although mild symptoms commonly lasted more than 6 months after infection.

2023 - Individualized Prediction of Drug Resistance in People with Post-Stroke Epilepsy: A Retrospective Study [Articolo su rivista]
Lattanzi, S.; Meletti, S.; Trinka, E.; Brigo, F.; Turcato, G.; Rinaldi, C.; Cagnetti, C.; Foschi, N.; Broggi, S.; Norata, D.; Silvestrini, M.
abstract

Background: The study aimed to develop a model and build a nomogram to predict the probability of drug resistance in people with post-stroke epilepsy (PSE). Methods: Subjects with epilepsy secondary to ischemic stroke or spontaneous intracerebral hemorrhage were included. The study outcome was the occurrence of drug-resistant epilepsy defined according to International League Against Epilepsy criteria. Results: One hundred and sixty-four subjects with PSE were included and 32 (19.5%) were found to be drug-resistant. Five variables were identified as independent predictors of drug resistance and were included in the nomogram: age at stroke onset (odds ratio (OR): 0.941, 95% confidence interval (CI) 0.907–0.977), intracerebral hemorrhage (OR: 6.292, 95% CI 1.957–20.233), severe stroke (OR: 4.727, 95% CI 1.573–14.203), latency of PSE (>12 months, reference; 7–12 months, OR: 4.509, 95% CI 1.335–15.228; 0–6 months, OR: 99.099, 95% CI 14.873–660.272), and status epilepticus at epilepsy onset (OR: 14.127, 95% CI 2.540–78.564). The area under the receiver operating characteristic curve of the nomogram was 0.893 (95% CI: 0.832–0.956). Conclusions: Great variability exists in the risk of drug resistance in people with PSE. A nomogram based on a set of readily available clinical variables may represent a practical tool for an individualized prediction of drug-resistant PSE.

2023 - Intracranial Stenosis Treated with Stenting in Patients with Suspected Cerebral Vasculitis: Two Case Reports [Articolo su rivista]
Vandelli, G; Giacobazzi, L; Ciolli, L; Dell'Acqua, Ml; Vandelli, L; Picchetto, L; Rosafio, F; Borzi, Gm; Ricceri, R; Meletti, S; Vallone, S; Salvarani, C; Sebastiani, M; Sacchetti, F; Verganti, L; Merolla, S; Zelent, G; Bigliardi, G
abstract

Central nervous system vasculitis (CNSV) is an uncommon and poorly understood form of vasculitis. Early recognition is important because medical treatment might improve the outcome. However, randomized clinical trials on CNSV treatment do not exist. Endovascular treatment has been reported in few cases, but no data exist for intracranial stenting. We report 2 cases of patients with suspected CNSV and recurrent clinical episodes, treated with intracranial stenting. A 48-year-old man had relapsing episodes of right hemiparesis. Neuroradiological exams showed severe left carotid terminus stenosis. Despite immunosuppressive therapy, neuroradiological follow-up exams showed a worsening of the aforementioned stenosis with many transient episodes of weakness in the right limbs and aphasia. A 64-year-old woman had a sudden onset of dysarthria and transient aphasia. Neuroradiological exams showed a severe arterial stenosis involving the origin of left anterior cerebral artery and middle cerebral artery (MCA). Despite dual antiplatelet therapy, she presented an acute onset of severe aphasia, due to an occlusion of the left carotid terminus and proximal MCA. In both cases, endovascular procedure and intracranial stenting was performed, with marked improvement of cerebral blood flow. No more clinical episodes were reported. Intracranial stenting may be a valid therapeutic option in selected patients with CNSV and involvement of medium or large size vessels with clinical worsening despite best medical treatment.

2023 - KCNT2-Related Disorders: Phenotypes, Functional, and Pharmacological Properties [Articolo su rivista]
Cioclu, M. C.; Mosca, I.; Ambrosino, P.; Puzo, D.; Bayat, A.; Wortmann, S. B.; Koch, J.; Strehlow, V.; Shirai, K.; Matsumoto, N.; Sanders, S. J.; Michaud, V.; Legendre, M.; Riva, A.; Striano, P.; Muhle, H.; Pendziwiat, M.; Lesca, G.; Mangano, G. D.; Nardello, R.; Servettini, I.; Belperio, G.; Kamsteeg, E. -J.; Takahashi, K.; Mitsuhashi, S.; Palmer, E. E.; Bye, A. M.; Madrigal, I.; Alvarez-Mora, M. I.; Sanchez, A.; Meletti, S.; Helbig, I.; Le Tanno, P.; Gerard, B.; El Chehadeh, S.; Lemke, J. R.; Moller, R. S.; Soldovieri, M. V.; Rubboli, G.; Taglialatela, M.
abstract

Objective: Pathogenic variants in KCNT2 are rare causes of developmental epileptic encephalopathy (DEE). We herein describe the phenotypic and genetic features of patients with KCNT2-related DEE, and the in vitro functional and pharmacological properties of KCNT2 channels carrying 14 novel or previously untested variants. Methods: Twenty-five patients harboring KCNT2 variants were investigated: 12 were identified through an international collaborative network, 13 were retrieved from the literature. Clinical data were collected and included in a standardized phenotyping sheet. Novel variants were detected using exome sequencing and classified using ACMG criteria. Functional and pharmacological studies were performed by whole-cell electrophysiology in HEK-293 and SH-SY5Y cells. Results: The phenotypic spectrum encompassed: (a) intellectual disability/developmental delay (21/22 individuals with available information), ranging from mild to severe/profound; (b) epilepsy (15/25); (c) neurological impairment, with altered muscle tone (14/22); (d) dysmorphisms (13/20). Nineteen pathogenic KCNT2 variants were found (9 new, 10 reported previously): 16 missense, 1 in-frame deletion of a single amino acid, 1 nonsense, and 1 frameshift. Among tested variants, 8 showed gain-of-function (GoF), and 6 loss-of-function (LoF) features when expressed heterologously in vitro. Quinidine and fluoxetine blocked all GoF variants, whereas loxapine and riluzole activated some LoF variants while blocking others. Interpretation: We expanded the phenotypic and genotypic spectrum of KCNT2-related disorders, highlighting novel genotype–phenotype associations. Pathogenic KCNT2 variants cause GoF or LoF in vitro phenotypes, and each shows a unique pharmacological profile, suggesting the need for in vitro functional and pharmacological investigation to enable targeted therapies based on the molecular phenotype. ANN NEUROL 2023;94:332–349.

2023 - Neuro-glial degeneration in Status Epilepticus: Exploring the role of serum levels of Neurofilament light chains and S100B as prognostic biomarkers for short-term functional outcome [Articolo su rivista]
Giovannini, G.; Bedin, R.; Orlandi, N.; Turchi, G.; Cioclu, M. C.; Biagioli, N.; Madrassi, L.; Pugnaghi, M.; Vaudano, A. E.; Meletti, S.
abstract

Background: The last ILAE definition of Status Epilepticus (SE) highlights that the persistence of the epileptic activity per se could determine irreversible brain damages that could be responsible for long-term consequences. The measurement of neuro-glial injury biomarkers could help in the identification of those patients who will eventually develop short- and long-term consequences of SE. At present none of the already studied biomarkers has been validated to be used in everyday clinical practice. In this study, we explore the role of NfL and S100B as a prognostic biomarkers to identify patients who will develop short-term disability after an episode of SE. Methods: This is a retrospective assessment of the serum levels of both NfL and S100B in a cohort of 87 adult patients with SE prospectively collected in our SE registry (Modena Status Epilepticus Registry – MoSER –) at Baggiovara Civil Hospital (Modena, Italy). All samples were acquired during SE within 72 hours of SE diagnosis. The comparison groups were: healthy controls (HC, n = 27) and patients with epilepsy (PWE, n = 30). Demographic, clinical, and therapeutical information and thirty-days follow-up information regarding disability development were acquired for every included patient and analyzed in relation to NfL and S100B values. Results: Serum levels of NfL were significantly higher in SE compared to those of PWE (median 7.35 pg/ml, IQR 6.4, p < 0.001) and HC (median 6.57 pg/ml, IQR 9.1, p < 0.001); S100B serum levels were higher in SE (median 0.11 ug/L, IQR 0.18) compared to PWE (median 0.03 ug/L, IQR 0.03, p < 0.001) and HC (median 0.02 ug/L, IQR 0.008, p < 0.001). However, only NfL serum levels were found to be an independent predictor of 30 days functional outcome whereas S100B levels did not. Conclusions: Our results suggest that NfL measurement in serum during SE could help predict the short-term functional outcome. This paper was presented at the 8th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures held in September 2022.

2023 - Pharmacotherapy for Dravet Syndrome: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials [Articolo su rivista]
Lattanzi, S.; Trinka, E.; Russo, E.; Del Giovane, C.; Matricardi, S.; Meletti, S.; Striano, P.; Damavandi, P. T.; Silvestrini, M.; Brigo, F.
abstract

Background: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy characterized by drug-resistant, lifelong seizures. The management of seizures in DS has changed in recent years with the approval of new antiseizure medications (ASMs). Objective: The aim of this study was to estimate the comparative efficacy and tolerability of the ASMs for the treatment of seizures associated with DS using a network meta-analysis (NMA). Methods: Studies were identified by conducting a systematic search (week 4, January 2023) of the MEDLINE (accessed by PubMed), EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and US National Institutes of Health Clinical Trials Registry (http://www.clinicaltrials.gov) databases. Any randomized, controlled, double- or single-blinded, parallel-group study comparing at least one ASM therapy against placebo, another ASM, or a different dose of the same ASM in participants with a diagnosis of DS was identified. The efficacy outcomes were the proportions of participants with ≥ 50% (seizure response) and 100% reduction (seizure freedom) in baseline convulsive seizure frequency during the maintenance period. The tolerability outcomes included the proportions of patients who withdrew from treatment for any reason and who experienced at least one adverse event (AE). Effect sizes were estimated by network meta-analyses within a frequentist framework. Results: Eight placebo-controlled trials were included, and the active add-on treatments were stiripentol (n = 2), pharmaceutical-grade cannabidiol (n = 3), fenfluramine hydrochloride (n = 2), and soticlestat (n = 1). The studies recruited 680 participants, of whom 409 were randomized to active treatments (stiripentol = 33, pharmaceutical-grade cannabidiol = 228, fenfluramine hydrochloride = 122, and soticlestat = 26) and 271 to placebo. Pharmaceutical-grade cannabidiol was associated with a lower rate of seizure response than fenfluramine hydrochloride (odds ratio [OR] 0.20, 95% confidence interval [CI] 0.07–0.54), and stiripentol was associated with a higher seizure response rate than pharmaceutical-grade cannabidiol (OR 14.07, 95% CI 2.57–76.87). No statistically significant differences emerged across the different ASMs for the seizure freedom outcome. Stiripentol was associated with a lower probability of drug discontinuation for any reason than pharmaceutical-grade cannabidiol (OR 0.45, 95% CI 0.04–5.69), and pharmaceutical-grade cannabidiol was associated with a lower proportion of participants experiencing any AE than fenfluramine hydrochloride (OR 0.22, 95% CI 0.06–0.78). Stiripentol had a higher risk of AE occurrence than pharmaceutical-grade cannabidiol (OR 75.72, 95% CI 3.59–1598.58). The study found high-quality evidence of efficacy and tolerability of the four ASMs in the treatment of convulsive seizures in DS. Conclusions: There exists first-class evidence that documents the efficacy and tolerability of stiripentol, pharmaceutical-grade cannabidiol, fenfluramine hydrochloride, and soticlestat for the treatment of seizures associated with DS, and allows discussion about the expected outcomes regarding seizure frequency reduction and tolerability profiles.

2023 - Proposal of multimodal computed tomography-based scoring system in prediction of hemorrhagic transformation in acute ischemic stroke [Articolo su rivista]
Elsaid, N.; Bigliardi, G.; Dell'Acqua, M. L.; Vandelli, L.; Ciolli, L.; Picchetto, L.; Borzi, G.; Ricceri, R.; Pentore, R.; Vallone, S.; Meletti, S.; Saied, A.
abstract

Introduction: The routinely used computed tomography (CT)-based workup in the setting of acute ischemic stroke (AIS) includes non-contrast brain CT, CT angiography (CTA), and CT perfusion. Several CT, CTA, CTP-based radiological biomarkers of hemorrhagic transformation (HT) were reported. Aim of the study: To assess the predictive value of the combined multimodal CT parameters for HT after AIS and proposal of predictive scoring scale. Methods: The source images of the NCCT, CTA and CTP of 282 AIS patients involving the anterior circulation (HT = 91, non-HT = 191) were retrospectively reviewed and the following biomarkers were recorded and analyzed: Early subtle ischemic signs, hyperdense middle cerebral artery sign (HMCAS) and Alberta Stroke Program Early CT Score (ASPECTS) < 7 in NCCT, large-vessel occlusion (LVO), clot burden score (CBS) < 6, large-vessel occlusion, poor collateral score (CS) and Tmax > 6 s ≥ 56.5 ml. A scoring system to predict HT based on these biomarkers was developed. Each biomarker counts for a single point with the total score ranging from 0 to 7. Results: All the aforementioned multimodal CT biomarkers and the selected cut offs were significantly associated with higher HT risk. The calculated scores were statistically significant different between the HT and the non-HT groups with AUC 0.761 (95% CI 0.703–0.819, P < 0.0000001). Rates of HT were approximately five times higher in patients with score ≥ 3. Conclusion: Multimodal CT-based scoring system may provide highly reliable predictive model of hemorrhagic transformation in acute ischemic stroke.

2023 - Retrospective External Validation of the Status Epilepticus Severity Score (STESS) to Predict In-hospital Mortality in Adults with Nonhypoxic Status Epilepticus: A Machine Learning Analysis [Articolo su rivista]
Brigo, Francesco; Turcato, Gianni; Lattanzi, Simona; Orlandi, Niccolò; Turchi, Giulia; Zaboli, Arian; Giovannini, Giada; Meletti, Stefano
abstract

Background The objective of this study was to validate the value of the Status Epilepticus Severity Score (STESS) in the prediction of the risk of in-hospital mortality in patients with nonhypoxic status epilepticus (SE) using a machine learning analysis. Methods We included consecutive patients with nonhypoxic SE (aged >= 16 years) admitted from 2013 to 2021 at the Modena Academic Hospital. A decision tree analysis was performed using in-hospital mortality as a dependent variable and the STESS predictors as input variables. We evaluated the accuracy of STESS in predicting in-hospital mortality using the area under the receiver operating characteristic curve (AUROC) with 95% confidence interval (CI). Results Among 629 patients with SE, the in-hospital mortality rate was 23.4% (147 of 629). The median STESS in the entire cohort was 2.9 (SD 1.6); it was lower in surviving compared with deceased patients (2.7, SD 1.5 versus 3.9, SD 1.6; p < 0.001). Of deceased patients, 82.3% (121 of 147) had scores of 3-6, whereas 17.7% (26 of 147) had scores of 0-2 (p < 0.001). STESS was accurate in predicting mortality, with an AUROC of 0.688 (95% CI 0.641-0.734) only slightly reduced after bootstrap resampling. The most significant predictor was the seizure type, followed by age and level of consciousness at SE onset. Nonconvulsive SE in coma and age >= 65 years predicted a higher risk of mortality, whereas generalized convulsive SE and age < 65 years were associated with a lower risk of death. The decision tree analysis using STESS variables correctly classified 90% of survivors and 34% of nonsurvivors after the SE, with an overall risk of error of 23.1%. Conclusions This validation study using a machine learning system showed that STESS is a valuable prognostic tool. The score appears particularly accurate and effective in identifying patients who are alive at discharge (high negative predictive value), whereas it has a lower predictive value for in-hospital mortality.

2023 - Sex-based electroclinical differences and prognostic factors in epilepsy with eyelid myoclonia [Articolo su rivista]
Cerulliirelli, E.; Cocchi, E.; Ramantani, G.; Morano, A.; Riva, A.; Caraballo, R. H.; Giuliano, L.; Yilmaz, T.; Panagiotakaki, E.; Operto, F. F.; Giraldez, B. G.; Balestrini, S.; Silvennoinen, K.; Casciato, S.; Comajuan, M.; Fortunato, F.; Giallonardo, A. T.; Gamirova, R.; Coppola, A.; Digennaro, G.; Labate, A.; Sofia, V.; Kluger, G. J.; Gambardella, A.; Kasteleijn-NolstTrenite, D.; Baykan, B.; Sisodiya, S. M.; Arzimanoglou, A.; Striano, P.; Dibonaventura, C.; Fisco, G.; Meletti, S.; Liukshina, N.; Tomenko, T.; Gobbi, G.; Buti, D.; Casellato, S.; Striano, S.; Messana, T.; Giordano, L.; Ferlazzo, E.; Vignoli, A.; Viri, M.; Bagnasco, I.; Bebek, N.; Altiokka-Uzun, G.
abstract

Although a striking female preponderance has been consistently reported in epilepsy with eyelid myoclonia (EEM), no study has specifically explored the variability of clinical presentation according to sex in this syndrome. Here, we aimed to investigate sex-specific electroclinical differences and prognostic determinants in EEM. Data from 267 EEM patients were retrospectively analyzed by the EEM Study Group, and a dedicated multivariable logistic regression analysis was developed separately for each sex. We found that females with EEM showed a significantly higher rate of persistence of photosensitivity and eye closure sensitivity at the last visit, along with a higher prevalence of migraine with/without aura, whereas males with EEM presented a higher rate of borderline intellectual functioning/intellectual disability. In female patients, multivariable logistic regression analysis revealed age at epilepsy onset, eyelid myoclonia status epilepticus, psychiatric comorbidities, and catamenial seizures as significant predictors of drug resistance. In male patients, a history of febrile seizures was the only predictor of drug resistance. Hence, our study reveals sex-specific differences in terms of both electroclinical features and prognostic factors. Our findings support the importance of a sex-based personalized approach in epilepsy care and research, especially in genetic generalized epilepsies.

2023 - Shared imaging markers of fatigue across multiple sclerosis, aquaporin-4 antibody neuromyelitis optica spectrum disorder and MOG antibody disease [Articolo su rivista]
Camera, Valentina; Mariano, Romina; Messina, Silvia; Menke, Ricarda; Griffanti, Ludovica; Craner, Matthew; Leite, Maria I; Calabrese, Massimiliano; Meletti, Stefano; Geraldes, Ruth; Palace, Jacqueline A
abstract

Fatigue is frequently reported by patients with multiple sclerosis, aquaporin-4-antibody neuromyelitis optica spectrum disorder and myelin-oligodendrocyte-glycoprotein antibody disease; thus they could share a similar pathophysiological mechanism. In this cross-sectional cohort study, we assessed the association of fatigue with resting-state functional MRI, diffusion and structural imaging measures across these three disorders. Sixteen patients with multiple sclerosis, 17 with aquaporin-4-antibody neuromyelitis optica spectrum disorder and 17 with myelin-oligodendrocyte-glycoprotein antibody disease assessed, outside of relapses, at the Oxford Neuromyelitis Optica Service underwent Modified Fatigue Impact Scale, Hospital Anxiety and Depression Scale and Expanded Disability Status Scale scoring. A 3T brain and spinal cord MRI was used to derive cortical, deep grey and white matter volumetrics, lesions volume, fractional anisotropy, brain functional connectivity metrics, cervical spinal cord cross-sectional area, spinal cord magnetic transfer ratio and average functional connectivity between the ventral and the dorsal horns of the cervical cord. Linear relationships between MRI measures and total-, cognitive- and physical-fatigue scores were assessed. All analyses were adjusted for correlated clinical regressors. No significant differences in baseline clinical characteristics, fatigue, depression and anxiety questionnaires and disability measures were seen across the three diseases, except for older age in patients with aquaporin-4-antibody neuromyelitis optica spectrum disorder (P = 0.0005). In the total cohort, median total-fatigue score was 35.5 (range 3-72), and 42% of patients were clinically fatigued. A positive correlation existed between the total-fatigue score and functional connectivity of the executive/fronto-temporal network in the in left middle temporal gyrus (P = 0.033) and between the physical-fatigue score and functional connectivity of the sensory-motor network (P = 0.032) in both pre- and post-central gyri. A negative relationship was found between the total-fatigue score and functional connectivity of the salience network (P = 0.023) and of the left fronto-parietal network (P = 0.026) in the right supramarginal gyrus and left superior parietal lobe. No clear relationship between fatigue subscores and the average functional connectivity of the spinal cord was found. Cognitive-fatigue scores were positively associated with white matter lesion volume (P = 0.018) and negatively associated with white matter fractional anisotropy (P = 0.032). Structural, diffusion and functional connectivity alterations were not influenced by the disease group. Functional and structural imaging metrics associated with fatigue relate to brain rather than spinal cord abnormalities. Salience and sensory-motor networks alterations in relation to fatigue might indicate a disconnection between the perception of the interior body state and activity and the actual behavioural responses and performances (reversible or irreversible). Future research should focus on functional rehabilitative strategies.Fatigue-related structural and functional MRI measures are in common across multiple sclerosis, myelin oligodendrocyte glycoprotein antibody disease and aquaporin4-antibody neuromyelitis optica spectrum disorder. Salience network alterations are correlated to global fatigue while sensory-motor network alterations to physical fatigue. Cervical cord functional connectivity disturbances appeared associated to global and physical fatigue.

2023 - Spatial patterns of gray and white matter compromise relate to age of seizure onset in temporal lobe epilepsy [Articolo su rivista]
Ballerini, A.; Arienzo, D.; Stasenko, A.; Schadler, A.; Vaudano, A. E.; Meletti, S.; Kaestner, E.; Mcdonald, C. R.
abstract

Objective: Temporal Lobe Epilepsy (TLE) is frequently a neurodevelopmental disorder, involving subcortical volume loss, cortical atrophy, and white matter (WM) disruption. However, few studies have addressed how these pathological changes in TLE relate to one another. In this study, we investigate spatial patterns of gray and white matter degeneration in TLE and evaluate the hypothesis that the relationship among these patterns varies as a function of the age at which seizures begin. Methods: Eighty-two patients with TLE and 59 healthy controls were enrolled. T1-weighted images were used to obtain hippocampal volumes and cortical thickness estimates. Diffusion-weighted imaging was used to obtain fractional anisotropy (FA) and mean diffusivity (MD) of the superficial WM (SWM) and deep WM tracts. Analysis of covariance was used to examine patterns of WM and gray matter alterations in TLE relative to controls, controlling for age and sex. Sliding window correlations were then performed to examine the relationships between SWM degeneration, cortical thinning, and hippocampal atrophy across ages of seizure onset. Results: Cortical thinning in TLE followed a widespread, bilateral pattern that was pronounced in posterior centroparietal regions, whereas SWM and deep WM loss occurred mostly in ipsilateral, temporolimbic regions compared to controls. Window correlations revealed a relationship between hippocampal volume loss and whole brain SWM disruption in patients who developed epilepsy during childhood. On the other hand, in patients with adult-onset TLE, co-occurring cortical and SWM alterations were observed in the medial temporal lobe ipsilateral to the seizure focus. Significance: Our results suggest that although cortical, hippocampal and WM alterations appear spatially discordant at the group level, the relationship among these features depends on the age at which seizures begin. Whereas neurodevelopmental aspects of TLE may result in co-occurring WM and hippocampal degeneration near the epileptogenic zone, the onset of seizures in adulthood may set off a cascade of SWM microstructural loss and cortical atrophy of a neurodegenerative nature.

2023 - Spectrum of epilepsy with eyelid myoclonia: delineation of disease subtypes from a large multicenter study [Articolo su rivista]
Cerulli Irelli, Emanuele; Cocchi, Enrico; Ramantani, Georgia; Riva, Antonella; Caraballo, Roberto H; Morano, Alessandra; Giuliano, Loretta; Yilmaz, Tülay; Panagiotakaki, Eleni; Operto, Francesca F; Giraldez, Beatriz Gonzalez; Balestrini, Simona; Silvennoinen, Katri; Casciato, Sara; Comajuan, Marion; Fortunato, Francesco; Giallonardo, Anna T; Gamirova, Rimma; Coppola, Antonietta; Di Gennaro, Giancarlo; Labate, Angelo; Sofia, Vito; Kluger, Gerhard J; Gambardella, Antonio; Kasteleijn-Nolst Trenite, Dorothee; Baykan, Betul; Sisodiya, Sanjay M; Arzimanoglou, Alexis; Striano, Pasquale; Di Bonaventura, Carlo; Meletti, Stefano
abstract

Objective Epilepsy with eyelid myoclonia (EEM) has been associated with marked clinical heterogeneity. Early epilepsy onset has been recently linked to lower chances of achieving sustained remission and to a less favorable neuropsychiatric outcome. However, much work is still needed to better delineate this epilepsy syndrome. Methods In this multicenter retrospective cohort study, we included 267 EEM patients from nine countries. Data on electroclinical and demographic features, intellectual functioning, migraine with or without aura, family history of epilepsy, and epilepsy syndromes in relatives were collected in each patient. The impact of age at epilepsy onset (AEO) on EEM clinical features was investigated, along with the distinctive clinical characteristics of patients showing sporadic myoclonia involving body regions other than eyelids (body-MYO). Results Kernel density estimation revealed a trimodal distribution of AEO, and Fisher-Jenks optimization disclosed three EEM subgroups: early onset (EO-EEM), intermediate onset (IO-EEM), and late onset (LO-EEM). EO-EEM was associated with the highest rate of intellectual disability, antiseizure medication refractoriness, and psychiatric comorbidities and with the lowest rate of family history of epilepsy. LO-EEM was associated with the highest proportion of body-MYO and generalized tonic-clonic seizures (GTCS), whereas IO-EEM had the lowest observed rate of additional findings. A family history of EEM was significantly more frequent in IO-EEM and LO-EEM compared with EO-EEM. In the subset of patients with body-MYO (58/267), we observed a significantly higher rate of migraine and GTCS but no relevant differences in other electroclinical features and seizure outcome. Significance Based on AEO, we identified consistent EEM subtypes characterized by distinct electroclinical and familial features. Our observations shed new light on the spectrum of clinical features of this generalized epilepsy syndrome and may help clinicians toward a more accurate classification and prognostic profiling of EEM patients.

2023 - The broad-spectrum activity of perampanel: state of the art and future perspective of AMPA antagonism beyond epilepsy [Articolo su rivista]
Perversi, F.; Costa, C.; Labate, A.; Lattanzi, S.; Liguori, C.; Maschio, M.; Meletti, S.; Nobili, L.; Operto, F. F.; Romigi, A.; Russo, E.; Di Bonaventura, C.
abstract

Glutamate is the brain’s main excitatory neurotransmitter. Glutamatergic neurons primarily compose basic neuronal networks, especially in the cortex. An imbalance of excitatory and inhibitory activities may result in epilepsy or other neurological and psychiatric conditions. Among glutamate receptors, AMPA receptors are the predominant mediator of glutamate-induced excitatory neurotransmission and dictate synaptic efficiency and plasticity by their numbers and/or properties. Therefore, they appear to be a major drug target for modulating several brain functions. Perampanel (PER) is a highly selective, noncompetitive AMPA antagonist approved in several countries worldwide for treating different types of seizures in various epileptic conditions. However, recent data show that PER can potentially address many other conditions within epilepsy and beyond. From this perspective, this review aims to examine the new preclinical and clinical studies—especially those produced from 2017 onwards—on AMPA antagonism and PER in conditions such as mesial temporal lobe epilepsy, idiopathic and genetic generalized epilepsy, brain tumor-related epilepsy, status epilepticus, rare epileptic syndromes, stroke, sleep, epilepsy-related migraine, cognitive impairment, autism, dementia, and other neurodegenerative diseases, as well as provide suggestions on future research agenda aimed at probing the possibility of treating these conditions with PER and/or other AMPA receptor antagonists.

2023 - The role of automated computed topography perfusion in prediction of hemorrhagic transformation after acute ischemic stroke [Articolo su rivista]
Elsaid, N.; Bigliardi, G.; Dell'Acqua, M. L.; Vandelli, L.; Ciolli, L.; Picchetto, L.; Borzi, G.; Ricceri, R.; Pentore, R.; Vallone, S.; Meletti, S.; Saied, A.
abstract

Introduction: The role of computed tomography perfusion (CTP) in prediction of hemorrhagic transformation (HT) has been evolving. We aimed to study the role of automated perfusion post-processing software in prediction of HT using the commercially available RAPID software. Methods: Two hundred eighty-two patients with anterior circulation ischemic stroke, who underwent CTP with RAPID automated post-processing, were retrospectively enrolled and divided into HT (n = 91) and non-HT groups (n = 191). The automated RAPID-generated perfusion maps were reviewed. Mismatch volume and ratio, time to maximum (Tmax) > 4‐10s volumes, hypoperfusion index, cerebral blood flow (CBF) < 20–38% volumes, cerebral blood volume (CBV) < 34%–42% volumes, and CBV index were recorded and analyzed. Results: The volumes of brain tissues suffering from reduction of cerebral blood flow (CBF < 20%–38%), reduction in cerebral blood volumes (CBV < 34–42%), and delayed contrast arrival times (Tmax > 4–10s) were significantly higher in the HT group. The mismatch volumes were also higher in the HT group (p =.001). Among these parameters, the Tmax > 6s volume was the most reliable and sensitive predictor of HT (p =.001, AUC = 0.667). However, the combination of the perfusion parameters can slightly improve the diagnostic efficiency (AUC = 0.703). There was no statistically significant difference between the non-HT group and either the parenchymal or the symptomatic subtypes. Conclusion: The RAPID automated CTP parameters can provide a reliable predictor of HT overall but not the parenchymal or the symptomatic subtypes. The infarct area involving the penumbra and core represented by the Tmax > 6s threshold is the most sensitive predictor; however, the combination of the perfusion parameters can slightly improve the diagnostic efficiency.

2023 - The role of the amygdala in ictal central apnea: insights from brain MRI morphometry [Articolo su rivista]
Micalizzi, E.; Ballerini, A.; Giovannini, G.; Cioclu, M. C.; Scolastico, S.; Pugnaghi, M.; Orlandi, N.; Malagoli, M.; Genovese, M.; Todeschini, A.; Giunta, L.; Villani, F.; Meletti, S.; Vaudano, A. E.
abstract

Objective: Ictal central apnea (ICA) is a frequent correlate of focal seizures, particularly in temporal lobe epilepsy (TLE), and regarded as a potential electroclinical biomarker of sudden unexpected death in epilepsy (SUDEP). Aims of this study are to investigate morphometric changes of subcortical structures in ICA patients and to find neuroimaging biomarkers of ICA in patients with focal epilepsy.Methods: We prospectively recruited focal epilepsy patients with recorded seizures during a video-EEG long-term monitoring with cardiorespiratory polygraphic recordings from April 2020 to September 2022. Participants were accordingly subdivided into two groups: patients with focal seizures with ICA (ICA) and without (noICA). A pool of 30 controls matched by age and sex was collected. All the participants underwent MRI scans with volumetric high-resolution T1-weighted images. Post-processing analyses included a whole-brain VBM analysis and segmentation algorithms performed with FreeSurfer.Results: Forty-six patients were recruited (aged 15-60 years): 16 ICA and 30 noICA. The whole-brain VBM analysis showed an increased gray matter volume of the amygdala ipsilateral to the epileptogenic zone (EZ) in the ICA group compared to the noICA patients. Amygdala sub-segmentation analysis revealed an increased volume of the whole amygdala, ipsilateral to the EZ compared to controls [F(1, 76) = 5.383, pFDR = 0.042] and to noICA patients ([F(1, 76) = 5.383, pFDR = 0.038], specifically of the basolateral complex (respectively F(1, 76) = 6.160, pFDR = 0.037; F(1, 76) = 5.121, pFDR = 0.034). Interpretation: Our findings, while confirming the key role of the amygdala in participating in ictal respiratory modifications, suggest that structural modifications of the amygdala and its subnuclei may be valuable morphological biomarkers of ICA.

2023 - What is the risk of unprovoked seizures after acute symptomatic status epilepticus? [Articolo su rivista]
Lattanzi, S.; Trinka, E.; Meletti, S.
abstract

2022 - Adjunctive Brivaracetam in Older Patients with Focal Seizures: Evidence from the BRIVAracetam add‑on First Italian netwoRk Study (BRIVAFIRST) [Articolo su rivista]
Lattanzi, S.; Canafoglia, L.; Canevini, M. P.; Casciato, S.; Cerulli Irelli, E.; Chiesa, V.; Dainese, F.; De Maria, G.; Didato, G.; Falcicchio, G.; Fanella, M.; Ferlazzo, E.; Gangitano, M.; Giorgi, F. S.; La Neve, A.; Mecarelli, O.; Montalenti, E.; Morano, A.; Piazza, F.; Pulitano, P.; Quarato, P. P.; Ranzato, F.; Rosati, E.; Tassi, L.; Di Bonaventura, C.; Alicino, A.; Ascoli, M.; Assenza, G.; Avorio, F.; Badioni, V.; Banfi, P.; Bartolini, E.; Basili, L. M.; Belcastro, V.; Beretta, S.; Berto, I.; Biggi, M.; Billo, G.; Boero, G.; Bonanni, P.; Bongiorno, J.; Brigo, F.; Caggia, E.; Cagnetti, C.; Calvello, C.; Cesnik, E.; Chianale, G.; Ciampanelli, D.; Ciuffini, R.; Cocito, D.; Colella, D.; Contento, M.; Costa, C.; Cumbo, E.; D'Aniello, A.; Deleo, F.; Difrancesco, J. C.; Di Gennaro, G.; Di Giacomo, R.; Di Liberto, A.; Domina, E.; Dono, F.; Durante, V.; Elia, M.; Estraneo, A.; Evangelista, G.; Faedda, M. T.; Failli, Y.; Fallica, E.; Fattouch, J.; Ferrari, A.; Ferreri, F.; Fisco, G.; Fonti, D.; Fortunato, F.; Foschi, N.; Francavilla, T.; Galli, R.; Gazzina, S.; Giallonardo, A. T.; Giuliano, L.; Habetswallner, F.; Izzi, F.; Kassabian, B.; Labate, A.; Luisi, C.; Magliani, M.; Maira, G.; Mari, L.; Marino, D.; Mascia, A.; Mazzeo, A.; Meletti, S.; Nilo, A.; Orlando, B.; Paladin, F.; Pascarella, M. G.; Pastori, C.; Pauletto, G.; Peretti, A.; Perri, G.; Pezzella, M.; Piccioli, M.; Pignatta, P.; Pilolli, N.; Pisani, F.; Pisani, L. R.; Placidi, F.; Pollicino, P.; Porcella, V.; Pradella, S.; Puligheddu, M.; Quadri, S.; Quintas, R.; Renna, R.; Rizzo, G. R.; Rum, A.; Salamone, E. M.; Savastano, E.; Sessa, M.; Stokelj, D.; Tartara, E.; Tombini, M.; Tumminelli, G.; Vaudano, A. E.; Ventura, M.; Vigano, I.; Viglietta, E.; Vignoli, A.; Villani, F.; Zambrelli, E.; Zummo, L.
abstract

Background: The management of epilepsy in older adults has become part of daily practice because of an aging population. Older patients with epilepsy represent a distinct and more vulnerable clinical group as compared with younger patients, and they are generally under-represented in randomized placebo-controlled trials. Real-world studies can therefore be a useful complement to characterize the drug’s profile. Brivaracetam is a rationally developed compound characterized by high-affinity binding to synaptic vesicle protein 2A and approved as adjunctive therapy for focal seizures in adults with epilepsy. Objective: The aim of this study was to assess the 12-month effectiveness and tolerability of adjunctive brivaracetam in older patients (≥65 years of age) with epilepsy treated in a real-world setting. Methods: The BRIVAFIRST (BRIVAracetam add-on First Italian netwoRk STudy) was a 12-month retrospective multicenter study including adult patients prescribed adjunctive brivaracetam. Effectiveness outcomes included the rates of seizure response (≥50% reduction in baseline seizure frequency), seizure freedom, and treatment discontinuation. Safety and tolerability outcomes included the rate of treatment discontinuation due to adverse events and the incidence of adverse events. Data were compared for patients aged ≥65 years of age (‘older’) vs those aged <65 years (‘younger’). Results: There were 1029 patients with focal epilepsy included in the study, of whom 111 (10.8%) were aged ≥65 years. The median daily dose of brivaracetam at 3 months was 100 [interquartile range, 100–175] mg in the older group and 100 [100–200] mg in the younger group (p = 0.036); it was 150 [100–200] mg in both groups either at 6 months (p = 0.095) or 12 months (p = 0.140). At 12 months, 49 (44.1%) older and 334 (36.4%) younger patients had a reduction in their baseline seizure frequency by at least 50% (p = 0.110), and the seizure freedom rates were 35/111 (31.5%) and 134/918 (14.6%) in older and younger groups, respectively (p < 0.001). During the 1-year study period, 20 (18.0%) patients in the older group and 245 (26.7%) patients in the younger group discontinued brivaracetam (p = 0.048). Treatment withdrawal because of insufficient efficacy was less common in older than younger patients [older: n = 7 (6.3%), younger: n = 152 (16.6%); p = 0.005]. Adverse events were reported by 24.2% of older patients and 30.8% of younger patients (p = 0.185); the most common adverse events were somnolence, nervousness and/or agitation, vertigo, and fatigue in both study groups. Conclusions: Adjunctive brivaracetam was efficacious, had good tolerability, and no new or unexpected safety signals emerged when used to treat older patients with uncontrolled focal seizures in clinical practice. Adjunctive brivaracetam can be a suitable therapeutic option in this special population.

2022 - Amygdala subnuclear volumes in temporal lobe epilepsy with hippocampal sclerosis and in non-lesional patients [Articolo su rivista]
Ballerini, Alice; Tondelli, Manuela; Talami, Francesca; Molinari, Maria Angela; Micalizzi, Elisa; Giovannini, Giada; Turchi, Giulia; Malagoli, Marcella; Genovese, Maurilio; Meletti, Stefano; Vaudano, Anna Elisabetta
abstract

Together with hippocampus, the amygdala is important in the epileptogenic network of patients with temporal lobe epilepsy. Recently, an increase in amygdala volumes (i.e. amygdala enlargement) has been proposed as morphological biomarker of a subtype of temporal lobe epilepsy patients without MRI abnormalities, although other data suggest that this finding might be unspecific and not exclusive to temporal lobe epilepsy. In these studies, the amygdala is treated as a single entity, while instead it is composed of different nuclei, each with peculiar function and connection. By adopting a recently developed methodology of amygdala's subnuclei parcellation based of high-resolution T-1-weighted image, this study aims to map specific amygdalar subnuclei participation in temporal lobe epilepsy due to hippocampal sclerosis (n = 24) and non-lesional temporal lobe epilepsy (n = 24) with respect to patients with focal extratemporal lobe epilepsies (n = 20) and healthy controls (n = 30). The volumes of amygdala subnuclei were compared between groups adopting multivariate analyses of covariance and correlated with clinical variables. Additionally, a logistic regression analysis on the nuclei resulting statistically different across groups was performed. Compared with other populations, temporal lobe epilepsy with hippocampal sclerosis showed a significant atrophy of the whole amygdala (p(Bonferroni) = 0.040), particularly the basolateral complex (p(Bonferroni) = 0.033), while the non-lesional temporal lobe epilepsy group demonstrated an isolated hypertrophy of the medial nucleus (p(Bonferroni) = 0.012). In both scenarios, the involved amygdala was ipsilateral to the epileptic focus. The medial nucleus demonstrated a volume increase even in extratemporal lobe epilepsies although contralateral to the seizure onset hemisphere (p(Bonferroni) = 0.037). Non-lesional patients with psychiatric comorbidities showed a larger ipsilateral lateral nucleus compared with those without psychiatric disorders. This exploratory study corroborates the involvement of the amygdala in temporal lobe epilepsy, particularly in mesial temporal lobe epilepsy and suggests a different amygdala subnuclei engagement depending on the aetiology and lateralization of epilepsy. Furthermore, the logistic regression analysis indicated that the basolateral complex and the medial nucleus of amygdala can be helpful to differentiate temporal lobe epilepsy with hippocampal sclerosis and with MRI negative, respectively, versus controls with a consequent potential clinical yield. Finally, the present results contribute to the literature about the amygdala enlargement in temporal lobe epilepsy, suggesting that the increased volume of amygdala can be regarded as epilepsy-related structural changes common across different syndromes whose meaning should be clarified.

2022 - An Italian consensus on the management of Lennox-Gastaut syndrome [Articolo su rivista]
Riva, A.; Coppola, A.; Bonaventura, C. D.; Elia, M.; Ferlazzo, E.; Gobbi, G.; Marini, C.; Meletti, S.; Romeo, A.; Santoro, K.; Verrotti, A.; Capovilla, G.; Striano, P.; Aguglia, U.; Bagnasco, I.; Bartolini, E.; Battaglia, D.; Beccaria, F.; Belcastro, V.; Bernardo, P.; Bonanni, P.; Boniver, C.; Bonuccelli, A.; Briatore, E.; Brigo, F.; Cesaroni, E.; Coa, R.; Costa, C.; D'Aniello, A.; De Giorgis, V.; Gennaro, G. D.; Ferrari, A. R.; Marchese, F.; Matricardi, S.; Messana, T.; Morano, A.; Operto, F. F.; Orsini, A.; Parmeggiani, L.; Peruzzi, C.; Pruna, D.; Puligheddu, M.; Pulitano, P.; Ragona, F.; Romigi, A.; Rosati, A.; Rosati, E.; Russo, A.; Sartori, S.; Spagnoli, C.; Spano, M.; Trabacca, A.; Troisi, S.; Viri, M.; Zucca, C.
abstract

Purpose: Although international guidelines exist, the clinical heterogeneity of Lennox-Gastaut syndrome (LGS) and the increasing availability of new and repurposed drugs (e.g., fenfluramine and cannabidiol) requires a practical guide to patient management in the clinical context. We report the results of a consensus survey among 42 Italian experts in the diagnosis and treatment of LGS. Methods: The consensus procedure followed a modified Delphi approach. Statements were formulated, based on the most recent published evidence and the clinicians’ personal experience, then discussed, and agreed upon by the experts through a two-round voting procedure. Approval of a statement was reached with an average score ≥7. Results: Thirteen statements dealing with three main topics (i.e., clinical diagnosis and prognosis, impact on the Quality of Life (QoL), and treatment strategies) were generated. Six statements achieved a level of agreement sufficient for approval on the first voting round. Following the discussion and a few consequent amendments, most of the statements increased their level of agreement and all 13 were approved. Conclusions: Overall, the statements draw a slightly more benign picture of this rare and severe disease, highlighting the possibility of remission - albeit modest -, an apparent trend towards lower mortality, and the availability of several effective drugs, to which greater accessibility would be hoped for. Valproate remains a major therapeutic option in LGS patients although lamotrigine, rufinamide, topiramate, cannabidiol, and clobazam are popular therapeutic options in Italy, allowing for a tailor-made antiseizure therapy.

2022 - An ultra-long new onset refractory status epilepticus: Winning the battle but losing the war? [Articolo su rivista]
Orlandi, N.; Giovannini, G.; Mirandola, L.; Monti, G.; Marudi, A.; Mosca, F.; Lalla, A.; D'Orsi, G.; Francavilla, M.; Meletti, S.
abstract

New onset refractory status epilepticus (NORSE), is a rare and challenging condition occurring in previously healthy people. The etiology often remains undiscovered and is frequently associated with an unfavorable outcome. We report the electroclinical and neuroradiological evolution of an ultra-long case of NORSE of unknown etiology. A 38-year-old woman with a prodrome of fever, vomiting and diarrhea was admitted to our Intensive Care Unit for refractory convulsive status epilepticus (SE). Her past medical history was unremarkable. Extensive examinations were negative for potential viral, autoimmune and metabolic etiologies. Despite multiple therapeutical attempts with antiseizures medications, anesthetics and immunotherapy, seizures persisted. After nearly 6 months of enduring seizures, SE finally ceased and the patient gradually recovered to a minimum state of awareness. She was then able to communicate through one-word utterances and to understand simple tasks. At a three-years follow-up, she developed multifocal drug-resistant epilepsy, subcortical myoclonus and severe spastic quadraparesis, becoming completely dependent for activities of daily living. To our knowledge, this represents one of the longest cases of NORSE with final status resolution at this time. However, ultra-long SE in this case led to severe and disabling neurological sequelae. Future studies focused on disease modifying treatments for refractory SE are needed.

2022 - Ataxia-myoclonus syndrome in patients with SARS-CoV2 infection [Articolo su rivista]
Guerra, A. F.; Martinelli, I.; Rispoli, V.; Marcacci, M.; Cavallieri, F.; Nizzoli, S.; Valzania, F.; Ventura, P.; Meletti, S.; Pietrangelo, A.
abstract

2022 - Brivaracetam as Early Add-On Treatment in Patients with Focal Seizures: A Retrospective, Multicenter, Real-World Study [Articolo su rivista]
Lattanzi, S.; Canafoglia, L.; Canevini, M. P.; Casciato, S.; Cerulli Irelli, E.; Chiesa, V.; Dainese, F.; De Maria, G.; Didato, G.; Di Gennaro, G.; Falcicchio, G.; Fanella, M.; Ferlazzo, E.; Gangitano, M.; La Neve, A.; Mecarelli, O.; Montalenti, E.; Morano, A.; Piazza, F.; Pizzanelli, C.; Pulitano, P.; Ranzato, F.; Rosati, E.; Tassi, L.; Di Bonaventura, C.; Alicino, A.; Ascoli, M.; Assenza, G.; Avorio, F.; Badioni, V.; Banfi, P.; Bartolini, E.; Basili, L. M.; Belcastro, V.; Beretta, S.; Berto, I.; Biggi, M.; Billo, G.; Boero, G.; Bonanni, P.; Bongorno, J.; Brigo, F.; Caggia, E.; Cagnetti, C.; Calvello, C.; Cesnik, E.; Chianale, G.; Ciampanelli, D.; Ciuffini, R.; Cocito, D.; Colella, D.; Contento, M.; Costa, C.; Cumbo, E.; D'Aniello, A.; Deleo, F.; Difrancesco, J. C.; Di Giacomo, R.; Di Liberto, A.; Domina, E.; Dono, F.; Durante, V.; Elia, M.; Estraneo, A.; Evangelista, G.; Faedda, M. T.; Failli, Y.; Fallica, E.; Fattouch, J.; Ferrari, A.; Ferreri, F.; Fisco, G.; Fonti, D.; Fortunato, F.; Foschi, N.; Francavilla, T.; Galli, R.; Gazzina, S.; Giallonardo, A. T.; Giorgi, F. S.; Giuliano, L.; Habetswallner, F.; Izzi, F.; Kassabian, B.; Labate, A.; Luisi, C.; Magliani, M.; Maira, G.; Mari, L.; Marino, D.; Mascia, A.; Mazzeo, A.; Meletti, S.; Milano, C.; Nilo, A.; Orlando, B.; Paladin, F.; Pascarella, M. G.; Pastori, C.; Pauletto, G.; Peretti, A.; Perri, G.; Pezzella, M.; Piccioli, M.; Pignatta, P.; Pilolli, N.; Pisani, F.; Pisani, L. R.; Placidi, F.; Pollicino, P.; Porcella, V.; Pradella, S.; Puligheddu, M.; Quadri, S.; Quarato, P. P.; Quintas, R.; Renna, R.; Rizzo, G. R.; Rum, A.; Salamone, E. M.; Savastano, E.; Sessa, M.; Stokelj, D.; Tartara, E.; Tombini, M.; Tumminelli, G.; Vaudano, A. E.; Ventura, M.; Vigano, I.; Viglietta, E.; Vignoli, A.; Villani, F.; Zambrelli, E.; Zummo, L.
abstract

Introduction In randomized controlled trials, add-on brivaracetam (BRV) reduced seizure frequency in patients with drug-resistant focal epilepsy. Most real-world research on BRV has focused on refractory epilepsy. The aim of this analysis was to assess the 12-month effectiveness and tolerability of adjunctive BRV when used as early or late adjunctive treatment in patients included in the BRIVAracetam add-on First Italian netwoRk Study (BRIVAFIRST). Methods BRIVAFIRST was a 12-month retrospective, multicenter study including adult patients prescribed adjunctive BRV. Effectiveness outcomes included the rates of sustained seizure response, sustained seizure freedom, and treatment discontinuation. Safety and tolerability outcomes included the rate of treatment discontinuation due to adverse events (AEs) and the incidence of AEs. Data were compared for patients treated with add-on BRV after 1-2 (early add-on) and >= 3 (late add-on) prior antiseizure medications. Results A total of 1029 patients with focal epilepsy were included in the study, of whom 176 (17.1%) received BRV as early add-on treatment. The median daily dose of BRV at 12 months was 125 (100-200) mg in the early add-on group and 200 (100-200) in the late add-on group (p < 0.001). Sustained seizure response was reached by 97/161 (60.3%) of patients in the early add-on group and 286/833 (34.3%) of patients in the late add-on group (p < 0.001). Sustained seizure freedom was achieved by 51/161 (31.7%) of patients in the early add-on group and 91/833 (10.9%) of patients in the late add-on group (p < 0.001). During the 1-year study period, 29 (16.5%) patients in the early add-on group and 241 (28.3%) in the late add-on group discontinued BRV (p = 0.001). Adverse events were reported by 38.7% and 28.5% (p = 0.017) of patients who received BRV as early and late add-on treatment, respectively. Conclusion Brivaracetam was effective and well tolerated both as first add-on and late adjunctive treatment in patients with focal epilepsy.

2022 - Brivaracetam as add-on treatment in patients with post-stroke epilepsy: real-world data from the BRIVAracetam add-on First Italian netwoRk Study (BRIVAFIRST) [Articolo su rivista]
Lattanzi, S.; Canafoglia, L.; Canevini, M. P.; Casciato, S.; Cerulli Irelli, E.; Chiesa, V.; Dainese, F.; De Maria, G.; Didato, G.; Di Gennaro, G.; Falcicchio, G.; Fanella, M.; Ferlazzo, E.; Gangitano, M.; La Neve, A.; Mecarelli, O.; Montalenti, E.; Morano, A.; Piazza, F.; Pizzanelli, C.; Pulitano, P.; Ranzato, F.; Rosati, E.; Tassi, L.; Di Bonaventura, C.; Alicino, A.; Ascoli, M.; Assenza, G.; Avorio, F.; Badioni, V.; Banfi, P.; Bartolini, E.; Basili, L. M.; Belcastro, V.; Beretta, S.; Berto, I.; Biggi, M.; Billo, G.; Boero, G.; Bonanni, P.; Bongiorno, J.; Brigo, F.; Caggia, E.; Cagnetti, C.; Calvello, C.; Cesnik, E.; Chianale, G.; Ciampanelli, D.; Ciuffini, R.; Cocito, D.; Colella, D.; Contento, M.; Costa, C.; Cumbo, E.; D'Aniello, A.; Deleo, F.; Difrancesco, J. C.; Di Giacomo, R.; Di Liberto, A.; Domina, E.; Dono, F.; Durante, V.; Elia, M.; Estraneo, A.; Evangelista, G.; Faedda, M. T.; Failli, Y.; Fallica, E.; Fattouch, J.; Ferrari, A.; Ferreri, F.; Fisco, G.; Fonti, D.; Fortunato, F.; Foschi, N.; Francavilla, T.; Galli, R.; Gazzina, S.; Giallonardo, A. T.; Giorgi, F. S.; Giuliano, L.; Habetswallner, F.; Izzi, F.; Kassabian, B.; Labate, A.; Luisi, C.; Magliani, M.; Maira, G.; Mari, L.; Marino, D.; Mascia, A.; Mazzeo, A.; Milano, C.; Meletti, S.; Nilo, A.; Orlando, B.; Paladin, F.; Pascarella, M. G.; Pastori, C.; Pauletto, G.; Peretti, A.; Perri, G.; Pezzella, M.; Piccioli, M.; Pignatta, P.; Pilolli, N.; Pisani, F.; Pisani, L. R.; Placidi, F.; Pollicino, P.; Porcella, V.; Pradella, S.; Puligheddu, M.; Quadri, S.; Quarato, P. P.; Quintas, R.; Renna, R.; Rizzo, G. R.; Rum, A.; Salamone, E. M.; Savastano, E.; Sessa, M.; Stokelj, D.; Tartara, E.; Tombini, M.; Tumminelli, G.; Vaudano, A. E.; Ventura, M.; Vigano, I.; Viglietta, E.; Vignoli, A.; Villani, F.; Zambrelli, E.; Zummo, L.
abstract

Objective: Post-stroke epilepsy (PSE) is one of the most common causes of acquired epilepsy and accounts for about 10-15% of all newly diagnosed epilepsy cases. However, evidence about the clinical profile of antiseizure medications in the PSE setting is currently limited. Brivaracetam (BRV) is a rationally developed compound characterized by high-affinity binding to synaptic vesicle protein 2A. The aim of this study was to assess the 12-month effectiveness and tolerability of adjunctive BRV in patients with PSE treated in a real-world setting. Methods: This was a subgroup analysis of patients with PSE included in the BRIVAracetam add-on First Italian netwoRk Study (BRIVAFIRST). The BRIVAFIRST was a 12-month retrospective, multicentre study including adult patients prescribed adjunctive BRV. Effectiveness outcomes included the rates of seizure response (≥50% reduction in baseline seizure frequency), seizure‐freedom, and treatment discontinuation. Safety and tolerability outcomes included the rate of treatment discontinuation due to adverse events (AEs) and the incidence of AEs. Results: Patients with PSE included in the BRIVAFIRST were 75 and had a median age of 57 (interquartile range, 42-66) years. The median daily doses of BRV at 3, 6, and 12 months from starting treatment were 100 (100-150) mg, 125 (100-200) mg and 100 (100-200) mg, respectively. At 12 months, 32 (42.7%) patients had a reduction in their baseline seizure frequency by at least 50%, and the seizure freedom rates was 26/75 (34.7%). During the 1-year study period, 10 (13.3%) patients discontinued BRV. The reasons of treatment withdrawal were insufficient efficacy in 6 (8.0%) patients and poor tolerability in 4 (5.3%) patients. Adverse events were reported by 13 (20.3%) patients and were rated as mild in 84.6% and moderate in 15.4% of cases. Significance: Adjunctive BRV was efficacious and generally well-tolerated when used in patients with PSE in clinical practice. Adjunctive BRV can be a suitable therapeutic option for patients with PSE.

2022 - Can Disruption of Basal Ganglia-Thalamocortical Circuit in Wilson Disease Be Associated with Juvenile Myoclonic Epilepsy Phenotype? [Articolo su rivista]
Rossi, J.; Cavallieri, F.; Giovannini, G.; Benuzzi, F.; Ballotta, D.; Vaudano, A. E.; Ferrara, F.; Contardi, S.; Pietrangelo, A.; Corradini, E.; Lui, F.; Meletti, S.
abstract

In this paper, we describe the multimodal MRI findings in a patient with Wilson disease and a seizure disorder, characterized by an electroclinical picture resembling juvenile myoclonic epilepsy. The brain structural MRI showed a deposition of ferromagnetic materials in the basal ganglia, with marked hypointensities in T2-weighted images of globus pallidus internus bilaterally. A resting-state fMRI study revealed increased functional connectivity in the patient, compared to control subjects, in the following networks: (1) between the primary motor cortex and several cortical regions, including the secondary somatosensory cortex and (2) between the globus pallidus and the thalamo-frontal network. These findings suggest that globus pallidus alterations, due to metal accumulation, can lead to a reduction in the normal globus pallidus inhibitory tone on the thalamo-(motor)-cortical pathway. This, in turn, can result in hyperconnectivity in the motor cortex circuitry, leading to myoclonus and tonic-clonic seizures. We suppose that, in this patient, Wilson disease generated a ‘lesion model’ of myoclonic epilepsy.

2022 - Delirium in Older Adults: What a Surgeon Needs to Know [Articolo su rivista]
Melegari, Gabriele; Gaspari, Arianna; Gualdi, Eugenia; Zoli, Michele; Meletti, Stefano; Barbieri, Alberto
abstract

2022 - Development and Validation of a Nomogram Based on the Epidemiology-Based Mortality Score in Status Epilepticus (EMSE) Parameters to Predict 30-day Mortality in Status Epilepticus [Articolo su rivista]
Brigo, Francesco; Turcato, Gianni; Lattanzi, Simona; Orlandi, Niccolò; Turchi, Giulia; Zaboli, Arian; Giovannini, Giada; Meletti, Stefano
abstract

Background: To develop a nomogram using the parameters of the Epidemiology-Based Mortality Score in Status Epilepticus (EMSE) and to evaluate its accuracy compared with the EMSE alone in the prediction of 30-day mortality in patients with status epilepticus (SE).Methods: We included a cohort of patients with SE aged >= 21 years admitted from 2013 to 2021. Regression coefficients from the multivariable logistic regression model were used to generate a nomogram predicting the risk of 30-day mortality. Discrimination of the nomogram was evaluated using the area under the receiver operating characteristic curve (AUCROC) with 95% confidence interval. Internal validation was performed by bootstrap resampling.Results: Among 698 patients with SE, the 30-day mortality rate was 28.9% (202 of 698). On the multivariable analysis, all EMSE parameters (except for the comorbidity group including metastatic solid tumor or AIDS) were associated with a significantly higher risk of 30-day mortality and were included in the nomogram. The discriminatory capability of the nomogram with bootstrap resampling (5000 resamples) had an AUCROC of 0.830 (95% confidence interval 0.798-0.862). Conversely, the AUCROC of the EMSE was 0.777 (95% confidence interval 0.742-0.813). Thus, the probability that a patient who died within 30 days from SE had a higher score than a patient who survived was 83%, indicating good discriminatory power of the nomogram. Conversely, the risk predicted using the EMSE alone was 77%. The nomogram was well calibrated.Conclusions: A nomogram based on EMSE parameters appears superior to the EMSE in predicting the risk of 30-day mortality after SE. The discrimination and calibration of the nomogram shows a better predictive accuracy than the EMSE alone.

2022 - Developmental and epileptic encephalopathies: Is prognosis related to different epileptic network dysfunctions? [Articolo su rivista]
Lin, J. -J.; Meletti, S.; Vaudano, A. E.; Lin, K. -L.
abstract

Developmental and epileptic encephalopathies are a group of rare, severe epilepsies, which are characterized by refractory seizures starting in infancy or childhood and developmental delay or regression. Developmental changes might be independent of epilepsy. However, interictal epileptic activity and seizures can further deteriorate cognition and behavior. Recently, the concept of developmental and epileptic encephalopathies has moved from the lesions associated with epileptic encephalopathies toward the epileptic network dysfunctions on the functioning of the brain. Early recognition and differentiation of patients with developmental and epileptic encephalopathies is important, as precision therapies need to be holistic to address the often devastating symptoms. In this review, we discuss the evolution of the concept of developmental and epileptic encephalopathies in recent years, as well as the current understanding of the genetic basis of developmental and epileptic encephalopathies. Finally, we will discuss the role of epileptic network dysfunctions on prognosis for these severe conditions.

2022 - Early predictors of disability of paediatric-onset AQP4-IgG-seropositive neuromyelitis optica spectrum disorders [Articolo su rivista]
Camera, V.; Messina, S.; Elhadd, K. T.; Sanpera-Iglesias, J.; Mariano, R.; Hacohen, Y.; Dobson, R.; Meletti, S.; Wassmer, E.; Lim, M. J.; Huda, S.; Hemingway, C.; Leite, M. I.; Ramdas, S.; Palace, J.
abstract

OBJECTIVE: To describe onset clinical features predicting time to first relapse and time to long-term visual, motor and cognitive disabilities in paediatric-onset aquaporin-4 antibody (AQP4-IgG) neuromyelitis optica spectrum disorders (NMOSDs). METHODS: In this retrospective UK multicentre cohort study, we recorded clinical data of paediatric-onset AQP4-IgG NMOSD. Univariate and exploratory multivariable Cox proportional hazard models were used to identify long-term predictors of permanent visual disability, Expanded Disability Status Scale (EDSS) score of 4 and cognitive impairment. RESULTS: We included 49 paediatric-onset AQP4-IgG patients (38.8% white, 34.7% black, 20.4% Asians and 6.1% mixed), mean onset age of 12±4.1 years, and 87.7% were female. Multifocal onset presentation occurred in 26.5% of patients, and optic nerve (47%), area postrema/brainstem (48.9%) and encephalon (28.6%) were the most involved areas. Overall, 52.3% of children had their first relapse within 1 year from disease onset. Children with onset age <12 years were more likely to have an earlier first relapse (p=0.030), despite showing no difference in time to immunosuppression compared with those aged 12-18 years at onset. At the cohort median disease duration of 79 months, 34.3% had developed permanent visual disability, 20.7% EDSS score 4 and 25.8% cognitive impairment. Visual disability was associated with white race (p=0.032) and optic neuritis presentations (p=0.002). Cognitive impairment was predicted by cerebral syndrome presentations (p=0.048), particularly if resistant to steroids (p=0.034). CONCLUSIONS: Age at onset, race, onset symptoms and resistance to acute therapy at onset attack predict first relapse and long-term disabilities. The recognition of these predictors may help to power future paediatric clinical trials and to direct early therapeutic decisions in AQP4-IgG NMOSD.

2022 - Epileptic phenotypes in autoimmune encephalitis: from acute symptomatic seizures to autoimmune-associated epilepsy [Articolo su rivista]
Matricardi, Sara; Casciato, Sara; Bozzetti, Silvia; Mariotto, Sara; Stabile, Andrea; Freri, Elena; Deleo, Francesco; Sartori, Stefano; Nosadini, Margherita; Pappalardo, Irene; Meletti, Stefano; Giovannini, Giada; Zucchi, Elisabetta; Di Bonaventura, Carlo; Di Gennaro, Giancarlo; Ferrari, Sergio; Zuliani, Luigi; Zoccarato, Marco; Vogrig, Alberto; Lattanzi, Simona; Michelucci, Roberto; Gambardella, Antonio; Ferlazzo, Edoardo; Fusco, Lucia; Granata, Tiziana; Villani, Flavio
abstract

Objective To describe the clinical and paraclinical findings, treatment options and long-term outcomes in autoimmune encephalitis (AE), with a close look to epilepsy. Methods In this retrospective observational cohort study, we enrolled patients with new-onset seizures in the context of AE. We compared clinical and paraclinical findings in patients with and without evidence of antibodies. Results Overall, 263 patients (138 females; median age 55 years, range 4-86) were followed up for a median time of 30 months (range 12-120). Antineuronal antibodies were detected in 63.50%. Antibody-positive patients had multiple seizure types (p=0.01) and prevalent involvement of temporal regions (p=0.02). A higher prevalence of episodes of SE was found in the antibody-negative group (p<0.001). Immunotherapy was prescribed in 88.60%, and effective in 61.80%. Independent predictors of favourable outcome of the AE were early immunotherapy (p<0.001) and the detection of antineuronal surface antibodies (p=0.01). Autoimmune-associated epilepsy was the long-term sequela in 43.73%, associated with cognitive and psychiatric disturbances in 81.73%. Independent predictors of developing epilepsy were difficult to treat seizures at onset (p=0.04), a high number of antiseizure medications (p<0.001), persisting interictal epileptiform discharges at follow-up (p<0.001) and poor response to immunotherapy during the acute phase (p<0.001). Conclusions The recognition of seizures secondary to AE represents a rare chance for aetiology-driven seizures management. Early recognition and treatment at the pathogenic level may reduce the risk of long-term irreversible sequelae. However, the severity of seizures at onset is the major risk factor for the development of chronic epilepsy. This study provides class IV evidence for management recommendations.

2022 - Evaluation of stroke prognostication using age and NIH Stroke Scale index (SPAN-100 index) in delayed intravenous thrombolysis patients (beyond 4.5 hours) [Articolo su rivista]
Elsaid, N.; Bigliardi, G.; Dell'Acqua, M. L.; Vandelli, L.; Ciolli, L.; Picchetto, L.; Borzi, G.; Ricceri, R.; Pentore, R.; Vallone, S.; Meletti, S.; Saied, A.
abstract

Objectives: the efficacy of delayed intravenous tissue plasminogen activator (tPA), beyond the 4.5 h window, is evolving. Advanced age and high admission National Institutes of Health Stroke Scale (NIHSS) score are proposed to adversely affect the outcome of delayed thrombolysis and limit the inclusion criteria. The summation of patient age and admission NIHSS score was introduced as the SPAN-100 index as a tool of prediction of the clinical outcome after acute ischemic stroke (AIS). We aimed to assess the SPAN-100 index in AIS thrombolysed patients after 4.5 h. Materials and Methods: The SPAN-100 index was applied to AIS patients receiving delayed IV thrombolysis (IVT) after 4.5 h. Patients demographics, risk factors, clinical, laboratory and radiological data, mismatch evidence, treatment onset and modality, NIHSS score at baseline and at discharge, and 3 months follow-up modified Rankin Scale (mRS) were reviewed. SPAN-100 score ≥ 100 is classified as SPAN-100 positive while score < 100 is SPAN-100 negative. Clinical outcomes, death and intracerebral hemorrhage (ICH) incidences were compared between SPAN-100 positive and negative groups. Results: SPAN-100-positive delayed IVT-patients (11/136) had a 6-fold increased risk for unfavorable outcome compared to SPAN-negative patients (OR 6.34; 95% CI 1.59–25.24 p=0.004), however there was no relation between the SPAN-100 positivity and mortality or ICH. Conclusion: SPAN-100-positive patients are more likely to achieve non-favorable outcome with delayed IVT in comparison to the SPAN-100-negative patients. SPAN-100 index may influence the eligibility criteria of delayed thrombolysis.

2022 - Event-based modelling in temporal lobe epilepsy demonstrates progressive atrophy from cross-sectional data [Articolo su rivista]
Lopez, Seymour M; Aksman, Leon M; Oxtoby, Neil P; Vos, Sjoerd B; Rao, Jun; Kaestner, Erik; Alhusaini, Saud; Alvim, Marina; Bender, Benjamin; Bernasconi, Andrea; Bernasconi, Neda; Bernhardt, Boris; Caciagli, Lorenzo; Caldairou, Benoit; Caligiuri, Maria Eugenia; Calvet, Angels; Cendes, Fernando; Concha, Luis; Conde-Blanco, Estefania; Davoodi-Bojd, Esmaeil; de Bézenac, Christophe; Delanty, Norman; Desmond, Patricia M; Devinsky, Orrin; Domin, Martin; Duncan, John S; Focke, Niels K; Foley, Sonya; Fortunato, Francesco; Galovic, Marian; Gambardella, Antonio; Gleichgerrcht, Ezequiel; Guerrini, Renzo; Hamandi, Khalid; Ives-Deliperi, Victoria; Jackson, Graeme D; Jahanshad, Neda; Keller, Simon S; Kochunov, Peter; Kotikalapudi, Raviteja; Kreilkamp, Barbara A K; Labate, Angelo; Larivière, Sara; Lenge, Matteo; Lui, Elaine; Malpas, Charles; Martin, Pascal; Mascalchi, Mario; Medland, Sarah E; Meletti, Stefano; Morita-Sherman, Marcia E; Owen, Thomas W; Richardson, Mark; Riva, Antonella; Rüber, Theodor; Sinclair, Ben; Soltanian-Zadeh, Hamid; Stein, Dan J; Striano, Pasquale; Taylor, Peter N; Thomopoulos, Sophia I; Thompson, Paul M; Tondelli, Manuela; Vaudano, Anna Elisabetta; Vivash, Lucy; Wang, Yujiang; Weber, Bernd; Whelan, Christopher D; Wiest, Roland; Winston, Gavin P; Yasuda, Clarissa Lin; Mcdonald, Carrie R; Alexander, Daniel C; Sisodiya, Sanjay M; Altmann, Andre
abstract

Objective: Recent work has shown that people with common epilepsies have characteristic patterns of cortical thinning, and that these changes may be progressive over time. Leveraging a large multi-centre cross-sectional cohort, we investigated whether regional morphometric changes occur in a sequential manner, and whether these changes in people with mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE-HS) correlate with clinical features. Methods: We extracted regional measures of cortical thickness, surface area and subcortical brain volumes from T1-weighted (T1W) MRI scans collected by the ENIGMA-Epilepsy consortium, comprising 804 people with MTLE-HS and 1,625 healthy controls from 25 centres. Features with a moderate case-control effect size (Cohen's d≥0.5) were used to train an Event-Based Model (EBM), which estimates a sequence of disease-specific biomarker changes from cross-sectional data and assigns a biomarker-based fine-grained disease stage to individual patients. We tested for associations between EBM disease stage and duration of epilepsy, age of onset and anti-seizure medicine (ASM) resistance. Results: In MTLE-HS, decrease in ipsilateral hippocampal volume along with increased asymmetry in hippocampal volume was followed by reduced thickness in neocortical regions, reduction in ipsilateral thalamus volume and, finally, increase in ipsilateral lateral ventricle volume. EBM stage was correlated to duration of illness (Spearman's ρ=0.293, p=7.03x10-16 ), age of onset (ρ=-0.18, p=9.82x10-7 ) and ASM resistance (AUC=0.59, p=0.043, Mann-Whitney U test). However, associations were driven by cases assigned to EBM stage zero, which represents MTLE-HS with mild or non-detectable abnormality on T1W MRI. Significance: From cross-sectional MRI, we reconstructed a disease progression model that highlights a sequence of MRI changes that aligns with previous longitudinal studies. This model could be used to stage MTLE-HS subjects in other cohorts and help establish connections between imaging-based progression staging and clinical features.

2022 - Expanding the spectrum of SOX1-antibodies in neuropathy: the coexistence of anti-SOX1 and Guillain-Barré syndrome—a case report [Articolo su rivista]
Coniglio, S.; Turchi, G.; Giovannini, G.; Mazzoli, M.; Meletti, S.; Vaudano, A. E.
abstract

Background and aims: Antibodies against SOX1 (or anti-glial nuclear antibody, AGNA) are partially characterized onconeural antibodies, firstly described in association with small cell lung cancer (SCLC). Lambert-Eaton myasthenic syndrome is the most frequent paraneoplastic syndrome (PNS) found in patients with anti-SOX1-antibody positivity. Other associations are chronic axonal polyneuropathy, paraneoplastic limbic encephalitis, and paraneoplastic cerebellar degeneration. Methods: We describe a case of Guillain-Barré syndrome (GBS) with classical demyelinating phenotype associated with a positivity for anti-SOX1-antibodies. Results: A therapy with intravenous immunoglobulin led to progressive clinical improvement. After 12 months, clinical and neurophysiological pictures showed complete recovery. A thorough paraneoplastic screening was negative for underlying tumors. Conclusions: This is the first case of GBS associated with anti-SOX1-antibodies described in literature. Although the concept of paraneoplastic GBS is controversial, different cases have been reported and GBS is considered a non-classical paraneoplastic syndrome. Our case expands the anti-SOX1-antibody clinical spectrum with relevant implications for the clinical practice.

2022 - Fibrinogen Depletion Coagulopathy Predicts Major Bleeding After Thrombolysis for Ischemic Stroke: A Multicenter Study [Articolo su rivista]
Romoli, Michele; Vandelli, Laura; Bigliardi, Guido; Naccarato, Marcello; Moller, Jessica; Balestrino, Maurizio; Giammello, Fabrizio; Gentile, Mauro; Dell'Acqua, Maria Luisa; Manganotti, Paolo; Forlivesi, Stefano; Melis, Maurizio; Picchetto, Livio; Rosafio, Francesca; Furlanis, Giovanni; Testoni, Stefania; Piras, Valeria; Malfatto, Laura; Musolino, Rosa Fortunata; Scali, Ilario; Maffei, Stefania; Migliaccio, Ludovica; Trenti, Tommaso; Mancini, Rita; Marietta, Marco; Randi, Vanda; Meletti, Stefano; Zini, Andrea
abstract

Symptomatic intracerebral hemorrhage (sICH) and major bleeding can be fatal complications of intravenous thrombolysis (IVT) for acute ischemic stroke. We investigated the impact of early fibrinogen depletion after IVT on major bleeding events.

2022 - Freezing of gait in Parkinson’s disease patients treated with bilateral subthalamic nucleus deep brain stimulation: A long-term overview [Articolo su rivista]
DI RAUSO, Giulia; Cavallieri, Francesco; Campanini, Isabella; Gessani, Annalisa; Fioravanti, Valentina; Feletti, Alberto; Damiano, Benedetta; Scaltriti, Sara; Bardi, Elisa; Corni, MARIA GIULIA; Antonelli, Francesca; Rispoli, Vittorio; Cavalleri, Francesca; Molinari, MARIA ANGELA; Contardi, Sara; Menozzi, Elisa; Puzzolante, Annette; Rossi, Jessica; Meletti, Stefano; Biagini, Giuseppe; Pavesi, Giacomo; Fraix, Valerie; Lusuardi, Mirco; Fraternali, Alessandro; Versari, Annibale; Budriesi, Carla; Moro, Elena; Merlo, Andrea; Valzania, Franco
abstract

Bilateral subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment in advanced Parkinson’s Disease (PD). However, the effects of STN-DBS on freezing of gait (FOG) are still debated, particularly in the long-term follow-up (>/=5-years). The main aim of the current study is to evaluate the long-term effects of STN-DBS on FOG. Twenty STN-DBS treated PD patients were included. Each patient was assessed before surgery through a detailed neurological evaluation, including FOG score, and reevaluated in the long-term (median follow-up: 5-years) in different stimulation and drug conditions. In the long term follow-up, FOG score significantly worsened in the off-stimulation/off-medication condition compared with the preoperative off-medication assessment (z = -1.930; p = 0.05) but not in the on-stimulation/off-medication (z = -0.357; p = 0.721). There was also a significant improvement of FOG at long-term assessment by comparing on-stimulation/off-medication and off-stimulation/off-medication conditions (z = -2.944; p = 0.003). These results highlight the possible beneficial long-term effects of STN-DBS on FOG.

2022 - Ictal apnea: A prospective monocentric study in patients with epilepsy [Articolo su rivista]
Micalizzi, E.; Vaudano, A. E.; Ballerini, A.; Talami, F.; Giovannini, G.; Turchi, G.; Cioclu, M. C.; Giunta, L.; Meletti, S.
abstract

Background and purpose: Ictal respiratory disturbances have increasingly been reported, in both generalized and focal seizures, especially involving the temporal lobe. Recognition of ictal breathing impairment has gained importance for the risk of sudden unexpected death in epilepsy (SUDEP). The aim of this study was to evaluate the incidence of ictal apnea (IA) and related hypoxemia during seizures. Methods: We collected and analyzed electroclinical data from consecutive patients undergoing long-term video-electroencephalographic (video-EEG) monitoring with cardiorespiratory polygraphy. Patients were recruited at the epilepsy monitoring unit of the Civil Hospital of Baggiovara, Modena Academic Hospital, from April 2020 to February 2022. Results: A total of 552 seizures were recorded in 63 patients. IA was observed in 57 of 552 (10.3%) seizures in 16 of 63 (25.4%) patients. Thirteen (81.2%) patients had focal seizures, and 11 of 16 patients showing IA had a diagnosis of temporal lobe epilepsy; two had a diagnosis of frontal lobe epilepsy and three of epileptic encephalopathy. Apnea agnosia was reported in all seizure types. Hypoxemia was observed in 25 of 57 (43.9%) seizures with IA, and the severity of hypoxemia was related to apnea duration. Apnea duration was significantly associated with epilepsy of unknown etiology (magnetic resonance imaging negative) and with older age at epilepsy onset (p < 0.001). Conclusions: Ictal respiratory changes are a frequent clinical phenomenon, more likely to occur in focal epilepsies, although detected even in patients with epileptic encephalopathy. Our findings emphasize the need for respiratory polygraphy during long-term video-EEG monitoring for diagnostic and prognostic purposes, as well as in relation to the potential link of ictal apnea with the SUDEP risk.

2022 - Identifying and predicting amyotrophic lateral sclerosis clinical subgroups: a population-based machine-learning study. [Articolo su rivista]
Faghri, Faraz; Brunn, Fabian; Dadu, Anant; Zucchi, Elisabetta; Martinelli, Ilaria; Mazzini, Letizia; Vasta, Rosario; Canosa, Antonio; Moglia, Cristina; Calvo, Andrea; A Nalls, Michael; H Campbell, Roy; Mandrioli, Jessica; Meletti, Stefano; J Traynor, Bryan; Chiò, Adriano
abstract

2022 - In-hospital and out-of-hospital stroke in patients with COVID-19: two different diseases? [Articolo su rivista]
Ciolli, L.; Righi, V.; Vandelli, G.; Giacobazzi, L.; Biagioli, N.; Marzullo, D.; Vandelli, L.; Rosafio, F.; Vinceti, G.; Maffei, S.; Picchetto, L.; Dell'Acqua, M. L.; Borzi, G. M.; Ricceri, R.; Bigliardi, G.; Meletti, S.
abstract

Background: Ischemic stroke is a known complication of COVID-19. It may have a different pathogenesis and worse outcome compared to stroke in patients without COVID-19. Furthermore, patients with COVID-19 and out-of-hospital stroke onset might have different characteristics compared to patients with COVID-19 and in-hospital stroke onset. The aim of our study was to analyze the characteristics of patients with stroke with and without COVID-19 and of patients with COVID-19 with in-hospital and out-of-hospital stroke. Methods: We performed a retrospective study of all consecutive patients admitted to our hospital with ischemic stroke between October 2020 and February 2021. We compared functional outcome, lab test, demographic, and clinical characteristics between patients with or without COVID-19. We performed a sub-analysis comparing patients with COVID-19 and in-hospital and out-of-hospital stroke onset. Results: We included in the final analysis 137 patients of whom 26 with COVID-19. Half (13) had out-of-hospital stroke and half in-hospital stroke onset. Overall, patients with COVID-19 had higher mortality compared to the control group (27% vs 9%, p: 0.02), and non-significantly lower rate of good functional outcome (50% vs 63%, p: 0.22). Patients with COVID-19 and out-of-hospital stroke had higher rate of good functional outcome (69% vs 39%, p: 0.05), higher lymphocyte count, and lower D-dimer compared with patients with in-hospital stroke onset. Conclusions: Patients with stroke and COVID-19 had higher mortality compared to patients without COVID-19. Among patients with COVID-19 those with out-of-hospital stroke had better outcome and fewer blood test abnormalities compared to patients with in-hospital stroke.

2022 - International consensus recommendations for management of new onset refractory status epilepticus (NORSE) including febrile infection-related epilepsy syndrome (FIRES): Summary and clinical tools [Articolo su rivista]
Wickstrom, R.; Taraschenko, O.; Dilena, R.; Payne, E. T.; Specchio, N.; Nabbout, R.; Koh, S.; Gaspard, N.; Hirsch, L. J.; Auvin, S.; van Baalen, A.; Beghi, E.; Benseler, S. M.; Bergin, P.; Bleck, T.; Brunklaus, A.; Caraballo, R. H.; Cervenka, M.; Costello, D.; Drislane, F.; Farias-Moeller, R.; Gallantine, W.; Gilmore, E. J.; Gofton, T.; Jimenez, M. A. P.; Hocker, S.; Kaliakatsos, M.; Kellogg, M.; Lee, J. W.; Loddenkemper, T.; Meletti, S.; Mizugushi, M.; Muscal, E.; Riviello, J. J.; Rosenthal, E. S.; Rossetti, A. O.; Ruegg, S.; Said, R.; Sculier, C.; Schmitt, S.; Schuele, S.; Stredny, C.; Trinka, E.; Wainwright, M.; Vanhaerents, S.; Wells, E.; Wirrell, E.; Zuberi, S. M.
abstract

Objective: To develop consensus-based recommendations for the management of adult and pediatric patients with new-onset refractory status epilepticus (NORSE)/febrile infection-related epilepsy syndrome (FIRES) based on best available evidence and expert opinion. Methods: The Delphi methodology was followed. A facilitator group of nine experts was established who defined the scope, users, and suggestions for recommendations. Following a review of the current literature, recommendation statements concerning diagnosis, treatment, and research directions were generated that were then voted on using a scale of 1 (strongly disagree) to 9 (strongly agree) by a panel of 48 experts in the field. Consensus that a statement was appropriate was reached if the median score was greater than or equal to 7, and inappropriate if the median score was less than or equal to 3. Results: Overall, 85 recommendation statements achieved consensus. The recommendations are divided into five sections: (1) disease characteristics; (2) diagnostic testing and sampling; (3) acute treatment; (4) treatment in the post-acute phase; and (5) research, registries, and future directions in NORSE/FIRES. These are summarized in this article along with two practical clinical flowsheets: one for diagnosis and evaluation and one for acute treatment. A corresponding evidence-based analysis of all 85 recommendations alongside responses by the Delphi panel is presented in a companion article. Significance: The recommendations generated by this consensus can be used as a guide for the diagnosis; evaluation; and management of patients with NORSE/FIRES; and for planning of future research.

2022 - International consensus recommendations for management of new onset refractory status epilepticus including febrile infection-related epilepsy syndrome: Statements and supporting evidence [Articolo su rivista]
Wickstrom, R.; Taraschenko, O.; Dilena, R.; Payne, E. T.; Specchio, N.; Nabbout, R.; Koh, S.; Gaspard, N.; Hirsch, L. J.; Auvin, S.; van Baalen, A.; Beghi, E.; Benseler, S. M.; Bergin, P.; Bleck, T.; Brunklaus, A.; Caraballo, R. H.; Cervenka, M.; Costello, D.; Drislane, F.; Farias-Moeller, R.; Gallantine, W.; Gilmore, E.; Gofton, T.; Jimenez, M. A. P.; Hocker, S.; Kaliakatsos, M.; Kellogg, M.; Lee, J. W.; Loddenkemper, T.; Meletti, S.; Mizugushi, M.; Muscal, E.; Riviello, J. J.; Rosenthal, E. S.; Rossetti, A. O.; Ruegg, S.; Said, R.; Sculier, C.; Schmitt, S.; Schuele, S.; Stredny, C.; Trinka, E.; Wainwright, M.; Vanhaerents, S.; Wells, E.; Wirrell, E.; Zuberi, S. M.
abstract

Objective: This study was undertaken to develop consensus-based recommendations for the management of adult and pediatric patients with new onset refractory status epilepticus (NORSE)/febrile infection-related epilepsy syndrome (FIRES) based on best evidence and experience. Methods: The Delphi methodology was followed. A facilitator group of nine experts was established, who defined the scope, users, and suggestions for recommendations. Following a review of the current literature, recommendation statements concerning diagnosis, treatment, and research directions were generated, which were then rated on a scale of 1 (strongly disagree) to 9 (strongly agree) by a panel of 48 experts in the field. Consensus that a statement was appropriate was reached if the median score was ≥7 and inappropriate if the median score was ≤3. The analysis of evidence was mapped to the results of each statement included in the Delphi survey. Results: Overall, 85 recommendation statements achieved consensus. The recommendations are divided into five sections: (1) disease characteristics; (2) diagnostic testing and sampling; (3) acute treatment; (4) treatment in the postacute phase; and (5) research, registries, and future directions in NORSE/FIRES. The detailed results and discussion of all 85 statements are outlined herein. A corresponding summary of findings and practical flowsheets are presented in a companion article. Significance: This detailed analysis offers insight into the supporting evidence and the current gaps in the literature that are associated with expert consensus statements related to NORSE/FIRES. The recommendations generated by this consensus can be used as a guide for the diagnosis, evaluation, and management of patients with NORSE/FIRES, and for planning of future research.

2022 - Lacosamide in monotherapy in BTRE (brain tumor-related epilepsy): results from an Italian multicenter retrospective study [Articolo su rivista]
Mo, F.; Meletti, S.; Belcastro, V.; Quadri, S.; Napolitano, M.; Bello, L.; Dainese, F.; Scarpelli, M.; Florindo, I.; Mascia, A.; Pauletto, G.; Bruno, F.; Pellerino, A.; Giovannini, G.; Polosa, M.; Sessa, M.; Conti Nibali, M.; Di Gennaro, G.; Gigli, G. L.; Pisanello, A.; Cavallieri, F.; Ruda, R.
abstract

Purpose: Lacosamide (LCM) is a third-generation anti-seizure medication (ASM) approved for focal onset epilepsy in patients aged ≥ 4.378 Previous studies have reported an efficacy of LCM as add-on treatment in brain tumor-related epilepsy (BTRE). To date, there are no studies in the literature focusing on lacosamide used in monotherapy to treat BTRE. In our retrospective study we investigated efficacy and tolerability of LCM in monotherapy in a multicenter national cohort of primary brain tumor patients. Methods: We collected from 12 Italian Centers 132 patients with primary brain tumors who were treated with LCM in monotherapy. For each patient we evaluated seizure freedom at 3 and 6 months (primary endpoints), side effects and drop-out rate (secondary endpoints). Results: Overall, LCM led to seizure freedom in 64.4% of patients at 3 months and 55% at 6 months. Patients who used two or more ASMs before LCM had a worse seizure control than patients in monotherapy with LCM as first choice. In 14 patients, we observed seizure control despite tumor progression on magnetic resonance (MRI). Multivariate analysis showed that gross-total resection at diagnosis was significantly associated with higher seizure freedom rate at 6 months. Side effects were mainly mild (grade 1–2 according to CTCAE classification) and drop-out rate was low (1.5%). Main side effects were dizziness and somnolence. Conclusions: This is the first study showing a good efficacy and tolerability of LCM when used in monotherapy in BTRE. Further prospective studies are needed to confirm these preliminary data, investigating also quality of life and neurocognitive functions.

2022 - Machine-learning validation through decision-tree analysis of the Epidemiology-based Mortality Score in Status Epilepticus [Articolo su rivista]
Brigo, Francesco; Turcato, Gianni; Lattanzi, Simona; Orlandi, Niccolò; Turchi, Giulia; Zaboli, Arian; Giovannini, Giada; Meletti, Stefano
abstract

To validate the accuracy of the Epidemiology-based Mortality Score in Status Epilepticus (EMSE) in predicting the risk of death at 30 days in a large cohort of patients with status epilepticus (SE) using a machine-learning system.

2022 - Needs and Perceptions of Patients With Dystonia During the COVID-19 Pandemic: A Qualitative Framework Analysis of Survey Responses From Italy [Articolo su rivista]
Rispoli, Vittorio; Díaz Crescitelli, Matías Eduardo; Cavallieri, Francesco; Antonelli, Francesca; Meletti, Stefano; Ghirotto, Luca; Valzania, Franco
abstract

Introduction:The COVID-19 pandemic and its countermeasures have created changes in both life and healthcare. With the prioritization of COVID-19-related management, the risks and experiences of patients suffering from rare conditions, such as dystonia, during the pandemic remain understudied. Materials and MethodsUsing a framework analysis of a nationwide qualitative online survey, we sought to explore the perspectives of patients with dystonia on their clinical assistance and possible unmet needs during the first pandemic wave. An online survey consisting of 37 items (such as demographic characteristics, dystonia-related features, neurological service provision, therapeutic relationship with the neurologist, perceptions related to virus infection, perceptions about healthcare-related needs, work-related questions, requesting information, and seeking support during the pandemic) was carried out using both close and open-ended questions. ResultsResponses from 62 participants were collected, with most of them from the red zones in Italy, where they were confined indoors. Social isolation was a relevant stressor. Motor and non-motor symptoms increased with detrimental consequences for patients' job and daily functionality. Outpatient clinics and rehabilitation sessions were temporarily shut down, and even telephone/mail support was sparse. Despite efforts, patients felt alone in dealing with dystonia. ConclusionThe first wave of the pandemic and its related restrictions had detrimental consequences for people living with dystonia, and their relevant needs remained unmet. These findings may contribute to implementing remedial healthcare provisions in this pandemic or in future pandemics.

2022 - Neutrophil-to-Lymphocyte Ratio Predicts Early Neurological Deterioration after Endovascular Treatment in Patients with Ischemic Stroke [Articolo su rivista]
Lattanzi, Simona; Norata, Davide; Broggi, Serena; Meletti, Stefano; Świtońska, Milena; Słomka, Artur; Silvestrini, Mauro
abstract

The worsening of neurological status that occurs early after acute ischemic stroke (AIS) remains a serious issue, and the inflammatory response plays a key role in stroke pathobiology. Recently, endovascular treatment (EVT) has revolutionized the management and outcome of patients with AIS due to either extracranial carotid disease or intracranial disease. The neutrophil-to-lymphocyte ratio (NLR) represents an easily available inflammatory biomarker. The aim of the study was to assess the relationship between the NLR at admission and the occurrence of early neurological deterioration (END) in patients with AIS who underwent EVT. Patients with AIS and proximal arterial occlusion in the anterior circulation undergoing EVT were retrospectively identified. Absolute neutrophil count (ANC) and absolute lymphocyte count (ALC) were collected from admission blood work to calculate the NLR. The study outcome was END defined as an increase in at least 4 points in NIHSS score or death between baseline and 24 h after the ischemic event. Patients included were 211, and END occurred in 30 (14.2%). Patients with older age (OR = 1.07, 95% CI: 1.02-1.13), higher serum glucose (OR = 1.01, 95% CI: 1.01-1.02), and higher NLR (OR = 1.011, 95% CI: 1.04-1.18) had an increased risk of END. The best predictive cut-off value of NLR was 6.4, and END occurred in 24.1% and 3.9% of the patients with NLR >= 6.4 and <6.4, respectively (p < 0.001). In patients with AIS undergoing EVT, higher NLR values predicted a higher risk of END. Biomarkers able to identify inflammatory mechanisms might identify novel treatment targets and enhance proof-of-concept trials of immunomodulation in stroke.

2022 - Out-of-hospital versus in-hospital status epilepticus: the role of etiology and comorbidities [Articolo su rivista]
Brigo, Francesco; Turcato, Gianni; Lattanzi, Simona; Orlandi, Niccolò; Turchi, Giulia; Zaboli, Arian; Giovannini, Giada; Meletti, Stefano
abstract

Background: To identify differences in clinical characteristics between patients with out-of-hospital and in-hospital status epilepticus (SE) onset, and to evaluate the influence of SE onset setting on 30-day mortality and SE cessation. Methods: We included consecutive patients with SE admitted from 2013 to 2021 at Modena Academic Hospital. A propensity score was performed with clinical variables unevenly distributed between the two groups. Results: 711 patients were included; 55.8% (397/711) with an out-of-hospital and 44.2% (314/711) with an in-hospital onset. Patients with in-hospital SE onset were older, had a higher frequency of comorbidities, acute and/or potentially fatal etiologies, impaired consciousness before treatment, and nonconvulsive or myoclonic SE. No difference was found in SE cessation between the groups. Patients with in-hospital SE had higher 30-day mortality (127/314, 62.9% versus 75/397, 37.1; p <0.001). In-hospital onset was an independent risk factor for 30-day mortality (adjusted OR of 1.720; 95% CI: 1.107-2.674; p = 0.016). In the propensity group (n = 244), no difference was found in 30-day mortality and SE cessation between out-of-hospital and in-hospital SE onset groups (36/122, 29.5% versus 34/122, 27.9%; p=0.888; and 47/122, 38.5% versus 39/122; 32%; p = 0.347, respectively). Conclusion: In-hospital SE is associated with higher 30-day mortality without difference in SE cessation. The two groups differ considerably for age, acute and possibly fatal etiologies, comorbidities, and SE semiology. The patient location at SE onset is an important prognostic predictor. However, the increased mortality is probably unrelated to the setting of SE onset and reflects intrinsic prognostic predictors.

2022 - Predicting functional impairment trajectories in amyotrophic lateral sclerosis: a probabilistic, multifactorial model of disease progression [Articolo su rivista]
Tavazzi, Erica; Daberdaku, Sebastian; Zandonà, Alessandro; Vasta, Rosario; Nefussy, Beatrice; Lunetta, Christian; Mora, Gabriele; Mandrioli, Jessica; Grisan, Enrico; Meletti, Stefano; Tarlarini, Claudia; Calvo, Andrea; Moglia, Cristina; Drory, Vivian; Gotkine, Marc; Chiò, Adriano; Di Camillo, Barbara
abstract

Objective: To employ Artificial Intelligence to model, predict and simulate the amyotrophic lateral sclerosis (ALS) progression over time in terms of variable interactions, functional impairments, and survival. Methods: We employed demographic and clinical variables, including functional scores and the utilisation of support interventions, of 3940 ALS patients from four Italian and two Israeli registers to develop a new approach based on Dynamic Bayesian Networks (DBNs) that models the ALS evolution over time, in two distinct scenarios of variable availability. The method allows to simulate patients' disease trajectories and predict the probability of functional impairment and survival at different time points. Results: DBNs explicitly represent the relationships between the variables and the pathways along which they influence the disease progression. Several notable inter-dependencies were identified and validated by comparison with literature. Moreover, the implemented tool allows the assessment of the effect of different markers on the disease course, reproducing the probabilistically expected clinical progressions. The tool shows high concordance in terms of predicted and real prognosis, assessed as time to functional impairments and survival (integral of the AU-ROC in the first 36 months between 0.80-0.93 and 0.84-0.89 for the two scenarios, respectively). Conclusions: Provided only with measurements commonly collected during the first visit, our models can predict time to the loss of independence in walking, breathing, swallowing, communicating, and survival and it can be used to generate in silico patient cohorts with specific characteristics. Our tool provides a comprehensive framework to support physicians in treatment planning and clinical decision-making.

2022 - Predicting the progression to super-refractory status epilepticus: A machine-learning study [Articolo su rivista]
Brigo, Francesco; Turcato, Gianni; Lattanzi, Simona; Orlandi, Niccolò; Turchi, Giulia; Zaboli, Arian; Giovannini, Giada; Meletti, Stefano
abstract

Aim: Super-refractory status epilepticus (SRSE) is a status epilepticus (SE) that continues or recurs >= 24 h after the onset of anesthesia. We aimed to identify the predictors of progression to SRSE and the risk of 30-day mortality in patients with SRSE by using a machine learning technique.Methods: We reviewed consecutive SE episodes in patients aged >= 14 years at Baggiovara Civil Hospital (Modena, Italy) from 2013 to 2021. A classification and regression tree analysis was performed to develop a predictive model of progression to SRSE in SE patients. In SRSE patients, a multivariate analysis was conducted to identify predictors of 30-day mortality.Results: We included 705 patients, 16% of whom (113/705) progressed to SRSE. Acute symptomatic hypoxic etiology and age <= 68.5 years predicted the highest risk (87.1%) of progression to SRSE. Etiology other than acute symptomatic hypoxic and absence of NCSE predicted the lowest risk (3.6%) of progression to SRSE. The predictive model was accurate in 96.1% of patients not evolving to SRSE and in 48.7% of those evolving to SRSE. Among patients with SRSE, 46.9% (53/113) died within 30 days compared to 25.2% (149/592) of patients without SRSE (p < 0.001). Among patients with SRSE, older age was associated with increased 30-day mortality (odds ratio 1.075; 95% confidence interval: 1.031-1.112; p = 0.001).Conclusions: Acute symptomatic hypoxic etiology and younger age are major predictors of progression to SRSE. In patients with SRSE, older age is associated with increased risk of short-term mortality.

2022 - Recurrent status epilepticus: Clinical features and recurrence risk in an adult population [Articolo su rivista]
Orlandi, N.; Gozzi, A.; Giovannini, G.; Turchi, G.; Cioclu, M. C.; Vaudano, A. E.; Meletti, S.
abstract

Background: Knowledge regarding consequences among status epilepticus (SE) survivors is still scarce. We assessed the risk of recurrence in a cohort of first-ever adult SE survivors, comparing the clinical features of patients with recurrent and incident events. Methods: We reviewed our prospective register of consecutive SE patients, from September 1st 2013 to September 1st 2020. We excluded post-anoxic events and those patients with a SE prior the study period. We examined the effect of clinical predictors on the risk of subsequent SE through Cox proportional hazard regression, while the risk of recurrence was estimated through a survival analysis. Results: 430 patients were considered (mean follow-up: 23.3 months). 44 patients experienced SE recurrence, whereas 386 patients presented an isolated event. The highest risk of recurrence was observed within 6 months from the index event (7.9%), whereas the cumulative recurrence rate was 9.5%, 13%, and 20.5% at 6 months, 1 year, and 4-years respectively. SE recurrence was independently associated to remote (HR 2.8 - 95% CI 1.4 to 6.0) or progressive symptomatic etiologies (HR 3.9 - 95% CI 1.8 to 8.7) and it was higher for Super-Refractory SE (SRSE) cases (HR 3.3 - 95% CI 1.4 to 7.8). High STESS values (p = 0.01) and SE refractoriness (p = 0.01) were associated with early relapses (within 6 months from the index event). Conclusions: SE recurrence involved a significantly proportion of our cohort. Etiology other than acute symptomatic and SRSE were independently associated with a higher risk of recurrence, in particular within 6 months from the index event.

2022 - Structural network alterations in focal and generalized epilepsy assessed in a worldwide ENIGMA study follow axes of epilepsy risk gene expression [Articolo su rivista]
Larivière, Sara; Royer, Jessica; Rodríguez-Cruces, Raúl; Paquola, Casey; Caligiuri, Maria Eugenia; Gambardella, Antonio; Concha, Luis; Keller, Simon S; Cendes, Fernando; Yasuda, Clarissa L; Bonilha, Leonardo; Gleichgerrcht, Ezequiel; Focke, Niels K; Domin, Martin; von Podewills, Felix; Langner, Soenke; Rummel, Christian; Wiest, Roland; Martin, Pascal; Kotikalapudi, Raviteja; O'Brien, Terence J; Sinclair, Benjamin; Vivash, Lucy; Desmond, Patricia M; Lui, Elaine; Vaudano, Anna Elisabetta; Meletti, Stefano; Tondelli, Manuela; Alhusaini, Saud; Doherty, Colin P; Cavalleri, Gianpiero L; Delanty, Norman; Kälviäinen, Reetta; Jackson, Graeme D; Kowalczyk, Magdalena; Mascalchi, Mario; Semmelroch, Mira; Thomas, Rhys H; Soltanian-Zadeh, Hamid; Davoodi-Bojd, Esmaeil; Zhang, Junsong; Winston, Gavin P; Griffin, Aoife; Singh, Aditi; Tiwari, Vijay K; Kreilkamp, Barbara A K; Lenge, Matteo; Guerrini, Renzo; Hamandi, Khalid; Foley, Sonya; Rüber, Theodor; Weber, Bernd; Depondt, Chantal; Absil, Julie; Carr, Sarah J A; Abela, Eugenio; Richardson, Mark P; Devinsky, Orrin; Severino, Mariasavina; Striano, Pasquale; Tortora, Domenico; Kaestner, Erik; Hatton, Sean N; Vos, Sjoerd B; Caciagli, Lorenzo; Duncan, John S; Whelan, Christopher D; Thompson, Paul M; Sisodiya, Sanjay M; Bernasconi, Andrea; Labate, Angelo; Mcdonald, Carrie R; Bernasconi, Neda; Bernhardt, Boris C
abstract

Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but associations between neurobiological mechanisms and macroscale connectomics remain unclear. This multisite ENIGMA-Epilepsy study examined whole-brain structural covariance networks in patients with epilepsy and related findings to postmortem epilepsy risk gene expression patterns. Brain network analysis included 578 adults with temporal lobe epilepsy (TLE), 288 adults with idiopathic generalized epilepsy (IGE), and 1328 healthy controls from 18 centres worldwide. Graph theoretical analysis of structural covariance networks revealed increased clustering and path length in orbitofrontal and temporal regions in TLE, suggesting a shift towards network regularization. Conversely, people with IGE showed decreased clustering and path length in fronto-temporo-parietal cortices, indicating a random network configuration. Syndrome-specific topological alterations reflected expression patterns of risk genes for hippocampal sclerosis in TLE and for generalized epilepsy in IGE. These imaging-transcriptomic signatures could potentially guide diagnosis or tailor therapeutic approaches to specific epilepsy syndromes.

2022 - Sustained seizure freedom with adjunctive brivaracetam in patients with focal onset seizures [Articolo su rivista]
Lattanzi, S.; Ascoli, M.; Canafoglia, L.; Paola Canevini, M.; Casciato, S.; Cerulli Irelli, E.; Chiesa, V.; Dainese, F.; De Maria, G.; Didato, G.; Di Gennaro, G.; Falcicchio, G.; Fanella, M.; Gangitano, M.; La Neve, A.; Mecarelli, O.; Montalenti, E.; Morano, A.; Piazza, F.; Pizzanelli, C.; Pulitano, P.; Ranzato, F.; Rosati, E.; Tassi, L.; Di Bonaventura, C.; Alicino, A.; Assenza, G.; Avorio, F.; Badioni, V.; Banfi, P.; Bartolini, E.; Basili, L. M.; Belcastro, V.; Beretta, S.; Berto, I.; Biggi, M.; Billo, G.; Boero, G.; Bonanni, P.; Bongiorno, J.; Brigo, F.; Caggia, E.; Cagnetti, C.; Calvello, C.; Cesnik, E.; Chianale, G.; Ciampanelli, D.; Ciuffini, R.; Cocito, D.; Colella, D.; Contento, M.; Costa, C.; Cumbo, E.; D'Aniello, A.; Deleo, F.; Difrancesco, J. C.; Di Giacomo, R.; Di Liberto, A.; Domina, E.; Donato, F.; Dono, F.; Durante, V.; Elia, M.; Estraneo, A.; Evangelista, G.; Faedda, M. T.; Failli, Y.; Fallica, E.; Fattouch, J.; Ferrari, A.; Ferreri, F.; Fisco, G.; Fonti, D.; Fortunato, F.; Foschi, N.; Francavilla, T.; Galli, R.; Gasparini, S.; Gazzina, S.; Giallonardo, A. T.; Giorgi, F. S.; Giuliano, L.; Habetswallner, F.; Izzi, F.; Kassabian, B.; Kiferle, L.; Labate, A.; Luisi, C.; Magliani, M.; Maira, G.; Mari, L.; Marino, D.; Mascia, A.; Mazzeo, A.; Meletti, S.; Milano, C.; Nilo, A.; Orlando, B.; Paladin, F.; Pascarella, M. G.; Pastori, C.; Pauletto, G.; Peretti, A.; Perri, G.; Pezzella, M.; Piccioli, M.; Pignatta, P.; Pilolli, N.; Pisani, F.; Pisani, L. R.; Placidi, F.; Pollicino, P.; Porcella, V.; Puligheddu, M.; Quadri, S.; Quarato, P. P.; Quintas, R.; Renna, R.; Rum, A.; Salamone, E. M.; Savastano, E.; Sessa, M.; Stokelj, D.; Tartara, E.; Tombini, M.; Tumminelli, G.; Vaudano, A. E.; Ventura, M.; Vigano, I.; Viglietta, E.; Vignoli, A.; Villani, F.; Zambrelli, E.; Zummo, L.
abstract

The maintenance of seizure control over time is a clinical priority in patients with epilepsy. The aim of this study was to assess the sustained seizure frequency reduction with adjunctive brivaracetam (BRV) in real-world practice. Patients with focal epilepsy prescribed add-on BRV were identified. Study outcomes included sustained seizure freedom and sustained seizure response, defined as a 100% and a ≥50% reduction in baseline seizure frequency that continued without interruption and without BRV withdrawal through the 12-month follow-up. Nine hundred ninety-four patients with a median age of 45 (interquartile range = 32–56) years were included. During the 1-year study period, sustained seizure freedom was achieved by 142 (14.3%) patients, of whom 72 (50.7%) were seizure-free from Day 1 of BRV treatment. Sustained seizure freedom was maintained for ≥6, ≥9, and 12 months by 14.3%, 11.9%, and 7.2% of patients from the study cohort. Sustained seizure response was reached by 383 (38.5%) patients; 236 of 383 (61.6%) achieved sustained ≥50% reduction in seizure frequency by Day 1, 94 of 383 (24.5%) by Month 4, and 53 of 383 (13.8%) by Month 7 up to Month 12. Adjunctive BRV was associated with sustained seizure frequency reduction from the first day of treatment in a subset of patients with uncontrolled focal epilepsy.

2022 - The ENIGMA-Epilepsy working group: Mapping disease from large data sets [Articolo su rivista]
Sisodiya, S. M.; Whelan, C. D.; Hatton, S. N.; Huynh, K.; Altmann, A.; Ryten, M.; Vezzani, A.; Caligiuri, M. E.; Labate, A.; Gambardella, A.; Ives-Deliperi, V.; Meletti, S.; Munsell, B. C.; Bonilha, L.; Tondelli, M.; Rebsamen, M.; Rummel, C.; Vaudano, A. E.; Wiest, R.; Balachandra, A. R.; Bargallo, N.; Bartolini, E.; Bernasconi, A.; Bernasconi, N.; Bernhardt, B.; Caldairou, B.; Carr, S. J. A.; Cavalleri, G. L.; Cendes, F.; Concha, L.; Desmond, P. M.; Domin, M.; Duncan, J. S.; Focke, N. K.; Guerrini, R.; Hamandi, K.; Jackson, G. D.; Jahanshad, N.; Kalviainen, R.; Keller, S. S.; Kochunov, P.; Kowalczyk, M. A.; Kreilkamp, B. A. K.; Kwan, P.; Lariviere, S.; Lenge, M.; Lopez, S. M.; Martin, P.; Mascalchi, M.; Moreira, J. C. V.; Morita-Sherman, M. E.; Pardoe, H. R.; Pariente, J. C.; Raviteja, K.; Rocha, C. S.; Rodriguez-Cruces, R.; Seeck, M.; Semmelroch, M. K. H. G.; Sinclair, B.; Soltanian-Zadeh, H.; Stein, D. J.; Striano, P.; Taylor, P. N.; Thomas, R. H.; Thomopoulos, S. I.; Velakoulis, D.; Vivash, L.; Weber, B.; Yasuda, C. L.; Zhang, J.; Thompson, P. M.; Mcdonald, C. R.
abstract

Epilepsy is a common and serious neurological disorder, with many different constituent conditions characterized by their electro clinical, imaging, and genetic features. MRI has been fundamental in advancing our understanding of brain processes in the epilepsies. Smaller-scale studies have identified many interesting imaging phenomena, with implications both for understanding pathophysiology and improving clinical care. Through the infrastructure and concepts now well-established by the ENIGMA Consortium, ENIGMA-Epilepsy was established to strengthen epilepsy neuroscience by greatly increasing sample sizes, leveraging ideas and methods established in other ENIGMA projects, and generating a body of collaborating scientists and clinicians to drive forward robust research. Here we review published, current, and future projects, that include structural MRI, diffusion tensor imaging (DTI), and resting state functional MRI (rsfMRI), and that employ advanced methods including structural covariance, and event-based modeling analysis. We explore age of onset- and duration-related features, as well as phenomena-specific work focusing on particular epilepsy syndromes or phenotypes, multimodal analyses focused on understanding the biology of disease progression, and deep learning approaches. We encourage groups who may be interested in participating to make contact to further grow and develop ENIGMA-Epilepsy.

2022 - Topographic divergence of atypical cortical asymmetry and atrophy patterns in temporal lobe epilepsy [Articolo su rivista]
Park, Bo-yong; Larivière, Sara; Rodríguez-Cruces, Raul; Royer, Jessica; Tavakol, Shahin; Wang, Yezhou; Caciagli, Lorenzo; Caligiuri, Maria Eugenia; Gambardella, Antonio; Concha, Luis; Keller, Simon S; Cendes, Fernando; Alvim, Marina K M; Yasuda, Clarissa; Bonilha, Leonardo; Gleichgerrcht, Ezequiel; Focke, Niels K; Kreilkamp, Barbara A K; Domin, Martin; von Podewils, Felix; Langner, Soenke; Rummel, Christian; Rebsamen, Michael; Wiest, Roland; Martin, Pascal; Kotikalapudi, Raviteja; Bender, Benjamin; O’Brien, Terence J; Law, Meng; Sinclair, Benjamin; Vivash, Lucy; Kwan, Patrick; Desmond, Patricia M; Malpas, Charles B; Lui, Elaine; Alhusaini, Saud; Doherty, Colin P; Cavalleri, Gianpiero L; Delanty, Norman; Kälviäinen, Reetta; Jackson, Graeme D; Kowalczyk, Magdalena; Mascalchi, Mario; Semmelroch, Mira; Thomas, Rhys H; Soltanian-Zadeh, Hamid; Davoodi-Bojd, Esmaeil; Zhang, Junsong; Lenge, Matteo; Guerrini, Renzo; Bartolini, Emanuele; Hamandi, Khalid; Foley, Sonya; Weber, Bernd; Depondt, Chantal; Absil, Julie; Carr, Sarah J A; Abela, Eugenio; Richardson, Mark P; Devinsky, Orrin; Severino, Mariasavina; Striano, Pasquale; Parodi, Costanza; Tortora, Domenico; Hatton, Sean N; Vos, Sjoerd B; Duncan, John S; Galovic, Marian; Whelan, Christopher D; Bargalló, Núria; Pariente, Jose; Conde-Blanco, Estefania; Vaudano, Anna Elisabetta; Tondelli, Manuela; Meletti, Stefano; Kong, Xiang-Zhen; Francks, Clyde; Fisher, Simon E; Caldairou, Benoit; Ryten, Mina; Labate, Angelo; Sisodiya, Sanjay M; Thompson, Paul M; Mcdonald, Carrie R; Bernasconi, Andrea; Bernasconi, Neda; Bernhardt, Boris C
abstract

2022 - Traduzione e adattamento alla lingua italiana del glossario dei termini più comunemente usati dagli elettroencefalografisti clinici e proposta per il formato del referto EEG (Revisione IFCN 2017) [Articolo su rivista]
Strigaro, Gionata; Bisulli, Francesca; Assenza, Giovanni; Mecarelli, Oriano; Grippo, Antonello; Meletti, Stefano
abstract

2021 - A systems-level analysis highlights microglial activation as a modifying factor in common epilepsies [Articolo su rivista]
Altmann, A.; Ryten, M.; Di Nunzio, M.; Ravizza, T.; Tolomeo, D.; Reynolds, R. H.; Somani, A.; Bacigaluppi, M.; Iori, V.; Micotti, E.; Di Sapia, R.; Cerovic, M.; Palma, E.; Ruffolo, G.; Botia, J. A.; Absil, J.; Alhusaini, S.; Alvim, M. K. M.; Auvinen, P.; Bargallo, N.; Bartolini, E.; Bender, B.; Bergo, F. P. G.; Bernardes, T.; Bernasconi, A.; Bernasconi, N.; Bernhardt, B. C.; Blackmon, K.; Braga, B.; Caligiuri, M. E.; Calvo, A.; Carlson, C.; Carr, S. J. A.; Cavalleri, G. L.; Cendes, F.; Chen, J.; Chen, S.; Cherubini, A.; Concha, L.; David, P.; Delanty, N.; Depondt, C.; Devinsky, O.; Doherty, C. P.; Domin, M.; Focke, N. K.; Foley, S.; Franca, W.; Gambardella, A.; Guerrini, R.; Hamandi, K.; Hibar, D. P.; Isaev, D.; Jackson, G. D.; Jahanshad, N.; Kalviainen, R.; Keller, S. S.; Kochunov, P.; Kotikalapudi, R.; Kowalczyk, M. A.; Kuzniecky, R.; Kwan, P.; Labate, A.; Langner, S.; Lenge, M.; Liu, M.; Martin, P.; Mascalchi, M.; Meletti, S.; Morita-Sherman, M. E.; O'Brien, T. J.; Pariente, J. C.; Richardson, M. P.; Rodriguez-Cruces, R.; Rummel, C.; Saavalainen, T.; Semmelroch, M. K.; Severino, M.; Striano, P.; Thesen, T.; Thomas, R. H.; Tondelli, M.; Tortora, D.; Vaudano, A. E.; Vivash, L.; von Podewils, F.; Wagner, J.; Weber, B.; Wiest, R.; Yasuda, C. L.; Zhang, G.; Zhang, J.; Leu, C.; Avbersek, A.; Thom, M.; Whelan, C. D.; Thompson, P.; Mcdonald, C. R.; Vezzani, A.; Sisodiya, S. M.
abstract

Aims: The causes of distinct patterns of reduced cortical thickness in the common human epilepsies, detectable on neuroimaging and with important clinical consequences, are unknown. We investigated the underlying mechanisms of cortical thinning using a systems-level analysis. Methods: Imaging-based cortical structural maps from a large-scale epilepsy neuroimaging study were overlaid with highly spatially resolved human brain gene expression data from the Allen Human Brain Atlas. Cell-type deconvolution, differential expression analysis and cell-type enrichment analyses were used to identify differences in cell-type distribution. These differences were followed up in post-mortem brain tissue from humans with epilepsy using Iba1 immunolabelling. Furthermore, to investigate a causal effect in cortical thinning, cell-type-specific depletion was used in a murine model of acquired epilepsy. Results: We identified elevated fractions of microglia and endothelial cells in regions of reduced cortical thickness. Differentially expressed genes showed enrichment for microglial markers and, in particular, activated microglial states. Analysis of post-mortem brain tissue from humans with epilepsy confirmed excess activated microglia. In the murine model, transient depletion of activated microglia during the early phase of the disease development prevented cortical thinning and neuronal cell loss in the temporal cortex. Although the development of chronic seizures was unaffected, the epileptic mice with early depletion of activated microglia did not develop deficits in a non-spatial memory test seen in epileptic mice not depleted of microglia. Conclusions: These convergent data strongly implicate activated microglia in cortical thinning, representing a new dimension for concern and disease modification in the epilepsies, potentially distinct from seizure control.

2021 - Adjunctive Brivaracetam in Focal Epilepsy: Real-World Evidence from the BRIVAracetam add-on First Italian netwoRk STudy (BRIVAFIRST) [Articolo su rivista]
Lattanzi, S.; Canafoglia, L.; Canevini, M. P.; Casciato, S.; Chiesa, V.; Dainese, F.; De Maria, G.; Didato, G.; Falcicchio, G.; Fanella, M.; Ferlazzo, E.; Fisco, G.; Gangitano, M.; Giallonardo, A. T.; Giorgi, F. S.; La Neve, A.; Mecarelli, O.; Montalenti, E.; Piazza, F.; Pulitano, P.; Quarato, P. P.; Ranzato, F.; Rosati, E.; Tassi, L.; Di Bonaventura, C.; Alicino, A.; Ascoli, M.; Assenza, G.; Avorio, F.; Badioni, V.; Banfi, P.; Bartolini, E.; Basili, L. M.; Belcastro, V.; Beretta, S.; Berto, I.; Biggi, M.; Billo, G.; Boero, G.; Bonanni, P.; Bongorno, J.; Brigo, F.; Caggia, E.; Cagnetti, C.; Calvello, C.; Irelli, E. C.; Cesnik, E.; Chianale, G.; Ciampanelli, D.; Ciuffini, R.; Cocito, D.; Colella, D.; Contento, M.; Costa, C.; Cumbo, E.; D'Aniello, A.; Deleo, F.; Difrancesco, J. C.; Di Gennaro, G.; Di Giacomo, R.; Di Liberto, A.; Domina, E.; Donato, F.; Dono, F.; Durante, V.; Elia, M.; Estraneo, A.; Evangelista, G.; Faedda, M. T.; Failli, Y.; Fallica, E.; Fattouch, J.; Ferrari, A.; Ferreri, F.; Fonti, D.; Fortunato, F.; Foschi, N.; Francavilla, T.; Galli, R.; Gazzina, S.; Giuliano, L.; Habetswallner, F.; Izzi, F.; Kassabian, B.; Labate, A.; Luisi, C.; Magliani, M.; Maira, G.; Mari, L.; Marino, D.; Mascia, A.; Mazzeo, A.; Meletti, S.; Morano, A.; Nilo, A.; Orlando, B.; Paladin, F.; Pascarella, M. G.; Pastori, C.; Pauletto, G.; Peretti, A.; Perri, G.; Pezzella, M.; Piccioli, M.; Pignatta, P.; Pilolli, N.; Pisani, F.; Pisani, L. R.; Placidi, F.; Pollicino, P.; Porcella, V.; Pradella, S.; Puligheddu, M.; Quadri, S.; Quintas, R.; Renna, R.; Rossi, J.; Rum, A.; Salamone, E. M.; Savastano, E.; Sessa, M.; Stokelj, D.; Tartara, E.; Tombini, M.; Tumminelli, G.; Ventura, M.; Vigano, I.; Viglietta, E.; Vignoli, A.; Villani, F.; Zambrelli, E.; Zummo, L.
abstract

Background: In randomized controlled trials, add-on brivaracetam (BRV) reduced seizure frequency in patients with drug-resistant focal epilepsy. Studies performed in a naturalistic setting are a useful complement to characterize the drug profile. Objective: This multicentre study assessed the effectiveness and tolerability of adjunctive BRV in a large population of patients with focal epilepsy in the context of real-world clinical practice. Methods: The BRIVAFIRST (BRIVAracetam add-on First Italian netwoRk STudy) was a retrospective, multicentre study including adult patients prescribed adjunctive BRV. Patients with focal epilepsy and 12-month follow-up were considered. Main outcomes included the rates of seizure‐freedom, seizure response (≥ 50% reduction in baseline seizure frequency), and treatment discontinuation. The incidence of adverse events (AEs) was also considered. Analyses by levetiracetam (LEV) status and concomitant use of strong enzyme-inducing antiseizure medications (EiASMs) and sodium channel blockers (SCBs) were performed. Results: A total of 1029 patients with a median age of 45 years (33–56) was included. At 12 months, 169 (16.4%) patients were seizure-free and 383 (37.2%) were seizure responders. The rate of seizure freedom was 22.3% in LEV-naive patients, 7.1% in patients with prior LEV use and discontinuation due to insufficient efficacy, and 31.2% in patients with prior LEV use and discontinuation due to AEs (p < 0.001); the corresponding values for ≥ 50% seizure frequency reduction were 47.9%, 29.7%, and 42.8% (p < 0.001). There were no statistically significant differences in seizure freedom and seizure response rates by use of strong EiASMs. The rates of seizure freedom (20.0% vs. 16.6%; p = 0.341) and seizure response (39.7% vs. 26.9%; p = 0.006) were higher in patients receiving SCBs than those not receiving SCBs; 265 (25.8%) patients discontinued BRV. AEs were reported by 30.1% of patients, and were less common in patients treated with BRV and concomitant SCBs than those not treated with SCBs (28.9% vs. 39.8%; p = 0.017). Conclusion: The BRIVAFIRST provided real-world evidence on the effectiveness of BRV in patients with focal epilepsy irrespective of LEV history and concomitant ASMs, and suggested favourable therapeutic combinations.

2021 - Artificial intelligence for classification of temporal lobe epilepsy with ROI-level MRI data: A worldwide ENIGMA-Epilepsy study [Articolo su rivista]
Gleichgerrcht, E.; Munsell, B. C.; Alhusaini, S.; Alvim, M. K. M.; Bargallo, N.; Bender, B.; Bernasconi, A.; Bernasconi, N.; Bernhardt, B.; Blackmon, K.; Caligiuri, M. E.; Cendes, F.; Concha, L.; Desmond, P. M.; Devinsky, O.; Doherty, C. P.; Domin, M.; Duncan, J. S.; Focke, N. K.; Gambardella, A.; Gong, B.; Guerrini, R.; Hatton, S. N.; Kalviainen, R.; Keller, S. S.; Kochunov, P.; Kotikalapudi, R.; Kreilkamp, B. A. K.; Labate, A.; Langner, S.; Lariviere, S.; Lenge, M.; Lui, E.; Martin, P.; Mascalchi, M.; Meletti, S.; O'Brien, T. J.; Pardoe, H. R.; Pariente, J. C.; Xian Rao, J.; Richardson, M. P.; Rodriguez-Cruces, R.; Ruber, T.; Sinclair, B.; Soltanian-Zadeh, H.; Stein, D. J.; Striano, P.; Taylor, P. N.; Thomas, R. H.; Vaudano, A.; Vivash, L.; von Podewills, F.; Vos, S. B.; Weber, B.; Yao, Y.; Lin Yasuda, C.; Zhang, J.; Thompson, P. M.; Sisodiya, S. M.; Mcdonald, C. R.; Bonilha, L.; Altmann, A.; Depondt, C.; Galovic, M.; Thomopoulos, S. I.; Wiest, R.
abstract

Artificial intelligence has recently gained popularity across different medical fields to aid in the detection of diseases based on pathology samples or medical imaging findings. Brain magnetic resonance imaging (MRI) is a key assessment tool for patients with temporal lobe epilepsy (TLE). The role of machine learning and artificial intelligence to increase detection of brain abnormalities in TLE remains inconclusive. We used support vector machine (SV) and deep learning (DL) models based on region of interest (ROI-based) structural (n = 336) and diffusion (n = 863) brain MRI data from patients with TLE with (“lesional”) and without (“non-lesional”) radiographic features suggestive of underlying hippocampal sclerosis from the multinational (multi-center) ENIGMA-Epilepsy consortium. Our data showed that models to identify TLE performed better or similar (68–75%) compared to models to lateralize the side of TLE (56–73%, except structural-based) based on diffusion data with the opposite pattern seen for structural data (67–75% to diagnose vs. 83% to lateralize). In other aspects, structural and diffusion-based models showed similar classification accuracies. Our classification models for patients with hippocampal sclerosis were more accurate (68–76%) than models that stratified non-lesional patients (53–62%). Overall, SV and DL models performed similarly with several instances in which SV mildly outperformed DL. We discuss the relative performance of these models with ROI-level data and the implications for future applications of machine learning and artificial intelligence in epilepsy care.

2021 - Brivaracetam as add-on treatment in focal epilepsy: A real-world time-based analysis [Articolo su rivista]
Lattanzi, S.; De Maria, G.; Rosati, E.; Didato, G.; Chiesa, V.; Ranzato, F.; Canafoglia, L.; Cesnik, E.; Anzellotti, F.; Meletti, S.; Pauletto, G.; Nilo, A.; Bartolini, E.; Marino, D.; Tartara, E.; Luisi, C.; Bonanni, P.; Marrelli, A.; Stokelj, D.; Dainese, F.; Foschi, N.; Cagnetti, C.; Gazzina, S.; Contento, M.; Biggi, M.; Magliani, M.; Di Giacomo, R.; Pastori, C.; Canevini, M. P.; Zambrelli, E.; Billo, G.; Casazza, M.; Fallica, E.; Rosa, G.; Dono, F.; Speranza, R.; Cioclu, C.; Vaudano, A. E.; Kiferle, L.; Galli, R.; Guadagni, M.; Galimberti, C. A.; Kassabian, B.; Ferreri, F.; Osanni, E.; Ciuffini, R.; Badioni, V.; Beretta, S.
abstract

The study assessed the clinical response to add-on brivaracetam (BRV) in real-world practice by means of time-to-baseline seizure count methodology. Patients with focal epilepsy who were prescribed add-on BRV were identified. Primary endpoint was the time-to-baseline seizure count defined as the number of days until each patient experienced the number of focal seizures that occurred in the 90 days before BRV initiation. Subgroup analysis was performed according to levetiracetam (LEV) status (naive vs prior use). Three-hundred eighty-seven patients were included. The overall median time-to-baseline seizure count was 150 (95% confidence interval [CI] = 130-175) days. The median time-to-baseline seizure count was 198 (lower limit of 95% CI = 168) days for LEV-naive patients, 126 (95% CI = 105-150) days for patients with prior LEV use and withdrawal due to insufficient efficacy, and 170 (95% CI = 128-291) days for patients who discontinued LEV due to adverse events (P =.002). The number of prior antiseizure medications (adjusted hazard ratio [adjHR] = 1.07, 95% CI = 1.02-1.13, P =.009) and baseline monthly seizure frequency (adjHR = 1.004, 95% CI = 1.001-1.008, P =.028) were independently associated with the primary endpoint. Add-on BRV improved seizure control in LEV-naive and LEV-prior patients. The time-to-baseline seizure count represents an informative endpoint alongside traditional study outcomes and designs.

2021 - Case Report: Ictal Central Apnea as First and Overlooked Symptom in Temporal Lobe Seizures [Articolo su rivista]
Micalizzi, E.; Vaudano, A. E.; Giovannini, G.; Turchi, G.; Giunta, L.; Meletti, S.
abstract

Ictal respiratory changes have been mainly described following generalized tonic-clonic seizures and recently considered to be a biomarker to assess the risk of sudden unexplained death in epilepsy (SUDEP). Nonetheless, modification of respiratory pattern can be related also to focal seizures, especially arising from the temporal lobe. Changes in cardiac function such as tachycardia or bradycardia could be often associated. We report a short case series of four patients with temporal lobe epilepsy admitted to our Epilepsy Monitoring Unit (EMU) presenting with an ictal central apnea as the first clinical manifestation of their seizures. None of these patients was aware of the occurrence of respiratory arrest. Age at onset ranged from 15 to 29 years. One patient had seizures with prolonged central apnea accompanied by a significant decrease in oxygen saturation. Neuroimaging in two patients showed alterations of mesial temporal lobe structures, including the amygdala. Recent neurophysiological studies supported the existence of a cortical network involving the limbic system that modulates downstream brainstem respiratory centers. Monitoring for respiratory changes and oxygen saturation in focal seizures is warranted for their potential value in identifying the epileptogenic zone and for a better understanding of ictal respiratory changes that could potentially define a subgroup of patients with high risk of seizure-related autonomic changes.

2021 - Clinical phenotypes within nonconvulsive status epilepticus [Articolo su rivista]
Lattanzi, S.; Giovannini, G.; Brigo, F.; Orlandi, N.; Trinka, E.; Meletti, S.
abstract

The study aimed to identify distinct phenotypes within nonconvulsive status epilepticus (NCSE). Consecutive episodes of NCSE in patients at least 14 years old were included. The level of consciousness was assessed through the Glasgow Coma Scale (GCS). Etiology of NCSE was defined as symptomatic (acute, remote, progressive) or unknown. Electroencephalographic (EEG) recordings were searched for lateralized periodic discharges (LPDs), generalized sharply and/or triphasic periodic potentials (GPDs), and spontaneous burst suppression (BS). According to treatment response, NCSE was classified as responsive, refractory, or superrefractory. Average linkage hierarchical cluster analysis was performed with Pearson correlation as similarity measure. Two hundred twenty-nine episodes of NCSE were included. Three clusters were identified. The first cluster linked GCS score 3–8, presence of spontaneous BS on EEG, acute symptomatic etiology, and treatment superrefractoriness. The second cluster gathered GCS score 9–12, presence of LPDs or GPDs on EEG, unknown etiology, and treatment refractoriness. The third cluster associated GCS score 13–15, absence of LPDs, GPDs, and spontaneous BS on EEG, and progressive and remote symptomatic etiology with treatment responsiveness. Phenotyping the heterogeneity of NCSE into electroclinical clusters can contribute to understanding correlations between pathologic and clinical domains, assessing the intrinsic severity of NCSE episodes, and estimating the likelihood of treatment responsiveness.

2021 - Combining perampanel and ketamine in super refractory post-traumatic status epilepticus: A case report [Articolo su rivista]
Manganotti, P.; Cheli, M.; Dinoto, A.; Biaduzzini, F.; Tomaselli, M.; Mazzon, G.; Roman-Pognuz, E.; Meletti, S.
abstract

2021 - Correction to: Adjunctive Brivaracetam in Focal Epilepsy: Real‑World Evidence from the BRIVAracetam add‑on First Italian netwoRk Study (BRIVAFIRST) (CNS Drugs, (2021), 10.1007/s40263-021-00856-3) [Articolo su rivista]
Lattanzi, S.; Canafoglia, L.; Canevini, M. P.; Casciato, S.; Chiesa, V.; Dainese, F.; De Maria, G.; Didato, G.; Falcicchio, G.; Fanella, M.; Ferlazzo, E.; Fisco, G.; Gangitano, M.; Giallonardo, A. T.; Giorgi, F. S.; La Neve, A.; Mecarelli, O.; Montalenti, E.; Piazza, F.; Pulitano, P.; Quarato, P. P.; Ranzato, F.; Rosati, E.; Tassi, L.; Di Bonaventura, C.; Alicino, A.; Ascoli, M.; Assenza, G.; Avorio, F.; Badioni, V.; Banfi, P.; Bartolini, E.; Basili, L. M.; Belcastro, V.; Beretta, S.; Berto, I.; Biggi, M.; Billo, G.; Boero, G.; Bonanni, P.; Bongorno, J.; Brigo, F.; Caggia, E.; Cagnetti, C.; Calvello, C.; Irelli, E. C.; Cesnik, E.; Chianale, G.; Ciampanelli, D.; Ciuffini, R.; Cocito, D.; Colella, D.; Contento, M.; Costa, C.; Cumbo, E.; D'Aniello, A.; Deleo, F.; Difrancesco, J. C.; Gennaro, G.; Di Giacomo, R.; Di Liberto, A.; Domina, E.; Donato, F.; Dono, F.; Durante, V.; Elia, M.; Estraneo, A.; Evangelista, G.; Faedda, M. T.; Failli, Y.; Fallica, E.; Fattouch, J.; Ferrari, A.; Ferreri, F.; Fonti, D.; Fortunato, F.; Foschi, N.; Francavilla, T.; Galli, R.; Gazzina, S.; Giuliano, L.; Habetswallner, F.; Izzi, F.; Kassabian, B.; Labate, A.; Luisi, C.; Magliani, M.; Maira, G.; Mari, L.; Marino, D.; Mascia, A.; Mazzeo, A.; Meletti, S.; Morano, A.; Nilo, A.; Orlando, B.; Paladin, F.; Pascarella, M. G.; Pastori, C.; Pauletto, G.; Peretti, A.; Perri, G.; Pezzella, M.; Piccioli, M.; Pignatta, P.; Pilolli, N.; Pisani, F.; Pisani, L. R.; Placidi, F.; Pollicino, P.; Porcella, V.; Pradella, S.; Puligheddu, M.; Quadri, S.; Quintas, R.; Renna, R.; Rossi, J.; Rum, A.; Salamone, E. M.; Savastano, E.; Sessa, M.; Stokelj, D.; Tartara, E.; Tombini, M.; Tumminelli, G.; Ventura, M.; Vigano, I.; Viglietta, E.; Vignoli, A.; Villani, F.; Zambrelli, E.; Zummo, L.
abstract

In the original publication, the names of the BRIVAFIRST group members were incorrectly presented and tagged in the Acknowledgements section. This has now been corrected as follows.

2021 - Cortical and Subcortical Network Dysfunction in a Female Patient With NEXMIF Encephalopathy [Articolo su rivista]
Cioclu, M. C.; Coppola, A.; Tondelli, M.; Vaudano, A. E.; Giovannini, G.; Krithika, S.; Iacomino, M.; Zara, F.; Sisodiya, S. M.; Meletti, S.
abstract

The developmental and epileptic encephalopathies (DEE) are the most severe group of epilepsies. Recently, NEXMIF mutations have been shown to cause a DEE in females, characterized by myoclonic–atonic epilepsy and recurrent nonconvulsive status. Here we used advanced neuroimaging techniques in a patient with a novel NEXMIF de novo mutation presenting with recurrent absence status with eyelid myoclonia, to reveal brain structural and functional changes that can bring the clinical phenotype to alteration within specific brain networks. Indeed, the alterations found in the patient involved the visual pericalcarine cortex and the middle frontal gyrus, regions that have been demonstrated to be a core feature in epilepsy phenotypes with visual sensitivity and eyelid myoclonia with absences.

2021 - Cortical and subcortical hemodynamic changes during sleep slow waves in human light sleep [Articolo su rivista]
Betta, Monica; Handjaras, Giacomo; Leo, Andrea; Federici, Alessandra; Farinelli, Valentina; Ricciardi, Emiliano; Siclari, Francesca; Meletti, Stefano; Ballotta, Daniela; Benuzzi, Francesca; Bernardi, Giulio
abstract

EEG slow waves, the hallmarks of NREM sleep are thought to be crucial for the regulation of several important processes, including learning, sensory disconnection and the removal of brain metabolic wastes. Animal research indicates that slow waves may involve complex interactions within and between cortical and subcortical structures. Conventional EEG in humans, however, has a low spatial resolution and is unable to accurately describe changes in the activity of subcortical and deep cortical structures. To overcome these limitations, here we took advantage of simultaneous EEG-fMRI recordings to map cortical and subcortical hemodynamic (BOLD) fluctuations time-locked to slow waves of light sleep. Recordings were performed in twenty healthy adults during an afternoon nap. Slow waves were associated with BOLD-signal increases in the posterior brainstem and in portions of thalamus and cerebellum characterized by preferential functional connectivity with limbic and somatomotor areas, respectively. At the cortical level, significant BOLD-signal decreases were instead found in several areas, including insula and somatomotor cortex. Specifically, a slow signal increase preceded slow-wave onset and was followed by a delayed, stronger signal decrease. Similar hemodynamic changes were found to occur at different delays across most cortical brain areas, mirroring the propagation of electrophysiological slow waves, from centro-frontal to inferior temporo-occipital cortices. Finally, we found that the amplitude of electrophysiological slow waves was positively related to the magnitude and inversely related to the delay of cortical and subcortical BOLD-signal changes. These regional patterns of brain activity are consistent with theoretical accounts of the functions of sleep slow waves.

2021 - Cortical and thalamic hyper-perfusion in non-convulsive status epilepticus. Relationship between perfusion CT patterns and Salzburg EEG criteria [Articolo su rivista]
Giovannini, G.; Malagoli, M.; Turchi, G.; Miani, A.; Orlandi, N.; Vaudano, A. E.; Meletti, S.
abstract

Introduction: Status epilepticus (SE) is a neurological emergency and in particular nonconvulsive SE (NCSE) represents a diagnostic challenge. To improve clinical decision-making, cerebral perfusion-computed tomography (PCT) has been shown as a helpful tool to support the diagnosis of focal NCSE. Materials and methods: This is a monocentric retrospective study. Among the 602 cases of SE observed between September 2013 and April 2020 we included 21 patients that were studied with PCT. The perfusion maps were first visually analysed then a quantitative analysis (by regions of interest, ROI) was obtained. For each patient, the diagnostic EEG was reviewed and classified in accordance to the Salzburg Criteria for NCSE (SCC) as definite (D-NCSE) and possible (P-NCSE). Finally, we analysed the relationship between PCT and EEG patterns. Results: Hyper-perfusion was observed in 18 patients (86%), while in the remaining 3 (14%) a normo-perfused pattern was present. Hyper-perfusion was observed in 14 of the D-NCSE group (88%) and in the two patients with a P-NCSE (100%). No one among the patients with a P-NCSE had a thalamic hyper-perfusion, while among the 6 patients with continuous sustained epileptiform discharges > 2.5 Hz (pattern 1 of SCC), 4 (67%) showed cortical plus thalamic hyper-perfusion. Conclusions: PCT could facilitate the differential diagnosis and speed-up the diagnostic process of NCSE in emergency situations. Finding cortical multi-lobar hyper-perfusion, especially if present together with homolateral thalamic hyper-perfusion in a patient with an acute-onset of motor/sensory/language deficits is highly suggestive for the presence of NCSE and is particularly related to continuous/sustained ictal patterns.

2021 - Efficacy of mechanical thrombectomy in patients with ischemic stroke and cancer [Articolo su rivista]
Ciolli, L.; Bigliardi, G.; Ferraro, D.; Maffei, S.; Vandelli, L.; Dell'Acqua, M. L.; Rosafio, F.; Picchetto, L.; Laterza, D.; Vincenzi, C.; Meletti, S.; Vallone, S.; Zini, A.
abstract

Cancer-related coagulopathy is a known cause of stroke and can lead to formation of thrombi with a unique composition. The effectiveness of mechanical thrombectomy in cancer patients is still unknown. The aim of the study was to evaluate the rate of successful reperfusion and the clinical outcome in cancer patients with stroke treated with endovascular therapies, compared to patients without cancer. We performed a retrospective analysis of consecutive patients with ischemic stroke treated with endovascular therapies at our hospital between January 2008 and January 2016. A sub-group analysis was performed including only patients with cryptogenic stroke. We included in the final analysis 14 patients with active cancer and 267 patients without cancer. Successful reperfusion was achieved in 79% of patients without cancer, and 71% of patients with active cancer (P = 0.68). Patients with cryptogenic stroke and active cancer had a lower reperfusion rate compared to patients with cryptogenic stroke without active cancer, although not significantly so (2/4 cancer patients, 50% vs 37/50, 74%, p: 0.31). Mortality rate was higher among cancer patients. Hemorrhagic transformation occurred in similar proportions in the two groups. Endovascular treatment in cancer patients seems, thus, effective.

2021 - Factors affecting the outcome of delayed intravenous thrombolysis (> 4.5 hours) [Articolo su rivista]
Elsaid, N.; Bigliardi, G.; Dell'Acqua, M. L.; Vandelli, L.; Ciolli, L.; Picchetto, L.; Borzi, G.; Ricceri, R.; Pentore, R.; Vallone, S.; Meletti, S.; Saied, A.
abstract

Introduction: Evidence of the intravenous tissue plasminogen activator (tPA) efficacy beyond the 4.5 hours window is emerging. We aim to study the factors affecting the outcome of delayed thrombolysis in patients of clear onset acute ischemic stroke (AIS). Methods: Data of patients with AIS who received intravenous thrombolytic after 4.5 hours were reviewed including: demographics, risk factors, clinical, laboratory, investigational and radiological data, evidence of mismatch, treatment type and onset, National Institutes of Health Stroke Scale (NIHSS) score at baseline, 24 hours, 7 days after thrombolysis and before discharge, and 3 months follow-up modified Rankin Scale (mRS). Results: We report 136 patients treated by intravenous tPA between 4.53 and 19.75 hours with average duration of 5.7 h. The ASPECT score of our patients was ≥ 7. Sixty-four cases showed intracranial arterial occlusion. Perfusion mismatch was detected in 117 (84.6%) patients, while clinical imaging mismatch was detected in 19 (15.4%). Early neurological improvement after 24 hours occurred in 114 (83.8%) patients. At 90 days, 91 patients (67%) achieved good outcome (mRS 0–2), while 45 (33%) had bad outcome (mRS 3–6). Age, endovascular treatment, NIHSS, AF, and HT were significantly higher in the bad outcome group. Age (P = 0.001, OR: 1.099, 95% CI: 1.042–1.160) and baseline NIHSS were predictive of the poor outcome (P = 0.002, OR: 1.151, 95% CI: 1.055–1.256). The best cutoff value of age was 72.5 with AUC of 0.76, sensitivity 73.3% and specificity 60.4%. While for NIHSS at admission, the cutoff value of 7 showed the best results with AUC of 0.73, sensitivity 71.1% and specificity 63.7%. Combination of age and admission NIHSS raised the sensitivity and specificity to 84.4% and 63.7%, respectively. Conclusion: Increased age and admission NIHSS may adversely affect the outcome of delayed thrombolysis and narrow the eligibility criteria. Age and baseline NIHSS based stratification of the patients may provide further evidence as regards the efficacy of the delayed thrombolysis.

2021 - Hypothalamus and amygdala functional connectivity at rest in narcolepsy type 1 [Articolo su rivista]
Ballotta, D.; Talami, F.; Pizza, F.; Vaudano, A. E.; Benuzzi, F.; Plazzi, G.; Meletti, S.
abstract

Introduction: functional and structural MRI studies suggest that the orexin (hypocretin) deficiency in the dorso-lateral hypothalamus of narcoleptic patients would influence both brain metabolism and perfusion and would cause reduction in cortical grey matter. Previous fMRI studies have mainly focused on cerebral functioning during emotional processing. The aim of the present study was to explore the hemodynamic behaviour of spontaneous BOLD fluctuation at rest in patients with Narcolepsy type 1 (NT1) close to disease onset. Methods: Fifteen drug naïve children/adolescents with NT1 (9 males; mean age 11.7 ± 3 years) and fifteen healthy children/adolescents (9 males; mean age 12.4 ± 2.8 years) participated in an EEG-fMRI study in order to investigate the resting-state functional connectivity of hypothalamus and amygdala. Functional images were acquired on a 3 T system. Seed-based functional connectivity analyses were performed using SPM12. Regions of Interest were the lateral hypothalamus and the amygdala. Results: compared to controls, NT1 patients showed decreased functional connectivity between the lateral hypothalamus and the left superior parietal lobule, the hippocampus and the parahippocampal gyrus. Decreased functional connectivity was detected between the amygdala and the post-central gyrus and several occipital regions, whereas it was increased between the amygdala and the inferior frontal gyrus, claustrum, insula, and putamen. Conclusion: in NT1 patients the abnormal connectivity between the hypothalamus and brain regions involved in memory consolidation during sleep, such as the hippocampus, may be linked to the loss of orexin containing neurons in the dorsolateral hypothalamus. Moreover, also functional connectivity of the amygdala seems to be influenced by the loss of orexin-containing neurons. Therefore, we can hypothesize that dysfunctional interactions between regions subserving the maintenance of arousal, memory and emotional processing may contribute to the main symptom of narcolepsy.

2021 - Intravenous brivaracetam in status epilepticus: A multicentric retrospective study in Italy [Articolo su rivista]
Orlandi, N.; Bartolini, E.; Audenino, D.; Moja, M. C.; Urso, L.; D'Orsi, G.; Pauletto, G.; Nilo, A.; Zinno, L.; Cappellani, R.; Zummo, L.; Giordano, A.; Dainese, F.; Nazerian, P.; Pescini, F.; Beretta, S.; Dono, F.; Gaudio, L. D.; Ferlisi, M.; Marino, D.; Piccioli, M.; Renna, R.; Rosati, E.; Rum, A.; Strigaro, G.; Giovannini, G.; Meletti, S.; Cavalli, S. M.; Contento, M.; Cottone, S.; Di Claudio, M. T.; Florindo, I.; Guadagni, M.; Kiferle, L.; Lazzaretti, D.; Lazzari, M.; Coco, D. L.; Pradella, S.; Rikani, K.; Rodorigo, D.; Sabetta, A.; Sicurella, L.; Tontini, V.; Turchi, G.; Vaudano, A. E.; Zanoni, T.
abstract

Purpose: to evaluate the use, effectiveness, and adverse events of intravenous brivaracetam (BRV) in status epilepticus (SE). Methods: a retrospective multicentric study involving 24 Italian neurology units was performed from March 2018 to June 2020. A shared case report form was used across participating centres to limit biases of retrospective data collection. Diagnosis and classification of SE followed the 2015 ILAE proposal. We considered a trial with BRV a success when it was the last administered drug prior the clinical and/or EEG resolution of seizures, and the SE did not recur during hospital observation. In addition, we considered cases with early response, defined as SE resolved within 6 h after BRV administration. Results: 56 patients were included (mean age 62 years; 57 % male). A previous diagnosis of epilepsy was present in 21 (38 %). Regarding SE etiology classification 46 % were acute symptomatic, 18 % remote and 16 % progressive symptomatic. SE episodes with prominent motor features were the majority (80 %). BRV was administered as first drug after benzodiazepine failure in 21 % episodes, while it was used as the second or the third (or more) drug in the 38 % and 38 % of episodes respectively. The median loading dose was 100 mg (range 50−300 mg). BRV was effective in 32 cases (57 %). An early response was documented in 22 patients (39 % of the whole sample). The use of the BRV within 6 h from SE onset was independently associated to an early SE resolution (OR 32; 95 % CI 3.39–202; p = 0.002). No severe treatment emergent adverse events were observed. Conclusion: BRV proved to be useful and safe for the treatment of SE. Time to seizures resolution appears shorter when it is administered in the early phases of SE.

2021 - Mild to severe neurological manifestations of covid-19: Cases reports [Articolo su rivista]
Melegari, G.; Rivi, V.; Zelent, G.; Nasillo, V.; De Santis, E.; Melegari, A.; Bevilacqua, C.; Zoli, M.; Meletti, S.; Barbieri, A.
abstract

The main focus of Coronavirus disease 2019 (COVID-19) infection is pulmonary complications through virus-related neurological manifestations, ranging from mild to severe, such as encephalitis, cerebral thrombosis, neurocognitive (dementia-like) syndrome, and delirium. The hospital screening procedures for quickly recognizing neurological manifestations of COVID-19 are often complicated by other coexisting symptoms and can be obscured by the deep sedation procedures required for critically ill patients. Here, we present two different case-reports of COVID-19 patients, describing neurological complications, diagnostic imaging such as olfactory bulb damage (a mild and unclear underestimated complication) and a severe and sudden thrombotic stroke complicated with hemorrhage with a low-level cytokine storm and respiratory symptom resolution. We discuss the possible mechanisms of virus entrance, together with the causes of COVID-19-related encephalitis, olfactory bulb damage, ischemic stroke, and intracranial hemorrhage.

2021 - Modulation of tregs and inkt by fingolimod in multiple sclerosis patients [Articolo su rivista]
Ferraro, D.; De Biasi, S.; Simone, A. M.; Orlandi, R.; Nasi, M.; Vitetta, F.; Pinti, M.; Fogliani, M.; Meletti, S.; Cossarizza, A.; Sola, P.
abstract

The altered numbers and functions of cells belonging to immunoregulatory cell networks such as T regulatory (Tregs) and invariant Natural Killer T (iNKT) cells have been reported in Multiple Sclerosis (MS), an immune-mediated disease. We aimed to assess the frequencies of Tregs and iNKT cells in MS patients throughout a one-year treatment with fingolimod (FTY) and to correlate immunological data with efficacy and safety data. The percentage of Tregs (defined as Live Dead-CD3 + CD4 + FoxP3 + CD25++/CD127− cells) increased steadily throughout the year, while there was no significant difference in the absolute number or percentage of iNKT cells (defined as CD3 + CD14−CD19− Vα24-Jα18 TCR+ cells). However, out of all the iNKT cells, the CD8+ iNKT and CD4−CD8− double-negative (DN) cell percentages steadily increased, while the CD4+ iNKT cell percentages decreased significantly. The mean percentage of CD8+ T cells at all time-points was lower in patients with infections throughout the study. The numbers and percentages of DN iNKT cells were more elevated, considering all time-points, in patients who presented a clinical relapse. FTY may, therefore, exert its beneficial effect in MS patients through various mechanisms, including the increase in Tregs and in iNKT subsets with immunomodulatory potential such as CD8+ iNKT cells. The occurrence of infections was associated with lower mean CD8+ cell counts during treatment with FTY.

2021 - New onset status epilepticus in influenza associated encephalopathy: The presenting manifestation of genetic generalized epilepsy [Articolo su rivista]
Giovannini, G.; Turchi, G.; Mazzoli, M.; Vaudano, A. E.; Meletti, S.
abstract

We hereby present a case of a young woman with no history of seizures or epilepsy who experienced a de novo generalized Non Convulsive Status Epilepticus (NCSE) followed by encephalopathy lasting for several days during influenza B infection. Influenza can have a broad spectrum of presentation ranging from an uncomplicated illness to many serious conditions as is the case of influenza associated encephalitis/encephalopathy (IAE). In this context however, it is possible to observe seizures and/or status epilepticus as the presenting manifestation of a genetic generalized epilepsy.

2021 - Olfactory function and viral recovery in COVID-19 [Articolo su rivista]
Mazzoli, Marco; Molinari, Maria Angela; Tondelli, Manuela; Giovannini, Giada; Ricceri, Riccardo; Ciolli, Ludovico; Picchetto, Livio; Meletti, Stefano
abstract

Olfactory and taste disorders were reported in up to 30%-80% of COVID-19 patients. The purpose of our study was to objectively assess smell impairment in COVID-19 patients and to correlate olfactory function with viral recovery.

2021 - Platelet Function Monitoring Performed after Carotid Stenting during Endovascular Stroke Treatment Predicts Outcome [Articolo su rivista]
Ciolli, L.; Lelli, N.; Rosafio, F.; Maffei, S.; Sacchetti, F.; Vandelli, L.; Dell'Acqua, M. L.; Picchetto, L.; Borzi, G. M.; Ricceri, R.; Pentore, R.; Tondelli, M.; Vandelli, G.; Rodriguez-Villatoro, N.; Meletti, S.; Zini, A.; Vallone, S.; Bigliardi, G.
abstract

Objectives: Many studies showed that platelet reactivity testing can predict ischemic events after carotid stenting or ischemic stroke. The aim of our study was to assess the role of early platelet function monitoring in predicting 90-days functional outcome, stent thrombosis and hemorrhagic transformation in patients with ischemic stroke treated with endovascular procedures requiring emergent extracranial stenting. Materials and methods: We performed a retrospective study on consecutive patients with acute anterior circulation stroke admitted to our hospital between January 2015 and March 2020, in whom platelet reactivity testing was performed within 10 days from stenting. Patients were divided according to validated cutoffs in acetylsalicylic acid and Clopidogrel responders and not responders. Group comparison and regression analyses were performed to identify differences between groups and outcome predictors. Results: We included in the final analysis 54 patients. Acetylsalicylic acid resistance was an independent predictor of poor 90 days outcome (OR for modified Rankin scale (mRS) ≤ 2: 0.10 95% CI: 0.02 – 0.69) whereas Clopidogrel resistance was an independent predictor of good outcome (OR for mRS ≤ 2: 7.09 95%CI: 1.33 – 37.72). Acetylsalicylic acid resistance was also associated with increased 90-days mortality (OR: 18.42; 95% CI: 1.67 – 203.14). Conclusion: We found a significant association between resistance to acetylsalicylic acid and poor 90-days functional outcome and between resistance to Clopidogrel and good 90-days functional outcome. If confirmed, our results might improve pharmacological management after acute carotid stenting.

2021 - Serum neurofilament light as biomarker of seizure-related neuronal injury in status epilepticus [Articolo su rivista]
Giovannini, G.; Bedin, R.; Ferraro, D.; Vaudano, A. E.; Mandrioli, J.; Meletti, S.
abstract

Biomarkers of neuronal damage in status epilepticus (SE) would be of great relevance for clinical and research purposes. In a retrospective cross-sectional study, serum neurofilament light chain (NfL) levels were measured in patients with SE (30 subjects), patients with drug-resistant epilepsy (30 subjects), and healthy controls (30 subjects). Serum NfL levels were higher in patients with SE (median = 26.15 pg/ml) compared to both epilepsy patients (median = 7.35 pg/ml) and healthy controls (median = 6.81 pg/ml; p <.001). In patients with SE, serum NfL levels showed a high correlation with cerebrospinal fluid (CSF) NfL (τ =.68, p <.001) as well as with CSF total tau (t-tau) levels (τ =.627, p <.001); they were higher in SE lasting >24 h (p =.013), in refractory/superrefractory SE (p =.004), and in patients who died within 30 days or who presented a worsening of clinical conditions (p =.001). Values of >28.8 pg/ml predicted 30-day clinical worsening or death (odds ratio [OR] = 10.83, 95% confidence interval [CI] = 1.96–59.83, p =.006) and SE refractoriness (OR = 9.33, 95% CI = 1.51–57.65, p =.016). In conclusion, serum NfL levels are increased in SE and correlate with SE treatment response, duration, and outcomes, therefore representing a promising biomarker of seizure-related neuronal damage.

2021 - Status epilepticus with prominent motor symptoms clusters into distinct electroclinical phenotypes [Articolo su rivista]
Lattanzi, Simona; Giovannini, Giada; Brigo, Francesco; Orlandi, Niccolò; Trinka, Eugen; Meletti, Stefano
abstract

Status epilepticus (SE) represents a heterogeneous condition and considerable variability exists in etiology, semiology, electroencephalographic correlates and response to treatment. The study explored whether distinct phenotypes may be identified within SE with prominent motor symptoms.

2021 - TeleNeurological evaluation and Support for the Emergency Department (TeleNS-ED): protocol for an open-label clinical trial [Articolo su rivista]
Mandrioli, J.; Santangelo, M.; Luciani, A.; Toscani, S.; Zucchi, E.; Giovannini, G.; Martinelli, I.; Cecoli, S.; Bigliardi, G.; Scanavini, S.; Meletti, S.
abstract

INTRODUCTION: The COVID-19 pandemic compelled health systems to protect patients and medical personnel during transit in hospitals by minimising transfers, prompting the use of telehealth systems. In the field of neurology, telemedicine has been used in emergency settings for acute stroke management between spoke and hub hospital networks, where good outcomes have been achieved. However, data on the use of telemedicine in non-stroke acute neurological conditions accessing the emergency department (ED) are currently missing. METHODS AND ANALYSES: This is an interventional, open-label trial on the use of teleconsultation in the ED for neurological diseases other than stroke. The study aims to develop a remote consultancy system (TeleNeurological Evaluation and Support, TeleNS) for patients with acute neurological symptoms referred to hospital facilities without a 24-hour availability of a neurologist consultant (spoke hospitals). The study population will include 100 ED patients referred to two spoke hospitals in 6 months, who will be asked to perform teleconsultation instead of inperson visits. As a control group, retrospectively available data from patients admitted to the ED of spoke hospitals during the same time period over the last 2 years will be evaluated. The primary objective is to assess whether a TeleNS for the ED guarantees a faster but qualitatively non-inferior diagnostic/therapeutic work-up if compared with inperson examination, assuring the availability of all the necessary examinations and treatments with consistent time-saving. ETHICS AND DISSEMINATION: The trial was designed following the national guidelines on clinical investigation on telemedicine provided by the Italian Ministry of Health and according to the Standard Protocol Items for Randomized Trials statement guidelines. This research protocol was approved by Comitato Etico Area Vasta Emilia Nord in September 2020 (number/identification: 942/2020/DISP/AOUMO SIRER ID 805) and was written without patient involvement. Patients' associations will be involved in the dissemination of study design and results. The results of the study will be presented during scientific symposia or published in scientific journals. TRIAL REGISTRATION NUMBER: NCT04611295.

2021 - Temporal Lobe Spikes Affect Distant Intrinsic Connectivity Networks [Articolo su rivista]
Mirandola, L.; Ballotta, D.; Talami, F.; Giovannini, G.; Pavesi, G.; Vaudano, A. E.; Meletti, S.
abstract

Objective: To evaluate local and distant blood oxygen level dependent (BOLD) signal changes related to interictal epileptiform discharges (IED) in drug-resistant temporal lobe epilepsy (TLE). Methods: Thirty-three TLE patients undergoing EEG–functional Magnetic Resonance Imaging (fMRI) as part of the presurgical workup were consecutively enrolled. First, a single-subject spike-related analysis was performed: (a) to verify the BOLD concordance with the presumed Epileptogenic Zone (EZ); and (b) to investigate the Intrinsic Connectivity Networks (ICN) involvement. Then, a group analysis was performed to search for common BOLD changes in TLE. Results: Interictal epileptiform discharges were recorded in 25 patients and in 19 (58%), a BOLD response was obtained at the single-subject level. In 42% of the cases, BOLD changes were observed in the temporal lobe, although only one patient had a pure concordant finding, with a single fMRI cluster overlapping (and limited to) the EZ identified by anatomo-electro-clinical correlations. In the remaining 58% of the cases, BOLD responses were localized outside the temporal lobe and the presumed EZ. In every patient, with a spike-related fMRI map, at least one ICN appeared to be involved. Four main ICNs were preferentially involved, namely, motor, visual, auditory/motor speech, and the default mode network. At the single-subject level, EEG–fMRI proved to have high specificity (above 65%) in detecting engagement of an ICN and the corresponding ictal/postictal symptom, and good positive predictive value (above 67%) in all networks except the visual one. Finally, in the group analysis of BOLD changes related to IED revealed common activations at the right precentral gyrus, supplementary motor area, and middle cingulate gyrus. Significance: Interictal temporal spikes affect several distant extra-temporal areas, and specifically the motor/premotor cortex. EEG–fMRI in patients with TLE eligible for surgery is recommended not for strictly localizing purposes rather it might be useful to investigate ICNs alterations at the single-subject level.

2021 - The management of epilepsy in clinical practice: Do the timing and severity of the disease influence the priorities of patients and the caring physicians? Data from the EPINEEDS study [Articolo su rivista]
Enia, G.; Giussani, G.; Bianchi, E.; Mecarelli, O.; Beghi, E.; Pulitano, P.; Cagnetti, C.; Baldinelli, S.; Lattanzi, S.; La Neve, A.; Tappata, M.; Francavilla, T.; De Maria, G.; Sofia, V.; Giuliano, L.; Mainieri, G.; Fatuzzo, D.; Belcastro, V.; Elia, M.; D'Orsi, G.; Lalla, A.; Salmaggi, A.; Brigo, F.; Magaudda, A.; Pisani, F.; Galletta, S.; Pisani, L. R.; Raffaele, M.; Cosenza, D.; Villani, F. S.; Quintas, R. M. M.; Cervellione, R.; Borroni, S.; Meletti, S.; Ferrarese, C.; Barbella, G.; Di Francesco, J.; Bogliun, G.; Beretta, S.; Galimberti, C. A.; Cantisani, T. A.; Cecconi, M.; Celani, M. G.; Papetti, R.; Giorgi, F. S.; Aguglia, U.; Gasparini, S.; Ferlazzo, E.; Manganotti, P.; Crichiutti, G.; Bravar, G.
abstract

Objective: The objective of this study was to assess the priorities of patients with epilepsy and their caring physicians with reference to the timing and severity of the disease. Methods: This is a national survey in which patients with epilepsy followed in 21 Italian epilepsy centers, and their caring physicians were asked to fill anonymous questionnaires to collect data on different aspects of the disease and their needs and priorities in its management. The collected information included demographics, clinical profile and diagnosis, treatment and outcome of epilepsy. The questions were designed to understand the expectations of the patients and their caring physicians and verify the degree of concordance between patient and doctor. The study population was divided in six prognostic categories: (1) Newly diagnosed epilepsy; (2) Absence of seizures for at least 2 years; (3) Absence of seizures for at least 1 year or occasional seizures; (4) Nondrug-resistant recurrent seizures; (5) drug-resistant seizures; (6) surgical candidate. Results: Of the 787 patients enrolled, 432 were women and 355 men aged 15 to 88 years (median 41 years). Disease duration ranged from 6 months to 75 years. The sample included 53 patients with newly diagnosed epilepsy, 283 without seizures for at least 2 years, 162 seizure-free for at least 1 year or with occasional seizures, 123 with nondrug-resistant recurrent seizures, 128 with drug-resistant seizures, and 38 surgical candidates. Significant differences were found between patients and physicians in terms of priorities and needs with reference to the management of the disease. While physicians tend to prioritize the information on the diagnosis and treatment of epilepsy depending on timing and severity, patients focus on the search of the cause, the side effects of drugs, and the effects of any new treatment on the control of seizures regardless of the prognostic category. In addition, physicians tend to undervalue the communication of specific information, like the risk of sudden unexpected death in epilepsy (SUDEP) or the existence of lay associations, which might be of special interest for selected categories of patients. Significance: Differences between patients with epilepsy and their caring physicians in terms of needs and priorities and suboptimal communication call for the implementation of programs aimed at addressing the factors deemed most relevant by patients and caregivers for the management of the disease.

2021 - Ultrasound assisted awake epilepsy surgery for type iiB focal cortical dysplasia in eloquent areas [Articolo su rivista]
Martinoni, M.; Marucci, G.; Meletti, S.; Volpi, L.; Michelucci, R.; Giulioni, M.
abstract

Focal cortical dysplasia (FCD) type IIb is a frequent cause of pharmacoresistant epilepsy. However, intraoperative identification of the pathological tissue still remains a challenge despite the use of neuronavigation, particularly when it lies in eloquent areas.

2021 - Unraveling the enigma of new-onset refractory status epilepticus: a systematic review of aetiologies [Articolo su rivista]
Lattanzi, S.; Leitinger, M.; Rocchi, C.; Salvemini, S.; Matricardi, S.; Brigo, F.; Meletti, S.; Trinka, E.
abstract

Background and purpose: New-onset refractory status epilepticus (NORSE) is a clinical presentation, neither a specific diagnosis nor a clinical entity. It refers to a patient without active epilepsy or other pre-existing relevant neurological disorder, with a NORSE without a clear acute or active structural, toxic or metabolic cause. This study reviews the currently available evidence about the aetiology of patients presenting with NORSE and NORSE-related conditions. Methods: A systematic search was carried out for clinical trials, observational studies, case series and case reports including patients who presented with NORSE, febrile-infection-related epilepsy syndrome or the infantile hemiconvulsion-hemiplegia and epilepsy syndrome. Results: Four hundred and fifty records were initially identified, of which 197 were included in the review. The selected studies were retrospective case–control (n = 11), case series (n = 83) and case reports (n = 103) and overall described 1334 patients both of paediatric and adult age. Aetiology remains unexplained in about half of the cases, representing the so-called ‘cryptogenic NORSE’. Amongst adult patients without cryptogenic NORSE, the most often identified cause is autoimmune encephalitis, either non-paraneoplastic or paraneoplastic. Infections are the prevalent aetiology of paediatric non-cryptogenic NORSE. Genetic and congenital disorders can have a causative role in NORSE, and toxic, vascular and degenerative conditions have also been described. Conclusions: Far from being a unitary condition, NORSE is a heterogeneous and clinically challenging presentation. The development and dissemination of protocols and guidelines to standardize diagnostic work-up and guide therapeutic approaches should be implemented. Global cooperation and multicentre research represent priorities to improve the understanding of NORSE.

2021 - Why Me? To Be an Ultra-Responder to Antiplatelet Therapy: A Case Report [Articolo su rivista]
Rosafio, F.; Bigliardi, G.; Lelli, N.; Vandelli, L.; Naldi, F.; Ciolli, L.; Meletti, S.; Zini, A.
abstract

Background: Platelet function testing is a valid tool to investigate the clinical response to antiplatelet therapy in different clinical settings; in particular, it might supply helpful information in patients with cerebrovascular disease. Oral antiplatelet treatment, such as Aspirin (ASA) and Clopidogrel, is the gold standard in secondary stroke prevention of non-cardiogenic ischemic stroke; conversely, its application as a primary prevention therapy is not routinely recommended in patients with vascular risk factors. Multiple electrode platelet aggregometry (MEA) impedance aggregometer is a validated device to test platelet inhibition induced by ASA or Clopidogrel. Case Report: We report the case of a 78-year-old patient without relevant clinical history, taking ASA as primary prevention strategy, who was admitted for sudden onset of dysarthria and left facial hyposthenia during physical effort. Brain CT revealed two small subcortical bilateral spontaneous intracranial hemorrhages. Platelet aggregometry with MEA performed upon admission revealed a very strong platelet inhibition induced by ASA (result of the ASPI Test was 5 U, consistent with an ultra-responsiveness to ASA, and the cutoff value of correct responsiveness is <40 U). MRI at longitudinal follow-up revealed the presence of two small cavernous angioma underlying hemorrhagic spots. Conclusion: The evaluation of platelet reactivity in stroke patients undergoing antiplatelet therapies, not commonly performed in clinical practice, could be useful to optimize prevention strategies; the verification of the biological effectiveness of ASA or Clopidogrel could be a valid tool in the definition of each patient's risk profile, particularly in patients with cerebrovascular disease known to be at increased risk for both hemorrhagic and thrombotic complications.

2021 - fMRI-Based Effective Connectivity in Surgical Remediable Epilepsies: A Pilot Study [Articolo su rivista]
Vaudano, A. E.; Mirandola, L.; Talami, F.; Giovannini, G.; Monti, G.; Riguzzi, P.; Volpi, L.; Michelucci, R.; Bisulli, F.; Pasini, E.; Tinuper, P.; Di Vito, L.; Gessaroli, G.; Malagoli, M.; Pavesi, G.; Cardinale, F.; Tassi, L.; Lemieux, L.; Meletti, S.
abstract

Simultaneous EEG-fMRI can contribute to identify the epileptogenic zone (EZ) in focal epilepsies. However, fMRI maps related to Interictal Epileptiform Discharges (IED) commonly show multiple regions of signal change rather than focal ones. Dynamic causal modeling (DCM) can estimate effective connectivity, i.e. the causal effects exerted by one brain region over another, based on fMRI data. Here, we employed DCM on fMRI data in 10 focal epilepsy patients with multiple IED-related regions of BOLD signal change, to test whether this approach can help the localization process of EZ. For each subject, a family of competing deterministic, plausible DCM models were constructed using IED as autonomous input at each node, one at time. The DCM findings were compared to the presurgical evaluation results and classified as: "Concordant" if the node identified by DCM matches the presumed focus, "Discordant" if the node is distant from the presumed focus, or "Inconclusive" (no statistically significant result). Furthermore, patients who subsequently underwent intracranial EEG recordings or surgery were considered as having an independent validation of DCM results. The effective connectivity focus identified using DCM was Concordant in 7 patients, Discordant in two cases and Inconclusive in one. In four of the 6 patients operated, the DCM findings were validated. Notably, the two Discordant and Invalidated results were found in patients with poor surgical outcome. Our findings provide preliminary evidence to support the applicability of DCM on fMRI data to investigate the epileptic networks in focal epilepsy and, particularly, to identify the EZ in complex cases.

2021 - “Don’t call me from the left side…”: ischemic stroke in a patient with uncommon vertebral artery dissection [Articolo su rivista]
Bigliardi, G.; Rosafio, F.; Dell'Acqua, M. L.; Vandelli, L.; Picchetto, L.; Mandrioli, J.; Bertellini, E.; Vallone, S.; Meletti, S.
abstract

2020 - Anti-NMDA receptor encephalitis presenting as new onset refractory status epilepticus in COVID-19 [Articolo su rivista]
Monti, G.; Giovannini, G.; Marudi, A.; Bedin, R.; Melegari, A.; Simone, A. M.; Santangelo, M.; Pignatti, A.; Bertellini, E.; Trenti, T.; Meletti, S.
abstract

2020 - Antidepressant effect of vagal nerve stimulation in epilepsy patients: a systematic review [Articolo su rivista]
Assenza, G.; Tombini, M.; Lanzone, J.; Ricci, L.; Di Lazzaro, V.; Casciato, S.; Morano, A.; Giallonardo, A. T.; Di Bonaventura, C.; Beghi, E.; Ferlazzo, E.; Gasparini, S.; Giuliano, L.; Pisani, F.; Benna, P.; Bisulli, F.; De Falco, F. A.; Franceschetti, S.; La Neve, A.; Meletti, S.; Mostacci, B.; Sartucci, F.; Striano, P.; Villani, F.; Aguglia, U.; Avanzini, G.; Belcastro, V.; Bianchi, A.; Cianci, V.; Labate, A.; Magaudda, A.; Michelucci, R.; Verri, A.; Zaccara, G.; Pizza, V.; Tinuper, P.; Di Gennaro, G.
abstract

Background: Vagal nerve stimulation (VNS) is an effective palliative therapy in drug-resistant epileptic patients and is also approved as a therapy for treatment-resistant depression. Depression is a frequent comorbidity in epilepsy and it affects the quality of life of patients more than the seizure frequency itself. The aim of this systematic review is to analyze the available literature about the VNS effect on depressive symptoms in epileptic patients. Material and methods: A comprehensive search of PubMed, Medline, Scopus, and Google Scholar was performed, and results were included up to January 2020. All studies concerning depressive symptom assessment in epileptic patients treated with VNS were included. Results: Nine studies were included because they fulfilled inclusion criteria. Six out of nine papers reported a positive effect of VNS on depressive symptoms. Eight out of nine studies did not find any correlation between seizure reduction and depressive symptom amelioration, as induced by VNS. Clinical scales for depression, drug regimens, and age of patients were broadly different among the examined studies. Conclusions: Reviewed studies strongly suggest that VNS ameliorates depressive symptoms in drug-resistant epileptic patients and that the VNS effect on depression is uncorrelated to seizure response. However, more rigorous studies addressing this issue are encouraged.

2020 - Cerebrospinal fluid kappa and lambda free light chains in oligoclonal band‐negative patients with suspected multiple sclerosis [Articolo su rivista]
Ferraro, Diana; Trovati, Alice; Bedin, Roberta; Natali, Patrizia; Franciotta, Diego; Santangelo, Mario; Camera, Valentina; Vitetta, Francesca; Varani, Manuela; Trenti, Tommaso; Gastaldi, Matteo; De Biasi, Sara; Nasi, Milena; Pinti, Marcello; Meletti, Stefano; Sola, Patrizia
abstract

Cerebrospinal fluid (CSF) free light kappa chains (kappa FLC) may be a more sensitive marker of intrathecal IgG synthesis compared to oligoclonal bands (OCBs). Our aim was to retrospectively determine the additional value of the kappa and lambda index (CSF FLC/serum FLC)/(CSF albumin/serum albumin) in predicting a Multiple Sclerosis (MS) diagnosis in a group of OCB-negative patients with suspected MS.

2020 - Clinical outcomes and treatments effectiveness in status epilepticus resolved by antiepileptic drugs: A five-year observational study [Articolo su rivista]
Orlandi, N.; Giovannini, G.; Rossi, J.; Cioclu, M. C.; Meletti, S.
abstract

Objective: To evaluate clinical outcomes and treatment effectiveness of status epilepticus finally resolved by nonbenzodiazepine antiepileptic drugs (AEDs). Methods: All consecutive SE episodes observed from September 1, 2013, to September 1, 2018, and resolved by AEDs were considered. Diagnosis and classification of SE followed the 2015 ILAE proposal. Nonconvulsive status (NCSE) diagnosis was confirmed according to the Salzburg EEG criteria. The modified Rankin Scale and deaths at 30 days from onset were used to evaluate outcomes. Results: A total of 277 status episodes (mean age 71 years; 61% female) were treated and resolved by antiepileptic drugs after 382 treatment trials. 68% of the SE resolved after AED use as first/second treatment line, while subsequent trials with AEDs gave an additional 32% resolution. A return to baseline conditions was observed in 48% of the patients, while overall mortality was 19% without significant changes across the study years. Mortality was higher in NCSE than in convulsive SE (22.5% vs 12.9%; P <.05), while mortality did not differ in SE episodes resolved by a first/second AED trial (17.2%) versus SE resolved by successive treatment trials (18.9%). The resolution rate of intravenous AEDs was 82% for valproate, 77% for lacosamide, 71% for phenytoin, and 62% for levetiracetam. No significant differences were found in head-to-head comparison, but for the valproate-levetiracetam one that was related to NCSE episodes in which valproate resulted to be effective in 86% of the trials while levetiracetam in 62% (P <.002). Significance: A high short-term mortality, stable over time, was observed in SE despite resolution of seizures, especially in SE with nonconvulsive semiology. Comparative AED efficacy showed no significant differences except for higher resolution rate for valproate versus levetiracetam in NCSE.

2020 - Intraoperative neurophysiological monitoring in aneurysm clipping: Does it make a difference? A systematic review and meta-analysis [Articolo su rivista]
Nasi, Davide; Meletti, Stefano; Tramontano, Vincenzo; Pavesi, Giacomo
abstract

2020 - Kappa Index Versus CSF Oligoclonal Bands in Predicting Multiple Sclerosis and Infectious/Inflammatory CNS Disorders [Articolo su rivista]
Ferraro, Diana; Bedin, Roberta; Natali, Patrizia; Franciotta, Diego; Smolik, Krzysztof; Santangelo, Mario; Immovilli, Paolo; Camera, Valentina; Vitetta, Francesca; Gastaldi, Matteo; Trenti, Tommaso; Meletti, Stefano; Sola, Patrizia
abstract

Cerebrospinal fluid (CSF) kappa free light chains (KFLC) are gaining increasing interest as markers of intrathecal immunoglobulin synthesis. The main aim of this study was to assess the diagnostic accuracy (AUC) of the kappa index (CSF/serum KFLC divided by the CSF/serum albumin ratio) compared to CSF oligoclonal IgG bands (OCB) in predicting Multiple Sclerosis (MS) or a central nervous system infectious/inflammatory disorder (CNSID).

2020 - Management of status epilepticus in adults. Position paper of the Italian League against Epilepsy [Articolo su rivista]
Minicucci, F.; Ferlisi, M.; Brigo, F.; Mecarelli, O.; Meletti, S.; Aguglia, U.; Michelucci, R.; Mastrangelo, M.; Specchio, N.; Sartori, S.; Tinuper, P.
abstract

Since the publication of the Italian League Against Epilepsy guidelines for the treatment of status epilepticus in 2006, advances in the field have ushered in improvements in the therapeutic arsenal. The present position paper provides neurologists, epileptologists, neurointensive care specialists, and emergency physicians with updated recommendations for the treatment of adult patients with status epilepticus. The aim is to standardize treatment recommendations in the care of this patient population.

2020 - Middle cerebral artery ischemic stroke and COVID-19: a case report [Articolo su rivista]
Bigliardi, G.; Ciolli, L.; Giovannini, G.; Vandelli, L.; Dell'Acqua, M. L.; Borzi, G. M.; Picchetto, L.; Rosafio, F.; Ricceri, R.; Meletti, S.
abstract

We present a clinical case of a patient with SARS-CoV-2 infection and respiratory symptoms, complicated with a pro-thrombotic state involving multiple vascular territories and concomitant interleukin-6 increase. This case underlines the possibility to develop a COVID-19-related coagulopathy.

2020 - Motor Manifestations in Epileptic Photosensitivity: Clinical Features and Pathophysiological Insights [Capitolo/Saggio]
Rubboli, G.; Gardella, E.; Meletti, S.
abstract

2020 - Motor and Limbic System Contribution to Emotional Laughter across the Lifespan [Articolo su rivista]
Talami, F.; Vaudano, A. E.; Meletti, S.
abstract

Laughter is a universal human behavior generated by the cooperation of different systems toward the construction of an expressive vocal pattern. Given the sensitivity of neuroimaging techniques to movements, the neural mechanisms underlying laughter expression remain unclear. Herein, we characterized the neural correlates of emotional laughter using the onsets and the duration of laughter bursts to inform functional magnetic resonance imaging. Laughter-related blood oxygen level-dependent (BOLD) increases involved both the motor (motor cortex, supplementary motor area, frontal operculum) and the emotional/limbic (anterior cingulate cortex, amygdala, n. accumbens, hippocampus) systems, as well as modulatory circuitries encompassing the basal ganglia, thalamus, and cerebellum. BOLD changes related to the 2 s preceding the laughter outbreak were selectively observed at the temporo-occipital junction and the periaqueductal gray matter, supporting the role of the former in the detection of incongruity and the gating role of the latter in the initiation of spontaneous laughter. Moreover, developmental changes were identified in laughter processing, consisting in a greater engagement of the reward circuitry in younger subjects; conversely, the default mode network appears more activated in older participants. Our findings contribute valuable information about the processing of real-life humorous materials and suggest a close link between laughter-related motor, affective, and cognitive elements, confirming its complex and multi-faceted nature.

2020 - Plasma neurofilaments correlate with disability in progressive multiple sclerosis patients [Articolo su rivista]
Ferraro, Diana; Guicciardi, Claudio; De Biasi, Sara; Pinti, Marcello; Bedin, Roberta; Camera, Valentina; Vitetta, Francesca; Nasi, Milena; Meletti, Stefano; Sola, Patrizia
abstract

Cerebrospinal fluid (CSF) and blood neurofilaments (NFLs) are markers of axonal damage and are being investigated, mostly in relapsing-remitting (RR) MS, as a marker of disease activity and of response to treatment, while there are less data in progressive MS patients. Primary aim was to measure NFL in plasma samples of untreated patients with primary (PP) and secondary (SP) progressive MS and to correlate them with disability, disease severity, and prior/subsequent disability progression.

2020 - Reply to Dr. Capovilla on “Reply to the article “Management of status epilepticus in adults. Position paper of the Italian League Against Epilepsy”” [Articolo su rivista]
Minicucci, F.; Ferlisi, M.; Brigo, F.; Mecarelli, O.; Meletti, S.; Aguglia, U.; Michelucci, R.; Mastrangelo, M.; Specchio, N.; Sartori, S.; Tinuper, P.
abstract

2020 - Sleep-related hypermotor epilepsy (SHE): Contribution of known genes in 103 patients [Articolo su rivista]
Licchetta, L.; Pippucci, T.; Baldassari, S.; Minardi, R.; Provini, F.; Mostacci, B.; Plazzi, G.; Tinuper, P.; Bisulli, F.; Bianchi, A.; Striano, P.; Gambardella, A.; Giordano, L.; Santucci, M.; Meletti, S.; Crichiutti, G.; Marini, C.; Vignoli, A.; Dilena, R.; Briatore, E.
abstract

Purpose: Genetics of Sleep-related Hypermotor Epilepsy (SHE) includes mutations in several genes that cumulatively account for 30 % of families. This approximate estimate comes from different case-series, each focused on the screening of a single gene. We systematically investigated a large cohort of SHE patients to estimate the frequency of pathogenic variants in the main genes thus far implicated in this epilepsy syndrome. Methods: We selected familial and isolated cases diagnosed with clinical/confirmed SHE who underwent genetic analysis by comparable next generation sequencing (NGS) techniques (WES/ multigene epilepsy panel). The identified heterozygous variants were classified according to the American College of Medical Genetics and Genomics guidelines. Results: We included 103 SHE patients (M/F:61/42) who underwent NGS. Sixteen (15.5 %) were familial cases, 16.5 % had focal cortical dysplasia (FCD). We identified three pathogenic variants in CHRNA4 (2.9 %, CI: 0.6–8.3 %), two of whom novel; one pathogenic variant in KCNT1 (1 %, CI: 0.02–5.29 %); four loss-of-function variants in DEPDC5 (3.9 %, CI: 1.1–9.7 %), one of whom never reported; finally, one missense change in NPRL2 (1 %, CI: 0.02–5.29 %), already reported as pathogenic. Three out of the four patients with DEPDC5 variants had FCD. Conclusions: The overall frequency of pathogenic variants in our SHE cohort was 8.7 %, 19 % and 7 % considering familial and sporadic cases, respectively. Pathogenic variants in the GATOR1-complex genes account for 5 % of the cases. DEPDC5 shows the highest variants frequency, especially in patients with genetic-structural etiology. From a practical perspective, analysis of this gene is recommended even in isolated cases, because of possible implications for patient management.

2020 - Spatio-temporal dynamics of interictal activity in musicogenic epilepsy: Two case reports and a systematic review of the literature [Articolo su rivista]
Nuara, A.; Mirandola, L.; Fabbri-Destro, M.; Giovannini, G.; Vecchiato, G.; Vaudano, A. E.; Tassinari, C. A.; Avanzini, P.; Meletti, S.
abstract

Objective: To explore neurophysiological features of musicogenic epilepsy (ME), discussing experimental findings in the framework of a systematic review on ME. Methods: Two patients with ME underwent high-density-electroencephalography (hd-EEG) while listening to ictogenic songs. In one case, musicogenic seizures were elicited. Independent component analysis (ICA) was applied to hd-EEG, and components hosting interictal and ictal elements were identified and localized. Finally, the temporal dynamics of spike-density was studied relative to seizures. All findings were compared against the results of a systematic review on ME, collecting 131 cases. Results: Interictal spikes appeared isolated in specific fronto-temporal independent components, whose cortical generators were located in the anterior temporal and inferior frontal lobe. In the patient undergoing seizure, ictal discharge relied in the same component, with the interictal spike-density decreasing before the seizure onset. Conclusion: Our study shows how ICA can isolate neurophysiological features of ictal and interictal discharges in ME, highlighting a fronto-temporal localization and a suppression of spike-density preceding the seizure onset. Significance: While the localization of ME activity could indicate which aspect within the musical stimulus might trigger musicogenic seizures for each patient, the study of ME dynamics could contribute to the development of models for seizure-prediction and their validation.

2020 - The EEG diagnosis of NCSE: Concordance between clinical practice and Salzburg Criteria for NCSE [Articolo su rivista]
Othman, A. S.; Meletti, S.; Giovannini, G.
abstract

Purpose: To evaluate the concordance between the EEG diagnosis of non-convulsive status epilepticus (NCSE) made by the treating physician and the application of the Salzburg Consensus Criteria (SCC) on consecutive urgent EEG requested for acute alteration of consciousness not otherwise explained. Methods: Retrospective evaluation of all urgent EEGs acquired between January 1st and March 31st 2018 in adolescents and adult patients (≥14 years old). The ‘reference’ was the neurologist who first evaluated the patient and reported the corresponding EEG diagnosis. All were blind to the SCC. All included EEG were evaluated and classified by three neurologists trained in the application of SCC blind to the clinical diagnosis. Results: 181 consecutive EEGs entered the study. The treating clinician diagnosed a NCSE in 17 cases (9%). According to the SCC, 12 EEGs were classified as Definite NCSE (7%), 71 (39 %) as Possible NCSE, and 98 (54 %) as no NCSE. A perfect concordance was found for the Definite- and No-NCSE categories, while only 5 patients with a Possible-NCSE were diagnosed by the treating clinician as having NCSE. It is relevant to note that aamong the 66 patients with a Possible NCSE not diagnosed as SE by the treating clinician, only two presented an evolution toward a definite SE. Conclusion: SCC have optimal performances for the ‘Definite NCSE’, and to exclude the presence of a NCSE. Conversely, the Possible NCSE category is still a a grey land of debate that could potentially include many different conditions.

2020 - The Relation Between Aortic Arch Branching Types and the Laterality of Cardio-Embolic Stroke [Articolo su rivista]
Elsaid, N.; Bigliardi, G.; Dell'Acqua, M. L.; Vandelli, L.; Ciolli, L.; Picchetto, L.; Borzi, G.; Ricceri, R.; Pentore, R.; Vallone, S.; Meletti, S.; Saied, A.
abstract

Background and purpose: The trajectory of cardiogenic emboli could be affected by anatomical and flow characteristics of the aortic arch. We aimed to study the relation between the different aortic arch patterns and the laterality of cardiogenic emboli. Methods: 192 cardioembolic strokes were classified into 3 groups according to the type of the aortic arch; type 1 (n = 69), type 2 (n = 49), type 3 (n = 74). The side and site of the cerebral vessels occlusion were divided into anterior and posterior circulation strokes, and anterior strokes were further subdivided into right or left internal carotid, middle or anterior cerebral arteries occlusion. Results: Overall, the anterior circulation embolic occlusions were more common than the posterior, and middle cerebral artery more commonly affected than internal carotid artery. The left side propensity was higher either in the total patients’ pool or after segregation into atrial fibrillation (AF) and non AF cardio-embolic cases in all types of aortic arch except for type 1 aortic arch in the non AF cases. This propensity tended to get higher with advancement of the aortic arch types but failed to show statistically significant difference between the 3 arch types, however combination of type 2 and 3 arches into a single group showed statistically significant rise in the left side propensity in the total cardioembolic cases (P = 0.039) and in the non AF cardioembolic cases (P = 0.029). The bovine arch also showed increased left side propensity. Conclusion: Cardioemboli tends to have left anterior cerebrovascular predilection especially with AF. Different geometrical patterns of aortic arch branching seem to affect the laterality of cardioemboli and increase its left side predilection.

2020 - The effect of chronic neuroglycopenia on resting state networks in GLUT1 syndrome across the lifespan [Articolo su rivista]
Vaudano, A. E.; Olivotto, S.; Ruggieri, A.; Gessaroli, G.; Talami, Francesca; Parmeggiani, Andrea; De Giorgis, V.; Veggiotti, P.; Meletti, S.
abstract

Glucose transporter type I deficiency syndrome (GLUT1DS) is an encephalopathic disorder due to a chronic insufficient transport of glucose into the brain. PET studies in GLUT1DS documented a widespread cortico-thalamic hypometabolism and a signal increase in the basal ganglia, regardless of age and clinical phenotype. Herein, we captured the pattern of functional connectivity of distinct striatal, cortical, and cerebellar regions in GLUT1DS (10 children, eight adults) and in healthy controls (HC, 19 children, 17 adults) during rest. Additionally, we explored for regional connectivity differences in GLUT1 children versus adults and according to the clinical presentation. Compared to HC, GLUT1DS exhibited increase connectivity within the basal ganglia circuitries and between the striatal regions with the frontal cortex and cerebellum. The excessive connectivity was predominant in patients with movement disorders and in children compared to adults, suggesting a correlation with the clinical phenotype and age at fMRI study. Our findings highlight the primary role of the striatum in the GLUT1DS pathophysiology and confirm the dependency of symptoms to the patients' chronological age. Despite the reduced chronic glucose uptake, GLUT1DS exhibit increased connectivity changes in regions highly sensible to glycopenia. Our results may portrait the effect of neuroprotective brain strategy to overcome the chronic poor energy supply during vulnerable ages.

2020 - The management of epilepsy in clinical practice: Do the needs manifested by the patients correspond to the priorities of the caring physicians? Findings from the EPINEEDS Study [Articolo su rivista]
Giussani, G.; Enia, G.; Bianchi, E.; Mecarelli, O.; Beghi, E.; Pulitano, P.; Cagnetti, C.; Baldinelli, S.; La Neve, A.; Tappata, M.; Francavilla, T.; De Maria, G.; Sofia, V.; Giuliano, L.; Mainieri, G.; Fatuzzo, D.; Belcastro, V.; Elia, M.; D'Orsi, G.; Lalla, A.; Salmaggi, A.; Brigo, F.; Magaudda, A.; Pisani, F.; Galletta, S.; Pisani, L. R.; Raffaele, M.; Cosenza, D.; Villani, F. S.; Quintas, R. M. M.; Cervellione, R.; Borroni, S.; Meletti, S.; Ferrarese, C.; Barbella, G.; Di Francesco, J.; Bogliun, G.; Beretta, S.; Galimberti, C. A.; Cantisani, T. A.; Cecconi, M.; Celani, M. G.; Papetti, R.; Giorgi, F. S.; Aguglia, U.; Gasparini, S.; Ferlazzo, E.; Manganotti, P.; Crichiutti, G.; Bravar, G.
abstract

Purpose: The purpose of this study was to assess the priorities of patients with epilepsy and caring physicians and the correspondence between these priorities. Methods: In this multicenter cross-sectional study, patients with epilepsy attending 21 Italian epilepsy centers and their caring physicians filled anonymously questionnaires on the needs and priorities in the management of the disease. Included were questions on patients' demographics, diagnosis, treatment, and outcome of epilepsy. The concordance between patients and their physicians was assessed on various aspects of the diagnosis and care of the disease. Patients' satisfaction with communication, services, and patient–doctor relationship was also assessed. Results: Included were 432 women and 355 men aged 15 to 88 years (median: 41 years). Disease duration ranged from 6 months to 75 years. A structural/metabolic etiology predominated (52.7%), followed by a (presumed) genetic etiology (33.0%). Seizure remission was present in 56.5% of cases. Comorbidities requiring chronic treatment were present in 27.5%, and comorbidities affecting self-sufficiency in 9.5%. Psychiatric comorbidity was present in 35.0%. Patients' priorities included discovery of the cause (89.1%), use of right drug (98.7%), use of a drug without chronic side effects (94.0%), and a life without restrictions (90.4%). Physicians' priorities included choice of right drug (83.5%) and use of drugs without chronic side effects (86.8%). Priorities varied with patients' age, sex, education, and occupation. Patient–doctor relationships were at least good in most cases. The information imparted was considered unsatisfactory by 21–44% of cases on seizure circumstances and complications, side effects of drugs, limitations of daily activities, and management of physiologic or pathologic conditions. Patients declared overall satisfaction, except for appointments (21.5%) and emergencies (30.8%). Conclusion: Patients and physicians' priorities in the management of epilepsy overlap only in part. Patients are satisfied with their caring physicians and less satisfied with communication and management of routine and emergency problems.

2020 - Valproate Use Is Associated With Posterior Cortical Thinning and Ventricular Enlargement in Epilepsy Patients [Articolo su rivista]
Tondelli, M.; Vaudano, A. E.; Sisodiya, S. M.; Meletti, S.
abstract

Valproate is a drug widely used to treat epilepsy, bipolar disorder, and occasionally to prevent migraine headache. Despite its clinical efficacy, prenatal exposure to valproate is associated with neurodevelopmental impairments and its use in children and adults was associated with rare cases of reversible brain atrophy and ventricular enlargement. To determine whether valproate use is related with structural brain changes we examined through a cross-sectional study cortical and subcortical structures in a group of 152 people with epilepsy and a normal clinical brain MRI. Patients were grouped into those currently using valproate (n = 54), those taking drugs other than valproate (n = 47), and drug-naïve patients (n = 51) at the time of MRI, irrespectively of their epilepsy syndrome. Cortical thickness and subcortical volumes were analyzed using Freesurfer, version 5.0. Subjects exposed to valproate (either in mono- or polytherapy) showed reduced cortical thickness in the occipital lobe, more precisely in the cuneus bilaterally, in the left lingual gyrus, and in left and right pericalcarine gyri when compared to patients who used other antiepileptic drugs, to drug-naïve epilepsy patients, and to healthy controls. Considering the subgroup of patients using valproate monotherapy (n = 25), both comparisons with healthy controls and drug-naïve groups confirmed occipital lobe cortical thickness reduction. Moreover, patients using valproate showed increased left and right lateral ventricle volume compared to all other groups. Notably, subjects who were non-valproate users at the time of MRI, but who had valproate exposure in the past (n = 27) did not show these cortical or subcortical brain changes. Cortical changes in the posterior cortex, particularly in the visual cortex, and ventricular enlargement, are present in people with epilepsy using valproate, independently from clinical and demographical variables. These findings are relevant both for the efficacy and adverse events profile of valproate use in people with epilepsy.

2019 - Contribution of ultrarare variants in mTOR pathway genes to sporadic focal epilepsies [Articolo su rivista]
Pippucci, Tommaso; Licchetta, Laura; Baldassari, Sara; Marconi, Caterina; De Luise, Monica; Myers, Candace; Nardi, Elena; Provini, Federica; Cameli, Cinzia; Minardi, Raffaella; Bacchelli, Elena; Giordano, Lucio; Crichiutti, Giovanni; D'Orsi, Giuseppe; Seri, Marco; Gasparre, Giuseppe; Mefford, Heather C.; Tinuper, Paolo; Bisulli, Francesca; Bianchi, Amedeo; Striano, Pasquale; Gambardella, Antonio; Meletti, Stefano; Dilena, Roberto; Santucci, Margherita; Marini, Carla; Vignoli, Aglaia; Gobbi, Giuseppe; Briatore, Eleonora; Mastrangelo, Massimo
abstract

Objective: We investigated the contribution to sporadic focal epilepsies (FE) of ultrarare variants in genes coding for the components of complexes regulating mechanistic Target Of Rapamycin (mTOR)complex 1 (mTORC1). Methods: We collected genetic data of 121 Italian isolated FE cases and 512 controls by Whole Exome Sequencing (WES) and single-molecule Molecular Inversion Probes (smMIPs) targeting 10 genes of the GATOR1, GATOR2, and TSC complexes. We collapsed “qualifying” variants (ultrarare and predicted to be deleterious or loss of function) across the examined genes and sought to identify their enrichment in cases compared to controls. Results: We found eight qualifying variants in cases and nine in controls, demonstrating enrichment in FE patients (P = 0.006; exact unconditional test, one-tailed). Pathogenic variants were identified in DEPDC5 and TSC2, both major genes for Mendelian FE syndromes. Interpretation: Our findings support the contribution of ultrarare variants in genes in the mTOR pathway complexes GATOR and TSC to the risk of sporadic FE and a shared genetic basis between rare and common epilepsies. The identification of a monogenic etiology in isolated cases, most typically encountered in clinical practice, may offer to a broader community of patients the perspective of precision therapies directed by the underlying genetic cause.

2019 - Do neurologists agree in diagnosing drug resistance in adults with focal epilepsy? [Articolo su rivista]
Zaccara, Gaetano; Mula, Marco; Ferrò, Bruno; Consoli, Domenico; Elia, Maurizio; Giallonardo, Anna Teresa; Iudice, Alfonso; La Neve, Angela; Meletti, Stefano; Tinuper, Paolo; Zummo, Leila; Perucca, Emilio
abstract

Objective: To evaluate interrater agreement in categorizing treatment outcomes and drug responsiveness status according to the International League Against Epilepsy (ILAE) definition of drug-resistant epilepsy. Methods: A total of 1053 adults with focal epilepsy considered by the investigators to meet ILAE criteria for drug resistance were enrolled consecutively at 43 centers and followed up prospectively for 18-34 months. Treatment outcomes for all antiepileptic drugs (AEDs) used up to enrollment (retrospective assessment), and on an AED newly introduced at enrollment, were categorized by individual investigators and by 2 rotating members of a 16-member expert panel (EP) that reviewed the patient records independently. Interrater agreement was tested by Cohen’s kappa (k) statistics and rated according to Landis and Koch’s criteria. Results: Agreement between EP members in categorizing outcomes on the newly introduced AED was almost perfect (90.1%, k = 0.84, 95% confidence interval [CI] 0.80-0.87), whereas agreement between the EP and individual investigators was moderate (70.4%, k = 0.57, 95% CI 0.53-0.61). Similarly, categorization of outcomes on previously used AEDs was almost perfect between EP members (91.7%, k = 0.83, 95% CI 0.81-0.84) and moderate between the EP and investigators (68.2%, k = 0.50, 95% CI 0.48-0.52). Disagreement was related predominantly to outcomes considered to be treatment failures by the investigators but categorized as undetermined by the EP. Overall, 19% of patients classified as having drug-resistant epilepsy by the investigators were considered by the EP to have “undefined responsiveness.”. Significance: Interrater agreement in categorizing treatment outcomes according to ILAE criteria ranges from moderate to almost perfect. Nearly 1 in 5 patients considered by enrolling neurologists to be “drug-resistant” were classified by the EP as having “undefined responsiveness.”.

2019 - Epidemiology of status epilepticus in adults: A population-based study on incidence, causes, and outcomes [Articolo su rivista]
Leitinger, Markus; Trinka, Eugen; Giovannini, Giada; Zimmermann, Georg; Florea, Cristina; Rohracher, Alexandra; Kalss, Gudrun; Neuray, Caroline; Kreidenhuber, Rudolf; Höfler, Julia; Kuchukhidze, Giorgi; Granbichler, Claudia; Dobesberger, Judith; Novak, Helmut F; Pilz, Georg; Meletti, Stefano; Siebert, Uwe
abstract

In 2015, the International League Against Epilepsy (ILAE) proposed a new definition of status epilepticus (SE): 5 minutes of ongoing seizure activity to diagnose convulsive SE (CSE, ie, bilateral tonic-clonic SE) and 10 minutes for focal SE and absence SE, rather than the earlier criterion of 30 minutes. Based on semiology, several types of SE with prominent motor phenomena at any time (including CSE) were distinguished from those without (ie, nonconvulsive SE, NCSE). We present the first population-based incidence study applying the new 2015 ILAE definition and classification of SE and report the impact of the evolution of semiology and level of consciousness (LOC) on outcome.

2019 - Mapping the Effect of Interictal Epileptic Activity Density During Wakefulness on Brain Functioning in Focal Childhood Epilepsies With Centrotemporal Spikes [Articolo su rivista]
Vaudano, A. E.; Avanzini, P.; Cantalupo, G.; Filippini, M.; Ruggieri, A.; Talami, F.; Caramaschi, E.; Bergonzini, P.; Vignoli, A.; Veggiotti, P.; Guerra, A.; Gessaroli, G.; Santucci, M.; Canevini, M. P.; Piccolo, B.; Pisani, F.; Gobbi, G.; Dalla Bernardina, B.; Meletti, S.
abstract

Childhood epilepsy with centrotemporal spikes (CECTS) is the most common type of “self-limited focal epilepsies.” In its typical presentation, CECTS is a condition reflecting non-lesional cortical hyperexcitability of rolandic regions. The benign evolution of this disorder is challenged by the frequent observation of associated neuropsychological deficits and behavioral impairment. The abundance (or frequency) of interictal centrotemporal spikes (CTS) in CECTS is considered a risk factor for deficits in cognition. Herein, we captured the hemodynamic changes triggered by the CTS density measure (i.e., the number of CTS for time bin) obtained in a cohort of CECTS, studied by means of video electroencephalophy/functional MRI during quite wakefulness. We aim to demonstrate a direct influence of the diurnal CTS frequency on epileptogenic and cognitive networks of children with CECTS. A total number of 8,950 CTS (range between 27 and 801) were recorded in 23 CECTS (21 male), with a mean number of 255 CTS/patient and a mean density of CTS/30 s equal to 10,866 ± 11.46. Two independent general linear model models were created for each patient based on the effect of interest: “individual CTS” in model 1 and “CTS density” in model 2. Hemodynamic correlates of CTS density revealed the involvement of a widespread cortical–subcortical network encompassing the sensory-motor cortex, the Broca's area, the premotor cortex, the thalamus, the putamen, and red nucleus, while in the CTS event-related model, changes were limited to blood–oxygen-level-dependent (BOLD) signal increases in the sensory-motor cortices. A linear relationship was observed between the CTS density hemodynamic changes and both disease duration (positive correlation) and age (negative correlation) within the language network and the bilateral insular cortices. Our results strongly support the critical role of the CTS frequency, even during wakefulness, to interfere with the normal functioning of language brain networks.

2019 - Simultaneous Recording EEG and fMRI [Capitolo/Saggio]
Meletti, S.
abstract

2019 - Spasmodic dysphonia as a presenting symptom of spinocerebellar ataxia type 12 [Articolo su rivista]
Rossi, J.; Cavallieri, F.; Giovannini, G.; Budriesi, C.; Gessani, A.; Carecchio, M.; Di Bella, D.; Sarto, E.; Mandrioli, J.; Contardi, S.; Meletti, S.
abstract

Autosomal dominant spinocerebellar ataxia (SCA) type 12 is a rare SCA characterized by a heterogeneous phenotype. Action tremor of the upper limbs is the most common presenting sign and cerebellar signs can appear subsequently. In many cases, minor signs, like dystonia, can be predominant even at onset. Laryngeal dystonia (spasmodic dysphonia) has been observed only in one case of SCA12 and never reported at disease onset. We present a 61-year-old female who developed spasmodic dysphonia followed by dystonic tremor and subsequent ataxia diagnosed with SCA12. Thus, spasmodic dysphonia can be a presenting symptom of SCA12.

2019 - The neuronal network of laughing in young patients with untreated narcolepsy [Articolo su rivista]
Vaudano, Anna Elisabetta; Pizza, Fabio; Talami, Francesca; Plazzi, Giuseppe; Meletti, Stefano
abstract

To investigate the neuronal correlates of spontaneous laughter in drug-naive pediatric patients with narcolepsy type I (NT1) compared to healthy controls by means of blood oxygen level-dependent (BOLD) MRI.

2019 - Tumor-associated status epilepticus in patients with glioma: Clinical characteristics and outcomes [Articolo su rivista]
Giovannini, G.; Pasini, F.; Orlandi, N.; Mirandola, L.; Meletti, S.
abstract

Between 3 and 12% of all adult status epilepticus (SE) are caused by a brain tumor. Gliomas, and in particular, high-grade gliomas (HGGs), are at high risk of SE development. In this study, we aimed to describe the clinical characteristic and outcomes of tumor-associated SE (TASE) in a population of adult patients with glioma prospectively collected between 2013 and 2019. In the aforementioned period, we observed 26 TASE (median age: 68 years). Overall, 22 patients (85%) presented a HGG (one anaplastic astrocytoma and 21 a glioblastoma) while 4 had a LGG (two diffuse astrocytoma and two ganglioglioma). All the lesions were supratentorial, and the temporal lobe was the most frequently involved (20 patients). Fourteen patients (54%) had the SE episode as the first manifestation of the tumor; in the remaining 12 (all patients with a HGG), the development of SE heralded tumor progression or reappearance. When TASE outcomes were compared with the ones observed in the general population of SE (SEGP), the response to treatment was not different between the two populations (refractory SE (RSE)/super-refractory SE (SRSE) 12% versus 13%, p = 0.75). In the short-term, group with TASE had a significantly lower global disability (modified Rankin scale (mRS) < 3 at discharge: 60% versus 32%, p < 0.001; at 30 days follow-up: 62% versus 30%, p < 0.001) and mortality (30 days mortality: 4% versus 27%, p = 0.008). Six months and 1 year mortality did not show any difference between the two groups (6 months: 46% and 45%, respectively, p = 0.9; 1 year: 68% and 52%, respectively, p = 0.22). The appearance of TASE often heralds tumor grow and progression. Even in this context, it appears to be as treatment-responsive as SEGP and the short-term disability and mortality related to SE episode are lower than those observed in the SEGP. Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures.

2019 - When the brain hurts the heart: status epilepticus inducing tako-tsubo cardiomyopathy [Articolo su rivista]
Giovannini, G.; Grassi, L.; Vincenzi, C.; Mirandola, L.; Meletti, S.
abstract

Tako-tsubo cardiomyopathy (TTC) is a transient myocardial dysfunction mainly affecting the left ventricle, mimicking an acute coronary syndrome. This condition can be precipitated either by psychological/physical stressful events or by a number of medical conditions among which are seizures and status epilepticus (SE). The evolution is mostly favourable but sometimes TTC can evolve into life-threatening conditions. We searched for cases of TTC among all consecutive SE episodes observed at our department during the period 2013-2018. In addition, we searched MEDLINE (accessed through PubMed from inception to August 31, 2018) to identify reports of patients with TTC associated with an SE episode. Three TTC cases among 392 SE episodes were identified. Adding our cases to those previously reported, overall, we identified 45 cases of TTC induced by SE. The majority were females of around 60 years of age experiencing a first episode of SE with prominent motor phenomena, mostly in the context of remote aetiology. The most frequent presenting symptom was mild hypotension but cases with a severe presentation were also reported. The overall evolution was positive in all cases but some severe complications such as pulmonary oedema, cardiogenic shock, ventricular fibrillation, and a giant apical thrombus were also reported (19%). TTC may be a rare potentially life-threatening consequence of SE. It is frequently unrecognized, and therefore underdiagnosed. Clinicians dealing with SE should be aware of this entity.

2018 - Correction to: Which elderly newly diagnosed glioblastoma patients can benefit from radiotherapy and temozolomide? A PERNO prospective study (Journal of Neuro-Oncology, (2016), 128, 1, (157-162), 10.1007/s11060-016-2093-1) [Articolo su rivista]
Franceschi, Enrico; Depenni, Roberta; Paccapelo, Alexandro; Ermani, Mario; Faedi, Marina; Sturiale, Carmelo; Michiara, Maria; Servadei, Franco; Pavesi, Giacomo; Urbini, Benedetta; Pisanello, Anna; Crisi, Girolamo; Cavallo, Michele A.; Dazzi, Claudio; Biasini, Claudia; Bertolini, Federica; Mucciarini, Claudia; Pasini, Giuseppe; Baruzzi, Agostino; Brandes, Alba A.; Baruzzi, A.; Albani, F.; Calbucci, F.; D’Alessandro, R.; Michelucci, R.; Brandes, A.; Eusebi, V.; Ceruti, S.; Fainardi, E.; Tamarozzi, R.; Emiliani, E.; Cavallo, M.; Franceschi, E.; Tosoni, A.; Cavallo, Marino; Fiorica, F.; Valentini, A.; Depenni, R.; Mucciarini, C.; Crisi, G.; Sasso, Enrico; Biasini, C.; Cavanna, L.; Guidetti, D.; Marcello, Norina; Pisanello, A.; Cremonini, A. M.; Guiducci, G.; de Pasqua, S.; Testoni, S.; Agati, R.; Ambrosetto, G.; Bacci, A.; Baldin, E.; Baldrati, A.; Barbieri, E.; Bartolini, Stefano; Bellavista, E.; Bisulli, F.; Bonora, E.; Bunkheila, F.; Carelli, V.; Crisci, M.; Dall’Occa, P.; de Biase, D.; Ferro, S.; Franceschi, C.; Frezza, G.; Grasso, Vincenzo; Leonardi, M.; Marucci, G.; Morandi, L.; Mostacci, B.; Palandri, G.; Pasini, E.; Pastore Trossello, M.; Pession, A.; Poggi, R.; Riguzzi, P.; Rinaldi, R.; Rizzi, S.; Romeo, G.; Spagnolli, F.; Tinuper, P.; Trocino, C.; Dall’Agata, M.; Frattarelli, M.; Gentili, G.; Giovannini, A.; Iorio, P.; Pasquini, U.; Galletti, G.; Guidi, C.; Neri, W.; Patuelli, A.; Strumia, S.; Faedi, M.; Casmiro, M.; Gamboni, A.; Rasi, F.; Cruciani, Giuseppe; Cenni, P.; Dazzi, C.; Guidi, A. R.; Zumaglini, F.; Amadori, A.; Pasini, G.; Pasquinelli, Mario; Pasquini, Elena; Polselli, A.; Ravasio, A.; Viti, B.; Sintini, M.; Ariatti, A.; Bertolini, F.; Bigliardi, G.; Carpeggiani, P.; Cavalleri, F.; Meletti, S.; Nichelli, P.; Pettorelli, E.; Pinna, Greta; Zunarelli, E.; Artioli, F.; Bernardini, I.; Costa, M.; Greco, G.; Guerzoni, R.; Stucchi, C.; Iaccarino, Corrado; Ragazzi, M.; Rizzi, R.; Zuccoli, G.; Api, P.; Cartei, F.; Colella, Margherita; Fallica, E.; Farneti, M.; Frassoldati, A.; Granieri, E.; Latini, F.; Monetti, C.; Saletti, A.; Schivalocchi, R.; Sarubbo, S.; Seraceni, S.; Tola, M. R.; Urbini, B.; Zini, G.; Giorgi, C.; Montanari, E.; Cerasti, D.; Crafa, P.; Dascola, I.; Florindo, I.; Giombelli, E.; Mazza, S.; Ramponi, V.; Servadei, F.; Silini, E. M.; Torelli, P.; Immovilli, P.; Morelli, N.; Vanzo, C.; Nobile, C.
abstract

The members of the PERNO Study Group were not individually captured in the metadata of the original publication. They are included in the metadata of this publication.

2018 - Cortical and Subcortical Brain Changes in Children and Adolescents With Narcolepsy Type 1 [Articolo su rivista]
Tondelli, Manuela; Pizza, Fabio; Vaudano, Anna Elisabetta; Plazzi, Giuseppe; Meletti, Stefano
abstract

Neuroimaging studies on structural alterations in patients with type 1 narcolepsy (NT1) have shown controversial and heterogeneous results. The purpose of this study was to investigate microstructural brain changes in patients with NT1 close to disease onset.

2018 - Facial emotion decoding in patients with Parkinson's disease [Articolo su rivista]
De Risi, Marco; Di Gennaro, Giancarlo; Picardi, Angelo; Casciato, Sara; Grammaldo, Liliana G.; D'Aniello, Alfredo; Lanni, Deborah; Meletti, Stefano; Modugno, Nicola
abstract

Purpose. In line with the growing attention on non-motor symptoms and disturbance of affective and emotional processing in Parkinson’s disease, we aimed to study the different aspects of facial emotion expression evaluation in a group of Parkinson’s disease without cognitive decline in treatment with common antiparkinsonian drugs, matched for sex, age and education with healthy subjects. Materials and methods. The study was conducted on 30 patients (13 male; mean age: 63.3 ± 6.7; mean age of disease onset: 56.5 ± 7.1; mean duration of the disease: 6.7 ± 2.6) with a diagnosis of Parkinson’s disease and receiving dopaminergic therapy, as compared with 30 healthy controls. Different tasks of facial expression evaluation were used. All patients were assessed for neuropsychological and psychological profiles during optimized medication-on condition. Results. The total number of errors in facial emotion recognition task is higher (p < 0.001) in patients than controls and it is due to errors in identifying sadness (p < 0.001), anger (p = 0.01) and fear (p < 0.001). No differences in the total amount of activation, valence and intensity ratings were found. The difference between patients and controls in emotion recognition appears to be independent by the severity of depressive symptoms. Conclusions. The present study provides further evidence of altered non-verbal emotional information processing in Parkinson’s disease patients, suggesting that nigrostriatal dopaminergic depletion leads also to emotional information processing dysfunction. The consequences of these emotional encoding disturbances in daily living and their relationship to mood and behavioural disorders remain to be clarified.

2018 - Low levels of progesterone and derivatives in cerebrospinal fluid of patients affected by status epilepticus [Articolo su rivista]
Meletti, Stefano; Lucchi, Chiara; Monti, Giulia; Giovannini, Giada; Bedin, Roberta; Trenti, Tommaso; Rustichelli, Cecilia; Biagini, Giuseppe
abstract

Neurosteroids such as allopregnanolone may play a role in epilepsy as positive modulators of inhibitory currents mediated by γ-aminobutyric acid type A (GABAA ) receptor. Indeed, these molecules have been consistently shown to be anticonvulsants in animal models, but their role is still unclear in patients. For this reason, we investigated neurosteroids in the cerebrospinal fluid (CSF) of patients with status epilepticus (SE) by liquid chromatography tandem-mass spectrometry. Patients were retrospectively identified within subjects who received a lumbar puncture in the 2007-2017 period. Seventy-three patients (median age 65, ranging from 13 to 94 years; 67% women) with SE were evaluated. Controls (n = 52, median age 53, ranging from 16 to 93 years; 65% women) were patients presenting with symptoms for which a lumbar puncture was required by clinical guidelines, and who were negative at the end of the diagnostic work-up. Progesterone was 64% lower in patients with SE (p < 0.001). With respect to progesterone, upstream pregnenolone sulfate and pregnenolone did not change. Instead, downstream 5α-dihydroprogesterone, pregnanolone and allopregnanolone were respectively 49% (p < 0.001), 21% (p < 0.01) and 37% (p < 0.001) lower than in controls. Duration or type of SE, age and sex did not consistently affect CSF neurosteroid levels in the SE cohort. Instead, pregnenolone sulfate (Spearman's ρ = 0.4335, p < 0.01), allopregnanolone (ρ = 0.4121, p < 0.05), and pregnanolone (ρ = 0.592, p < 0.001) levels significantly increased by ageing in controls. We conclude that neurosteroidogenesis is defective in patients with SE. This article is protected by copyright. All rights reserved.

2018 - Neuroimaging alterations related to status epilepticus in an adult population: Definition of MRI findings and clinical-EEG correlation [Articolo su rivista]
Giovannini, Giada; Kuchukhidze, Giorgi; Mccoy, Mark R.; Meletti, Stefano; Trinka, Eugen
abstract

Magnetic resonance imaging (MRI) provides an opportunity for identifying peri-ictal MRI abnormalities (PMAs) related to status epilepticus (SE). Extremely variable MRI alterations have been reported previously during or after SE, mainly in small selected populations. In a retrospective monocentric study, we analyzed brain MRI changes observed in the ictal/postictal periods of SE in an adult population. We included all consecutive patients observed in a 5-year period with an electroclinical diagnosis of SE and an MRI performed within 30 days from the beginning of SE. We identified 277 patients. Among them, 32 (12%) showed PMAs related to SE. The duration of SE was strongly associated with MRI alterations, showing a mean duration of 6 days vs 2 days (P =.011) in the group with and without MRI alterations, respectively. Focal electroencephalography (EEG) abnormalities (P =.00003) and in particular, lateralized periodic discharges (LPDs) (P <.0001) were strongly associated with PMAs. MRI alterations were unilateral (23 patients, 72%), located in multiple brain structures (19 patients, 59%), and involving mesiotemporal structures (17 patients, 53%). Sixteen patients (50%) had good spatial correspondence between cortical PMAs and the focal EEG pattern; 12 patients (38%) with focal EEG pattern showed cortical PMAs plus MRI signal changes also involving subcortical structures. A follow-up MRI was available for 14 of 32 patients (44%): 10 patients presented a disappearance of PMAs, whereas in 4, PMAs were still present. This study demonstrates that a long duration SE and the presence of certain EEG patterns (LPDs) are associated with the occurrence of PMAs. A good spatial concordance was observed between cortical PMA location and the EEG focus.

2018 - Neuroimaging of status epilepticus [Articolo su rivista]
Meletti, Stefano; Monti, Giulia; Mirandola, Laura; Vaudano, Anna Elisabetta; Giovannini, Giada
abstract

In the past 2 decades we have observed an extensive use of different neuroimaging techniques to evaluate patients with status epilepticus. Magnetic resonance imaging (MRI) in particular may show a broad spectrum of abnormalities that are either the causes or the consequences of sustained epileptic activity. Neuroimaging techniques can offer a contribution both in the clinical management of individual patients, identifying hemodynamic patterns that support the diagnosis, and also in the recognition of periictal reversible or irreversible alterations. For the future it is necessary to develop larger and prospective studies in which imaging techniques and electroencephalography (EEG) recordings are acquired closely to understand which EEG patterns are related to imaging biomarkers of neuronal damage.

2018 - Perampanel in the treatment of status epilepticus: A systematic review of the literature [Articolo su rivista]
Brigo, Francesco; Lattanzi, Simona; Rohracher, Alexandra; Russo, Emilio; Meletti, Stefano; Grillo, Elisabetta; Trinka, Eugen
abstract

Objective: Perampanel (PER) is a noncompetitive β-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propionic acid (AMPA) receptor antagonist with demonstrated efficacy in animal models of status epilepticus (SE). We performed a systematic review of the literature to assess the efficacy and tolerability of PER in the treatment of refractory and super-refractory SE. Methods: We searched Medline, Embase, and CENTRAL (accessed from inception to April 30, 2018) to identify studies evaluating oral PER as treatment of SE of any type. We also searched the OpenGrey repository and conference proceedings of international congresses by the International League Against Epilepsy and by the American Epilepsy Society from 2012 onwards. Results: Ten articles were included, with a total of 69 episodes of SE occurring in 68 patients (aged 18 to 91 years). The type and etiology of SE varied remarkably across studies. The number of drugs used prior to PER ranged from 1 to 9. The time from SE onset to PER administration ranged from 9.25 h to 35 days. The initial PER dose ranged from 2 to 32 mg. The proportion of patients achieving clinical SE cessation varied from 17% to 100%. The time from PER administration to SE cessation ranged from 1 h to 4 weeks. Conclusions: The currently available evidence supporting the use of PER in SE is weak and hampered by several confounding factors. Further studies should be performed in more clinically homogeneous and larger cohorts to evaluate the efficacy and safety of PER administered in earlier stages of SE, at higher dosages, and at intervals shorter than 24 h.

2018 - Presurgical language fMRI: Clinical practices and patient outcomes in epilepsy surgical planning [Articolo su rivista]
Benjamin, Christopher F. A.; Li, Alexa X.; Blumenfeld, Hal; Constable, R. Todd; Alkawadri, Rafeed; Bickel, Stephan; Helmstaedter, Christoph; Meletti, Stefano; Bronen, Richard; Warfield, Simon K.; Peters, Jurriaan M.; Reutens, David; Połczyńska, Monika; Spencer, Dennis D.; Hirsch, Lawrence J.
abstract

The goal of this study was to document current clinical practice and report patient outcomes in presurgical language functional MRI (fMRI) for epilepsy surgery. Epilepsy surgical programs worldwide were surveyed as to the utility, implementation, and efficacy of language fMRI in the clinic; 82 programs responded. Respondents were predominantly US (61%) academic programs (85%), and evaluated adults (44%), adults and children (40%), or children only (16%). Nearly all (96%) reported using language fMRI. Surprisingly, fMRI is used to guide surgical margins (44% of programs) as well as lateralize language (100%). Sites using fMRI for localization most often use a distance margin around activation of 10mm. While considered useful, 56% of programs reported at least one instance of disagreement with other measures. Direct brain stimulation typically confirmed fMRI findings (74%) when guiding margins, but instances of unpredicted decline were reported by 17% of programs and 54% reported unexpected preservation of function. Programs reporting unexpected decline did not clearly differ from those which did not. Clinicians using fMRI to guide surgical margins do not typically map known language-critical areas beyond Broca's and Wernicke's. This initial data shows many clinical teams are confident using fMRI not only for language lateralization but also to guide surgical margins. Reported cases of unexpected language preservation when fMRI activation is resected, and cases of language decline when it is not, emphasize a critical need for further validation. Comprehensive studies comparing commonly-used fMRI paradigms to predict stimulation mapping and post-surgical language decline remain of high importance.

2018 - Presurgical language fMRI: Technical practices in epilepsy surgical planning [Articolo su rivista]
Benjamin, Christopher F A; Dhingra, Isha; Li, Alexa X; Blumenfeld, Hal; Alkawadri, Rafeed; Bickel, Stephan; Helmstaedter, Christoph; Meletti, Stefano; Bronen, Richard A; Warfield, Simon K; Peters, Jurriaan M; Reutens, David; Połczyńska, Monika M; Hirsch, Lawrence J; Spencer, Dennis D
abstract

Little is known about how language functional MRI (fMRI) is executed in clinical practice in spite of its widespread use. Here we comprehensively documented its execution in surgical planning in epilepsy. A questionnaire focusing on cognitive design, image acquisition, analysis and interpretation, and practical considerations was developed. Individuals responsible for collecting, analyzing, and interpreting clinical language fMRI data at 63 epilepsy surgical programs responded. The central finding was of marked heterogeneity in all aspects of fMRI. Most programs use multiple tasks, with a fifth routinely using 2, 3, 4, or 5 tasks with a modal run duration of 5 min. Variants of over 15 protocols are in routine use with forms of noun-verb generation, verbal fluency, and semantic decision-making used most often. Nearly all aspects of data acquisition and analysis vary markedly. Neither of the two best-validated protocols was used by more than 10% of respondents. Preprocessing steps are broadly consistent across sites, language-related blood flow is most often identified using general linear modeling (76% of respondents), and statistical thresholding typically varies by patient (79%). The software SPM is most often used. fMRI programs inconsistently include input from experts with all required skills (imaging, cognitive assessment, MR physics, statistical analysis, and brain-behavior relationships). These data highlight marked gaps between the evidence supporting fMRI and its clinical application. Teams performing language fMRI may benefit from evaluating practice with reference to the best-validated protocols to date and ensuring individuals trained in all aspects of fMRI are involved to optimize patient care.

2018 - Ridotta concentrazione del progesterone e di altri neurosteroidi nel liquor di pazienti in stato di male epilettico [Abstract in Atti di Convegno]
Biagini, G.; Lucchi, C.; Monti, G.; Giovannini, G.; Bedin, R.; Rustichelli, C.; Meletti, S.
abstract

Lo stato di male epilettico (SE) costituisce una grave emergenza neurologica. In tale condizione, mediante cromatografia liquida e spettrometria di massa, abbiamo misurato e confrontato i livelli di pregnenolone solfato, pregnenolone, progesterone, 5α-diidroprogesterone, pregnanolone e allopregnanolone nel liquor di pazienti affetti da SE e in una coorte di controllo. Sono stati studiati 73 pazienti ricoverati per SE, con età di 65 anni (intervallo di variazione da 13 a 94 anni), dei quali il 67% donne. I controlli esaminati, pari a 52, avevano età compresa tra 16 e 93 anni (mediana pari a 53), dei quali il 65% donne. I risultati sono stati analizzati con il test di Mann-Whitney. Abbiamo anche correlato le concentrazioni dei neurosteroidi e l’età, il genere, la durata ed il tipo di SE. Il progesterone è risultato essere diminuito del 64% nel liquor dei pazienti con SE (p < 0.001). I neurosteroidi pregnenolone solfato e pregnenolone, precursori del progesterone, sono risultati a livelli analoghi a quelli dei controlli. I derivati del progesterone, al contrario, in particolare il 5α-diidroprogesterone (-49%, p < 0.001), il pregnanolone (-21%, p = 0.005) e l’allopregnanolone (-37%, p < 0.001), sono risultati essere inferiori ai controlli. Le variazioni osservate nei livelli liquorali di neurosteroidi non hanno travato spiegazioni nelle differenze di genere, età o tipo di SE. Inoltre, non sono stati riscontrati effetti dovuti alla durata del SE. In conclusione, questi risultati indicano che vari neurosteroidi anticonvulsivanti sono presenti a ridotte concentrazioni liquorali nei pazienti che presentano un’attività epilettica protratta.

2018 - Structural brain abnormalities in the common epilepsies assessed in a worldwide ENIGMA study [Articolo su rivista]
Whelan, Christopher D; Altmann, Andre; Botía, Juan A; Jahanshad, Neda; Hibar, Derrek P; Absil, Julie; Alhusaini, Saud; Alvim, Marina K M; Auvinen, Pia; Bartolini, Emanuele; Bergo, Felipe P G; Bernardes, Tauana; Blackmon, Karen; Braga, Barbara; Caligiuri, Maria Eugenia; Calvo, Anna; Carr, Sarah J; Chen, Jian; Chen, Shuai; Cherubini, Andrea; David, Philippe; Domin, Martin; Foley, Sonya; França, Wendy; Haaker, Gerrit; Isaev, Dmitry; Keller, Simon S; Kotikalapudi, Raviteja; Kowalczyk, Magdalena A; Kuzniecky, Ruben; Langner, Soenke; Lenge, Matteo; Leyden, Kelly M; Liu, Min; Loi, Richard Q; Martin, Pascal; Mascalchi, Mario; Morita, Marcia E; Pariente, Jose C; Rodríguez-Cruces, Raul; Rummel, Christian; Saavalainen, Taavi; Semmelroch, Mira K; Severino, Mariasavina; Thomas, Rhys H; Tondelli, Manuela; Tortora, Domenico; Vaudano, Anna Elisabetta; Vivash, Lucy; Von Podewils, Felix; Wagner, Jan; Weber, Bernd; Yao, Yi; Yasuda, Clarissa L; Zhang, Guohao; Bargalló, Nuria; Bender, Benjamin; Bernasconi, Neda; Bernasconi, Andrea; Bernhardt, Boris C; Blümcke, Ingmar; Carlson, Chad; Cavalleri, Gianpiero L; Cendes, Fernando; Concha, Luis; Delanty, Norman; Depondt, Chantal; Devinsky, Orrin; Doherty, Colin P; Focke, Niels K; Gambardella, Antonio; Guerrini, Renzo; Hamandi, Khalid; Jackson, Graeme D; Kälviäinen, Reetta; Kochunov, Peter; Kwan, Patrick; Labate, Angelo; Mcdonald, Carrie R; Meletti, Stefano; O'Brien, Terence J; Ourselin, Sebastien; Richardson, Mark P; Striano, Pasquale; Thesen, Thomas; Wiest, Roland; Zhang, Junsong; Vezzani, Annamaria; Ryten, Mina; Thompson, Paul M; Sisodiya, Sanjay M
abstract

Progressive functional decline in the epilepsies is largely unexplained. We formed the ENIGMA-Epilepsy consortium to understand factors that influence brain measures in epilepsy, pooling data from 24 research centres in 14 countries across Europe, North and South America, Asia, and Australia. Structural brain measures were extracted from MRI brain scans across 2149 individuals with epilepsy, divided into four epilepsy subgroups including idiopathic generalized epilepsies (n =367), mesial temporal lobe epilepsies with hippocampal sclerosis (MTLE; left, n = 415; right, n = 339), and all other epilepsies in aggregate (n = 1026), and compared to 1727 matched healthy controls. We ranked brain structures in order of greatest differences between patients and controls, by meta-Analysing effect sizes across 16 subcortical and 68 cortical brain regions. We also tested effects of duration of disease, age at onset, and age-by-diagnosis interactions on structural measures. We observed widespread patterns of altered subcortical volume and reduced cortical grey matter thickness. Compared to controls, all epilepsy groups showed lower volume in the right thalamus (Cohen's d = â '0.24 to â '0.73; P < 1.49 × 10 â '4), and lower thickness in the precentral gyri bilaterally (d = â '0.34 to â '0.52; P < 4.31 × 10 â '6). Both MTLE subgroups showed profound volume reduction in the ipsilateral hippocampus (d = â '1.73 to â '1.91, P < 1.4 × 10 â '19), and lower thickness in extrahippocampal cortical regions, including the precentral and paracentral gyri, compared to controls (d = â '0.36 to â '0.52; P < 1.49 × 10 â '4). Thickness differences of the ipsilateral temporopolar, parahippocampal, entorhinal, and fusiform gyri, contralateral pars triangularis, and bilateral precuneus, superior frontal and caudal middle frontal gyri were observed in left, but not right, MTLE (d = â '0.29 to â '0.54; P < 1.49 × 10 â '4). Contrastingly, thickness differences of the ipsilateral pars opercularis, and contralateral transverse temporal gyrus, were observed in right, but not left, MTLE (d = â '0.27 to â '0.51; P < 1.49 × 10 â '4). Lower subcortical volume and cortical thickness associated with a longer duration of epilepsy in the all-epilepsies, all-other-epilepsies, and right MTLE groups (beta, b < â '0.0018; P < 1.49 × 10 â '4). In the largest neuroimaging study of epilepsy to date, we provide information on the common epilepsies that could not be realistically acquired in any other way. Our study provides a robust ranking of brain measures that can be further targeted for study in genetic and neuropathological studies. This worldwide initiative identifies patterns of shared grey matter reduction across epilepsy syndromes, and distinctive abnormalities between epilepsy syndromes, which inform our understanding of epilepsy as a network disorder, and indicate that certain epilepsy syndromes involve more widespread structural compromise than previously assumed.

2018 - The Distinguishing Motor Features of Cataplexy: A Study from Video Recorded Attacks [Articolo su rivista]
Pizza, Fabio; Antelmi, Elena; Vandi, Stefano; Meletti, Stefano; Erro, Roberto; Baumann, Christian R; Bhatia, Kailash P; Dauvilliers, Yves; Edwards, Mark J; Iranzo, Alex; Overeem, Sebastiaan; Tinazzi, Michele; Liguori, Rocco; Plazzi, Giuseppe
abstract

To describe the motor pattern of cataplexy and to determine its phenomenological differences from pseudocataplexy in the differential diagnosis of episodic falls.

2018 - The Prognostic Roles of Gender and O6-Methylguanine-DNA Methyltransferase Methylation Status in Glioblastoma Patients: The Female Power [Articolo su rivista]
Franceschi, Enrico; Tosoni, Alicia; Minichillo, Santino; Depenni, Roberta; Paccapelo, Alexandro; Bartolini, Stefania; Michiara, Maria; Pavesi, Giacomo; Urbini, Benedetta; Crisi, Girolamo; Cavallo, Michele A.; Tosatto, Luigino; Dazzi, Claudio; Biasini, Claudia; Pasini, Giuseppe; Balestrini, Damiano; Zanelli, Francesca; Ramponi, Vania; Fioravanti, Antonio; Meletti, Stefano; Giombelli, Ermanno; De Biase, Dario; Baruzzi, Agostino; Brandes, ; Alba, A.; Iaccarino, Corrado
abstract

Background: Clinical and molecular factors are essential to define the prognosis in patients with glioblastoma (GBM). O6-methylguanine-DNA methyltransferase (MGMT) methylation status, age, Karnofsky Performance Status (KPS), and extent of surgical resection are the most relevant prognostic factors. Our investigation of the role of gender in predicting prognosis shows a slight survival advantage for female patients. Methods: We performed a prospective evaluation of the Project of Emilia Romagna on Neuro-Oncology (PERNO) registry to identify prognostic factors in patients with GBM who received standard treatment. Results: A total of 169 patients (99 males [58.6%] and 70 females [41.4%]) were evaluated prospectively. MGMT methylation was evaluable in 140 patients. Among the male patients, 36 were MGMT methylated (25.7%) and 47 were unmethylated (33.6%); among the female patients, 32 were methylated (22.9%) and 25 were unmethylated (17.9%). Survival was longer in the methylated females compared with the methylated males (P = 0.028) but was not significantly different between the unmethylated females and the unmethylated males (P = 0.395). In multivariate analysis, gender and MGMT methylation status considered together (methylated females vs. methylated males; hazard ratio [HR], 0.459; 95% confidence interval [CI], 0.242-0.827; P = 0.017), age (HR, 1.025; 95% CI, 1.002-1.049; P = 0.032), and KPS (HR, 0.965; 95% CI, 0.948-0.982; P &lt; 0.001) were significantly correlated with survival. Conclusions: Survival was consistently longer among MGMT methylated females compared with males. Gender can be considered as a further prognostic factor.

2018 - The role of AMPA receptors and their antagonists in status epilepticus [Articolo su rivista]
Leo, Antonio; Giovannini, Giada; Russo, Emilio; Meletti, Stefano
abstract

Status epilepticus (SE) is typically defined as a prolonged self-sustaining seizure or repeated seizures showing an incomplete recovery between them. SE represents a medical emergency often associated with significant disability, morbidity, and mortality. Despite the clinical impact, the mechanisms underlying the transition from self-limited seizures to protracted, medically refractory seizures are not completely understood. About 40% of patients in established SE are refractory to antiepileptic drugs (first-line treatment); therefore, there is a need for more efficacious drugs. In this review, we focused on the current knowledge about the involvement of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors during SE, the preclinical efficacy of its antagonists, and the currently published clinical studies involving drugs with this mechanism of action. We carried out an extensive literature search to recognize experimental and clinical articles both on AMPA receptors and AMPA antagonists and SE. Recently, the role of AMPA receptors during and after SE has become clearer, and it is now widely accepted that early changes occur in the initial stages and probably contribute both to the maintenance of SE and to its refractoriness to treatment. The therapeutic potential of AMPA receptor inhibition has been sustained by studies in which AMPA receptor antagonists have been shown to terminate seizures in several SE animal models. To date, promising, but limited, data in humans support the use of AMPA receptor antagonists in patients with SE. AMPA receptor antagonists could become a new therapeutic option in patients with established SE when the first trials with second-line agents have failed or probably even better after failure of benzodiazepines as a second-line option.

2017 - AMPA receptors and perampanel behind selected epilepsies: current evidence and future perspectives [Articolo su rivista]
Di Bonaventura, Carlo; Labate, Angelo; Maschio, Marta; Meletti, Stefano; Russo, Emilio
abstract

The alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors are the major mediators of glutamate-mediated excitatory neurotransmission, and are critical for synchronization and spread of epileptic activity. Areas covered: AMPA receptor antagonists have been also developed as antiepileptic drugs and perampanel (PER) is the first highly selective, non-competitive AMPA-type glutamate receptor antagonist that is available on the market. It is approved as adjunctive therapy for the treatment of partial-onset seizures with or without secondary generalization, and for primary generalized tonic-clonic seizures in idiopathic generalized epilepsy, in patients aged ≥ 12 years. This article reviews the role of AMPA receptors in the neuronal hyperexcitability underlying epilepsy, the mechanism of action and clinical experience on the anti-seizure activity of PER. Moreover, the rationale for targeting AMPA receptor in specific epileptic disorders, including brain tumor-related epilepsy, mesial temporal lobe epilepsy with/without hippocampal sclerosis, and status epilepticus is evaluated. Finally, the pharmacological rationale for the development of AMPA receptor antagonists in other neurological disorders beyond epilepsy is considered. Expert opinion: Further research aimed at better understanding the pharmacology and blocking mechanism of PER and other AMPA receptor antagonists will drive future development of therapeutic agents that target epilepsy and other neurological diseases.

2017 - Acute hemichorea as unusual first multiple sclerosis presentation [Articolo su rivista]
Giovannini, Giada; Cavallieri, Francesco; Meletti, Stefano; Chiari, Annalisa; Mandrioli, Jessica; Ferraro, Diana; Valzania, Franco
abstract

Patient 1 was a 39-year-old woman with an unremarkable medical history who developed acute involuntary right arm and leg movements. Neurologic examination revealed moderate dysarthria and subcontinuous, choreic movements in her right limbs, prevailing in the arm, which worsened during postural tasks. She occasionally had ballistic movements in her right limbs and abnormal dystonic postures. Continuous peribuccal and tongue involuntary movements were noted. Moreover, bilateral upper limb ataxia, gait and trunk ataxia, and brisk right tendon reflexes were found. There was no strength or sensory loss (video 1 at Neurology.org/cp). Brain MRI revealed a tumefactive, T2/fluid-attenuated inversion recovery (FLAIR) hyperintense, T1 hypointense contrast-enhancing demyelinating lesion in the left cerebral peduncle, extending to the substantia nigra and subthalamic nucleus (STN) (figure, A-C). Multiple hyperintense T2/FLAIR, T1 hypointense, non-contrast-enhancing demyelinating lesions in the hemispheric and periventricular deep white matter, brainstem, and cerebellar hemispheres were also found. All serologic tests were within normal limits. Isoelectric focusing (IEF) revealed 9 CSF oligoclonal bands (OCBs). A diagnosis of multiple sclerosis (MS) was made and the patient was treated with high-dose methylprednisolone with improvement of symptoms.

2017 - Brain correlates of spike and wave discharges in GLUT1 deficiency syndrome [Articolo su rivista]
Vaudano, Anna Elisabetta; Olivotto, Sara; Ruggieri, Andrea; Gessaroli, Giuliana; De Giorgis, Valentina; Parmeggiani, Antonia; Veggiotti, Pierangelo; Meletti, Stefano
abstract

Purpose To provide imaging biomarkers of generalized spike-and-wave discharges (GSWD) in patients with GLUT1 deficiency syndrome (GLUT1DS). Methods Eighteen GLUT1DS patients with pathogenetic mutation in SLC2A1 gene were studied by means of Video-EEG simultaneously recorded with functional MRI (VideoEEG-fMRI). A control group of sex and age-matched patients affected by Genetic Generalized Epilepsy (GGE) with GSWD were investigated with the same protocol. Within and between groups comparison was performed as appropriated. For GLUT1DS, correlations analyses between the contrast of interest and the main clinical measurements were provided. Results EEG during fMRI revealed interictal GSWD in 10 GLUT1DS patients. Group-level analysis showed BOLD signal increases at the premotor cortex and putamen. With respect to GGE, GLUT1DS patients demonstrated increased neuronal activity in the putamen, precuneus, cingulate cortex, SMA and paracentral lobule. Whole-brain correlation analyses disclosed a linear relationship between the GSWD-related BOLD changes and the levels of glycorrhachia at diagnosis over the sensory-motor cortex and superior parietal lobuli. Conclusion The BOLD dynamics related to GSWD in GLUT1DS are substantially different from typical GGE showing the former an increased activity in the premotor-striatal network and a decrease in the thalamus. The revealed hemodynamic maps might represent imaging biomarkers of GLUT1DS, being potentially useful for a precocious diagnosis of this genetic disorder.

2017 - Decreased allopregnanolone levels in cerebrospinal fluid obtained during status epilepticus [Articolo su rivista]
Meletti, Stefano; Lucchi, Chiara; Monti, Giulia; Giovannini, Giada; Bedin, Roberta; Trenti, Tommaso; Rustichelli, Cecilia; Biagini, Giuseppe
abstract

Neuroactive steroids are increasingly considered as relevant modulators of neuronal activity. Especially allopregnanolone (AP) and pregnenolone sulfate (PS) have been shown to possess, respectively, anticonvulsant or proconvulsant properties. In view of the potential role of these steroids, we aimed at evaluating AP and PS levels in cerebrospinal fluid (CSF) and blood samples obtained from patients with status epilepticus (SE). To this purpose, we enrolled 41 patients affected by SE and 41 subjects investigated for nonepileptic neurologic disorders. Liquid chromatographic procedures coupled with electrospray tandem mass spectrometry and routine laboratory investigations were performed. Significantly lower AP levels were found in the CSF of patients affected by SE (-30%; p &lt; 0.05, Mann-Whitney test). Notably, AP was not detectable in 28 of 41 patients affected by SE (p &lt; 0.01 vs. controls, Fisher's exact test). In serum, AP levels did not differ in the two considered groups. Conversely, PS was present at similar levels in the investigated groups. Finally, differences in AP levels could not be explained by a variation in CSF albumin content. These findings indicate that AP is defective in the CSF of patients affected by SE. This phenomenon was not dependent on carriers for steroids, such as albumin.

2017 - Erratum to: Incidence of neuroepithelial primary brain tumors among adult population of Emilia-Romagna Region, Italy [Articolo su rivista]
Baldin, E; Testoni, S; de Pasqua, S; Ferro, S; Albani, F; Baruzzi, A; D'Alessandro, R; PERNO study group Participants: Agati, R.; Ambrosetto, G.; Bacci, A.; Baldin, E.; Baldrati, A.; Barbieri, E.; Bartolini, S.; Bellavista, E.; Bisulli, F.; Bonora, E.; Bunkheila, F.; Carelli, V.; Cerasoli, S.; Crisci, M.; Dall’Occa, P.; de Biase, D.; Ferro, S.; Franceschi, C.; Frezza, G.; Grasso, V.; Leonardi, M.; Marucci, G.; Morandi, L.; Mostacci, B.; Palandri, G.; Pasini, E.; Pastore Trossello, M.; Pession, A.; Poggi, R.; Riguzzi, P.; Rinaldi, R.; Rizzi, S.; Romeo, G.; Spagnolli, F.; Tinuper, P.; Trocino, C.; Visani M., (Bologna); Dall’Agata, M.; Faedi, M.; Frattarelli, M.; Gentili, G.; Giovannini, A.; Iorio, P.; Pasquini, U.; Galletti, G.; Guidi, C.; Neri, W.; Patuelli, A. .; Strumia S., (ForlI´-Cesena); Casmiro, M.; Gamboni, A.; Rasi F., (Faenza; RA), ; Cruciani G., (Lugo; RA), ; Cenni, P.; Dazzi, C.; Guidi, A. R.; Zumaglini F., (Ravenna); Amadori, A.; Pasini, G.; Pasquinelli, M.; Pasquini, E.; Polselli, A.; Ravasio, A.; Viti B., (Rimini); Sintini M., (Cattolica; RN), ; Ariatti, A.; Bertolini, F.; Bigliardi, G.; Carpeggiani, P.; Cavalleri, F.; Meletti, S.; Nichelli, P.; Pettorelli, E.; Pinna, G.; Zunarelli E., (Modena); Artioli, F.; Bernardini, I.; Costa, M.; Greco, G.; Guerzoni, R.; Stucchi C., (Carpi; MO), ; Iaccarino, C; Ragazzi, M.; Rizzi, R.; Zuccoli G., (Reggio Emilia); Api, P.; Cartei, F.; Fallica, E.; Granieri, E.; Latini, F.; Lelli, G.; Monetti, C.; Saletti, A.; Schivalocchi, R.; Seraceni, S.; Tola, M. R.; Urbini B., (Ferrara); Giorgi, C.; Montanari E., (Fidenza; PR), ; Cerasti, D.; Crafa, P.; Dascola, I.; Florindo, I.; Giombelli, E.; Mazza, S.; Ramponi, V.; Servadei, F.; Silini, Em.; Torelli P., (Parma); Immovilli, P.; Morelli, N.; Vanzo C., (Piacenza); Nobile, C. (Padova).
abstract

Erratum to: Neurol Sci DOI 10.1007/s10072-016-2747-y Unfortunately, some of the participants of the PERNO Study Group are missing in the original publication of the article. The correct details are given below

2017 - Incidence of neuroepithelial primary brain tumors among adult population of Emilia-Romagna Region, Italy [Articolo su rivista]
Baldin, Elisa; Testoni, Stefania; de Pasqua, Silvia; Ferro, Salvatore; Albani, Fiorenzo; Baruzzi, Agostino; D’Alessandro, Roberto; On behalf of PERNO study group, Null; Baruzzi, A.; Albani, F.; Calbucci, F.; D’Alessandro, R.; Michelucci, R.; Brandes, A.; Eusebi, V.; Ceruti, S.; Fainardi, E.; Tamarozzi, R.; Emiliani, E.; Cavallo, M.; Franceschi, E.; Tosoni, A.; Cavallo, M.; Fiorica, F.; Valentini, A.; Depenni, R.; Mucciarini, C.; Crisi, G.; Sasso, E.; Biasini, C.; Cavanna, L.; Guidetti, D.; Marcello, N.; Pisanello, A.; Cremonini, A. M.; Guiducci, G.; de Pasqua, S.; Testoni, S.; Agati, R.; Ambrosetto, G.; Bacci, A.; Baldin, E.; Baldrati, A.; Barbieri, E.; Bartolini, S.; Bellavista, E.; Bisulli, F.; Bonora, E.; Bunkheila, F.; Carelli, V.; Crisci, M.; Dall’Occa, P.; Ferro, S.; Franceschi, C.; Frezza, G.; Grasso, V.; Leonardi, M.; Mostacci, B.; Palandri, G.; Pasini, E.; Pastore Trossello, M.; Poggi, R.; Riguzzi, P.; Rinaldi, R.; Rizzi, S.; Romeo, G.; Spagnolli, F.; Tinuper, P.; Trocino, C.; Dall’Agata, M.; Faedi, M.; Frattarelli, M.; Gentili, G.; Giovannini, A.; Iorio, P.; Pasquini, U.; Galletti, G.; Guidi, C.; Neri, W.; Patuelli, A.; Strumia, S.; Casmiro, M.; Gamboni, A.; Rasi, F.; Cruciani, G.; Cenni, P.; Dazzi, C.; Guidi, A. R.; Zumaglini, F.; Amadori, A.; Pasini, G.; Pasquinelli, M.; Pasquini, E.; Polselli, A.; Ravasio, A.; Viti, B.; Sintini, M.; Ariatti, A.; Bertolini, F.; Bigliardi, G.; Carpeggiani, P.; Cavalleri, F.; Meletti, Stefano; Nichelli, Paolo Frigio; Pettorelli, E.; Pinna, G.; Zunarelli, E.; Artioli, F.; Bernardini, I.; Costa, M.; Greco, G.; Guerzoni, R.; Stucchi, C.; Iaccarino, C.; Ragazzi, M.; Rizzi, R.; Zuccoli, G.; Api, P.; Cartei, F.; Fallica, E.; Granieri, E.; Latini, F.; Lelli, G.; Monetti, C.; Saletti, A.; Schivalocchi, R.; Seraceni, S.; Tola, M. R.; Urbini, B.; Giorgi, C.; Montanari, E.; Cerasti, D.; Crafa, P.; Dascola, I.; Florindo, I.; Giombelli, E.; Mazza, S.; Ramponi, V.; Servadei, F.; Silini, E. M.; Torelli, P.; Immovilli, P.; Morelli, N.; Vanzo, C.; Nobile, C.
abstract

Incidence of neuroepithelial Primary Brain Tumors (nPBT) varies, ranging from 7.3 to 11.6 cases/100,000/year across Europe. We present incidence and survival of nPBT in the Emilia-Romagna region (ER), Italy. This study is the largest in Southern Europe. Specialists in neurosurgery, neurology, neuroradiology, oncology, radiotherapy, genetics, and pathology of ER notified all suspected nPBT adult cases residing in ER (4,337,966 inhabitants) observed during 2009. Furthermore, through ICD-9 discharge codes, we identified and reviewed all possible cases. Neuroepithelial PBT diagnosis was based on histological or radiological findings. We included 400 incident nPBT cases, of which 102 (25%) were retrospectively identified. These latter were significantly older. The standardized incidence was 10.5/100,000/year (95% CI 9.4–11.5), higher for men. It was 9.2/100,000/year (95% CI 8.3–10.2) for astrocytic tumors, 0.6/100,000/year (95% CI 0.4–0.9) for oligodendroglial tumors, and 7.1 (95% CI 6.3–8.0) for glioblastoma (GBM). Among GBM patients, median survival was 249 days if prospectively identified vs. 132 days when identified through ICD-9 codes (p < 0.0001). The incidence of nPBT in the ER region is among the highest in the literature. Older patients were more likely to escape an active surveillance system. This should be considered when comparing incidence rates across studies, giving the increasing number of elderly people in the general population.

2017 - Mortality, morbidity and refractoriness prediction in status epilepticus: Comparison of STESS and EMSE scores [Articolo su rivista]
Giovannini, Giada; Monti, Giulia; Tondelli, Manuela; Marudi, Andrea; Valzania, Franco; Leitinger, Markus; Trinka, Eugen; Meletti, Stefano
abstract

Purpose Status epilepticus (SE) is a neurological emergency, characterized by high short-term morbidity and mortality. We evaluated and compared two scores that have been developed to evaluate status epilepticus prognosis: STESS (Status Epilepticus Severity Score) and EMSE (Epidemiology based Mortality score in Status Epilepticus). Methods A prospective observational study was performed on consecutive patients with SE admitted between September 2013 and August 2015. Demographics, clinical variables, STESS-3 and -4, and EMSE-64 scores were calculated for each patient at baseline. SE drug response, 30-day mortality and morbidity were the outcomes measure. Results 162 episodes of SE were observed: 69% had a STESS ≥3; 34% had a STESS ≥4; 51% patients had an EMSE ≥64. The 30-days mortality was 31.5%: EMSE-64 showed greater negative predictive value (NPV) (97.5%), positive predictive value (PPV) (59.8%) and accuracy in the prediction of death than STESS-3 and STESS-4 (p < 0.001). At 30 days, the clinical condition had deteriorated in 59% of the cases: EMSE-64 showed greater NPV (71.3%), PPV (87.8%) and accuracy than STESS-3 and STESS-4 (p < 0.001) in the prediction of this outcome. In 23% of all cases, status epilepticus proved refractory to non-anaesthetic treatment. All three scales showed a high NPV (EMSE-64: 87.3%; STESS-4: 89.4%; STESS-3: 87.5%) but a low PPV (EMSE-64: 40.9%; STESS-4: 52.9%; STESS-3: 32%) for the prediction of refractoriness to first and second line drugs. This means that accuracy for the prediction of refractoriness was equally poor for all scales. Conclusions EMSE-64 appears superior to STESS-3 and STESS-4 in the prediction of 30-days mortality and morbidity. All scales showed poor accuracy in the prediction of response to first and second line antiepileptic drugs. At present, there are no reliable scores capable of predicting treatment responsiveness.

2017 - New-Onset Refractory Status Epilepticus with Claustrum Damage: Definition of the Clinical and Neuroimaging Features [Articolo su rivista]
Meletti, Stefano; Giovannini, Giada; D'Orsi, Giuseppe; Toran, Lisa; Monti, Giulia; Guha, Rahul; Kiryttopoulos, Andreas; Pascarella, Maria Grazia; Martino, Tommaso; Alexopoulos, Haris; Spilioti, Martha; Slonkova, Jana
abstract

New-onset refractory status epilepticus (NORSE) is a rare but challenging condition occurring in a previously healthy patient, often with no identifiable cause. We describe the electro-clinical features and outcomes in a group of patients with NORSE who all demonstrated a typical magnetic resonance imaging (MRI) sign characterized by bilateral lesions of the claustrum. The group includes 31 patients (12 personal and 19 previously published cases; 17 females; mean age of 25 years). Fever preceded status epilepticus (SE) in 28 patients, by a mean of 6 days. SE was refractory/super-refractory in 74% of the patients, requiring third-line agents and a median of 15 days staying in an intensive care unit. Focal motor and tonic-clonic seizures were observed in 90%, complex partial seizures in 14%, and myoclonic seizures in 14% of the cases. All patients showed T2/FLAIR hyperintense foci in bilateral claustrum, appearing on average 10 days after SE onset. Other limbic (hippocampus, insular) alterations were present in 53% of patients. Within the personal cases, extensive search for known autoantibodies was inconclusive, though 7 of 11 patients had cerebrospinal fluid lymphocytic pleocytosis and 3 cases had oligoclonal bands. Two subjects died during the acute phase, one in the chronic phase (probable sudden unexplained death in epilepsy), and one developed a persistent vegetative state. Among survivors, 80% developed drug-resistant epilepsy. Febrile illness-related SE associated with bilateral claustrum hyperintensity on MRI represents a condition with defined clinical features and a presumed but unidentified autoimmune etiology. A better characterization of de novo SE is mandatory for the search of specific etiologies.

2017 - Photosensitive epilepsy is associated with reduced inhibition of alpha rhythm generating networks [Articolo su rivista]
Vaudano, Anna Elisabetta; Ruggieri, Andrea; Avanzini, Pietro; Gessaroli, Giuliana; Cantalupo, Gaetano; Coppola, Antonietta; Sisodiya, Sanjay M; Meletti, Stefano
abstract

Photosensitivity is a condition in which lights induce epileptiform activities. This abnormal electroencephalographic response has been associated with hyperexcitability of the visuo-motor system. Here, we evaluate if intrinsic dysfunction of this network is present in brain activity at rest, independently of any stimulus and of any paroxysmal electroencephalographic activity. To address this issue, we investigated the haemodynamic correlates of the spontaneous alpha rhythm, which is considered the hallmark of the brain resting state, in photosensitive patients and in people without photosensitivity. Second, we evaluated the whole-brain functional connectivity of the visual thalamic nuclei in the various populations of subjects under investigation. Forty-four patients with epilepsy and 16 healthy control subjects underwent an electroencephalography-correlated functional magnetic resonance imaging study, during an eyes-closed condition. The following patient groups were included: (i) genetic generalized epilepsy with photosensitivity, 16 subjects (mean age 25 +/- 10 years); (ii) genetic generalized epilepsy without photosensitivity, 13 patients (mean age 25 +/- 11 years); (iii) focal epilepsy, 15 patients (mean age 25 +/-9 years). For each subject, the posterior alpha power variations were convolved with the standard haemodynamic response function and used as a regressor. Within-and between-groups second level analyses were performed. Whole brain functional connectivity was evaluated for two thalamic regions of interest, based on the haemodynamic findings, which included the posterior thalamus (pulvinar) and the medio-dorsal thalamic nuclei. Genetic generalized epilepsy with photosensitivity demonstrated significantly greater mean alpha-power with respect to controls and other epilepsy groups. In photosensitive epilepsy, alpha-related blood oxygen level-dependent signal changes demonstrated lower decreases relative to all other groups in the occipital, sensory-motor, anterior cingulate and supplementary motor cortices. Coherently, the same brain regions demonstrated abnormal connectivity with the visual thalamus only in epilepsy patients with photosensitivity. As predicted, our findings indicate that the cortical-subcortical network generating the alpha oscillation at rest is different in people with epilepsy and visual sensitivity. This difference consists of a decreased alpharelated inhibition of the visual cortex and sensory-motor networks at rest. These findings represent the substrate of the clinical manifestations (i. e. myoclonus) of the photoparoxysmal response. Moreover, our results provide the first evidence of the existence of a functional link between the circuits that trigger the visual sensitivity phenomenon and those that generate the posterior alpha rhythm.

2017 - Prevalence of Sleep-Related Hypermotor Epilepsy (She) - Formerly Named Nocturnal Frontal Lobe Epilepsy - in the Adult Population of the Emilia-Romagna Region, Italy [Articolo su rivista]
Vignatelli, Luca; Bisulli, Francesca; Giovannini, Giada; Licchetta, Laura; Naldi, Ilaria; Mostacci, Barbara; Rubboli, Guido; Provini, Federica; Tinuper, Paolo; Meletti, Stefano
abstract

we report the incidence of sleep related hyper motor epilepsy in two Italian province.

2017 - Stereo-EEG: Diagnostic and therapeutic tool for periventricular nodular heterotopia epilepsies [Articolo su rivista]
Mirandola, Laura; Mai, Roberto F.; Francione, Stefano; Pelliccia, Veronica; Gozzo, Francesca; Sartori, Ivana; Nobili, Lino; Cardinale, Francesco; Cossu, Massimo; Meletti, Stefano; Tassi, Laura
abstract

Objective: Periventricular nodular heterotopias (PNHs) are malformations of cortical development related to neuronal migration disorders, frequently associated with drug-resistant epilepsy (DRE). Stereo-electroencephalography (SEEG) is considered a very effective step of the presurgical evaluation, providing the recognition of the epileptogenic zone (EZ). At the same time, via the intracerebral electrodes it is possible to perform radiofrequency thermocoagulation (SEEG-guided RF-TC) with the aim of ablating and/or disrupting the EZ. The purpose of this study was to evaluate both the relationships between PNH and the EZ, and the efficacy of SEEG-guided RF-TC. Methods: Twenty patients with DRE related to PNHs were studied. Inclusion criteria were the following: (1) patients with epilepsy and PNHs (unilateral or bilateral, single or multiple nodules) diagnosed on brain magnetic resonance imaging (MRI); (2) SEEG recordings available as part of the presurgical investigations, with at least one intracerebral electrode inside the heterotopia; (3) complete surgical workup with SEEG-guided RF-TC and/or with traditional neurosurgery, with a follow-up of at least 12 months. Results: Complex and heterogenic epileptic networks were found in these patients. SEEG-guided RF-TC both into the nodules and/or the cortex was efficacious in the 76% of patients. Single or multiple, unilateral or bilateral PNHs are the most suitable for this procedure, whereas patients with PNHs associated with complex cortical malformations obtained excellent outcome only with traditional resective surgery. Significance: Each patient had a specific epileptogenic network, independent from the number, size, or location of nodules and from the cortical malformation associated with. SEEG-guided RF-TC appears as a new and very effective diagnostic and therapeutic approach for DRE related to PNHs.

2016 - Acute hemichorea as unusual first multiple sclerosis presentation: two case reports [Abstract in Atti di Convegno]
Cavallieri, F; Giovannini, G; Menozzi, E; Meletti, S; Chiari, A; Mandrioli, J; Ferraro, D; Contardi, S; Nichelli, P; Valzania, F
abstract

2016 - Analysis of a peculiar motor speech disorder in a case of probable progressive supranuclear palsy [Abstract in Atti di Convegno]
Menozzi, E; Cavallieri, F; Gessani, A; Budriesi, C; Molinari, M; Mandrioli, J; Vitetta, F; Nichelli, P; Meletti, S; Chiari, A
abstract

2016 - Cortical and subcortical brain alterations in Juvenile Absence Epilepsy [Articolo su rivista]
Tondelli, Manuela; Vaudano, Anna Elisabetta; Ruggieri, Andrea; Meletti, Stefano
abstract

Despite the common assumption that genetic generalized epilepsies are characterized by a macroscopically normal brain on magnetic resonance imaging, subtle structural brain alterations have been detected by advanced neuroimaging techniques in Childhood Absence Epilepsy syndrome. We applied quantitative structural MRI analysis to a group of adolescents and adults with Juvenile Absence Epilepsy (JAE) in order to investigate micro-structural brain changes using different brain measures. We examined grey matter volumes, cortical thickness, surface areas, and subcortical volumes in 24 patients with JAE compared to 24 healthy controls; whole-brain voxel-based morphometry (VBM) and Freesurfer analyses were used. When compared to healthy controls, patients revealed both grey matter volume and surface area reduction in bilateral frontal regions, anterior cingulate, and right mesial-temporal lobe. Correlation analysis with disease duration showed that longer disease was correlated with reduced surface area in right pre- and post-central gyrus. A possible effect of valproate treatment on brain structures was excluded. Our results indicate that subtle structural brain changes are detectable in JAE and are mainly located in anterior nodes of regions known to be crucial for awareness, attention and memory.

2016 - Endogenous Neurosteroids Levels are Decreased in CSF During Status Epilepticus [Abstract in Rivista]
Monti, G; Lucchi, C; Rustichelli, C; Giovannini, G; Meletti, S; Biagini, G
abstract

Purpose: Neuroactive steroids, such as allopregnanolone (AP), are positive allosteric modulators of GABA-A receptors enhancing both synaptic and extrasynaptic GABA-A mediated inhibition and might be effective in the treatment of benzodiazepine-resistant status epilepticus (SE). No data are available on AP levels in central nervous system (CNS) of patients suffering from SE. This lack of information hampers the possibility to correctly design a rational therapeutic approach to SE. We designed a study to evaluate AP in serum and cerebrospinal fluid (CSF) of patients affected by SE. Method: We retrospectively (2007–2015) evaluated blood and CSF samples from 41 adult patients with diagnosis of SE who received lumbar puncture at SE onset (median of 4 days) for clinical purposes and for whom a CNS infection was finally excluded. 41 subjects (matched for age and sex) that had negative results after lumbar puncture for suspected idiopathic intracranial hypertension, CNS infection, or inflammatory disease served as control group. Quantitative analysis of neurosteroids was performed by liquid chromatography-electrospray tandem mass spectrometry. Results: Serum AP levels did not revealed significant differences between controls and SE patients. However, CSF AP levels were decreased by approximately 30% (p &lt; 0.05, Mann-Whitney test) in patients compared with controls. Interestingly, linear regression did not reveal a relationship between serum and CSF levels for AP in controls (R2 = 0.06, p = 0.27). On the contrary, a significant relationship (R2 = 0.57, p = 0.003) was present in patients affected by SE. Conclusion: We demonstrated that endogenous allopregnenolone is significantly reduced during SE in CSF. Administration of AP to patients suffering of SE could be useful to reestablish AP level in the CNS. In addition, exogenously administered AP may result to have a privileged access to brain tissue by virtue of the higher permeability of the blood- brain barrier during SE.

2016 - Extrastriate visual cortex in idiopathic occipital epilepsies: The contribution of retinotopic areas to spike generation [Articolo su rivista]
Meletti, Stefano; Ruggieri, Andrea; Avanzini, Pietro; Caramaschi, Elisa; Filippini, Melissa; Bergonzini, Patrizia; Monti, Giulia; Vignoli, Aglaia; Olivotto, Sara; Mastrangelo, Massimo; Santucci, Margherita; Gobbi, Giuseppe; Veggiotti, Pierangelo; Vaudano, Anna Elisabetta
abstract

Objectives To provide insight into the pathophysiology of idiopathic childhood occipital epilepsies (ICOEs), by mapping the contribution of retinotopic visual areas to the generation and sustainment of epileptic activity. Methods Thirteen patients affected by ICOEs (mean age = 10.9 years) underwent a video electroencephalography-functional magnetic resonance imaging (EEG-fMRI) study. A flexible-related fMRI analysis was applied to estimate the shape of the blood oxygen level-dependent (BOLD) response in each patient. Second-level analysis was performed using the interictal EEG discharge (IED)-specific response shape for the ICOE group. The resulting fMRI t-maps were warped to the Population-Average, Landmark- and Surface-based (PALS)-B12 atlas in Caret. For localization purposes, functional results were plotted and compared against 19 retinotopic areas for each hemisphere. A correlation analysis was performed between the hemodynamic maps and electroclinical variables. Results The shape of the group-averaged hemodynamic response in ICOE patients showed an earlier time-to-peak and a more pronounced undershoot than the canonical hemodynamic response function (HRF). The random-effect analysis showed positive hemodynamic changes in the bilateral temporooccipital network. With regard to the retinotopic subdivision of the visual cortex, the primary visual area was consistently spared. Conversely, an extensive involvement of the occipitotemporal cortex, including the fusiform gyrus, and the occipitoparietal areas was observed. Moreover, a linear relationship was detected between the occipital spike-density and BOLD increases at the postcentral gyrus and temporooccipital cortex. Significance Our data indicate that both the ventral and dorsal visual pathways are involved in spike generation in ICOEs, to extents that vary between patients, and reinforce the concept of benign childhood seizure susceptibility syndrome as a substrate for ICOEs. Finally, these results underscore the need for appropriate neuropsychological testing in these children, aimed at revealing selective impairments in functions subserved by both visual pathways.

2016 - Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy [Articolo su rivista]
Ricos, Michael G.; Hodgson, Bree L.; Pippucci, Tommaso; Saidin, Akzam; Ong, Yeh Sze; Heron, Sarah E.; Licchetta, Laura; Bisulli, Francesca; Bayly, Marta A.; Hughes, James; Baldassari, Sara; Palombo, Flavia; Santucci, Margherita; Meletti, Stefano; Berkovic, Samuel F.; Rubboli, Guido; Thomas, Paul Q.; Scheffer, Ingrid E.; Tinuper, Paolo; Geoghegan, Joel; Schreiber, Andreas W.; Dibbens, Leanne M.
abstract

Objective Focal epilepsies are the most common form observed and have not generally been considered to be genetic in origin. Recently, we identified mutations in DEPDC5 as a cause of familial focal epilepsy. In this study, we investigated whether mutations in the mammalian target of rapamycin (mTOR) regulators, NPRL2 and NPRL3, also contribute to cases of focal epilepsy. Methods We used targeted capture and next-generation sequencing to analyze 404 unrelated probands with focal epilepsy. We performed exome sequencing on two families with multiple members affected with focal epilepsy and linkage analysis on one of these. Results In our cohort of 404 unrelated focal epilepsy patients, we identified five mutations in NPRL2 and five in NPRL3. Exome sequencing analysis of two families with focal epilepsy identified NPRL2 and NPRL3 as the top candidate-causative genes. Some patients had focal epilepsy associated with brain malformations. We also identified 18 new mutations in DEPDC5. Interpretation We have identified NPRL2 and NPRL3 as two new focal epilepsy genes that also play a role in the mTOR-signaling pathway. Our findings show that mutations in GATOR1 complex genes are the most significant cause of familial focal epilepsy identified to date, including cases with brain malformations. It is possible that deregulation of cellular growth control plays a more important role in epilepsy than is currently recognized.

2016 - Social cognition in temporal lobe epilepsy: A systematic review and meta-analysis [Articolo su rivista]
Bora, Emre; Meletti, Stefano
abstract

Objective: There is increasing evidence suggesting that social cognitive abilities are impaired in temporal lobe epilepsy (TLE), the most common form of focal epilepsies. Methods: In this meta-analysis, 31 studies investigating theory of mind (ToM) and facial emotion recognition performances of 1356 patients with TLE (351 postsurgery) and 859 healthy controls were included. Results: Patients with TLE had significant deficits in ToM (d = 0.73-0.89) and recognition of facial emotions. There were no significant differences in severity of social cognitive deficits between patients with TLE with or without medial temporal lobectomy. Earlier onset of seizures was associated with ToM impairment. Rightsided TLE was associated with more severe deficits in recognition of fear, sadness, and disgust. Conclusions: Social cognitive information processing is impaired in TLE, and the potential role of these deficits in functional impairment needs to be further investigated.

2016 - Which elderly newly diagnosed glioblastoma patients can benefit from radiotherapy and temozolomide? A PERNO prospective study [Articolo su rivista]
Franceschi, Enrico; Depenni, R.; Paccapelo, Alexandro; Ermani, Mario; Faedi, M.; Sturiale, Carmelo; Michiara, Maria; Servadei, F.; Pavesi, Giacomo; Urbini, B.; Pisanello, A.; Crisi, G.; Cavallo, Michele A.; Dazzi, C.; Biasini, C.; Bertolini, F.; Mucciarini, C.; Pasini, G.; Baruzzi, Agostino; Brandes, Alba A; Albani, F.; Calbucci, F.; D’Alessandro, R.; Michelucci, R.; de Pasqua, S.; Testoni, S.; Brandes, A.; Franceschi, E.; Tosoni, A.; Eusebi, V.; Ceruti, S.; Fainardi, E.; Tamarozzi, R.; Emiliani, E.; Cavallo, M.; Fiorica, F.; Sasso, E.; Cavanna, L.; Guidetti, D.; Marcello, N.; Cremonini, A. M.; Guiducci, G.; Agati, R.; Ambrosetto, G.; Bacci, A.; Baldin, E.; Baldrati, A.; Barbieri, E.; Bartolini, S.; Bellavista, E.; Bisulli, F.; Bonora, E.; Bunkheila, F.; Carelli, V.; Crisci, M.; Dall’Occa, P.; de Biase, D.; Ferro, S.; Franceschi, C.; Frezza, G.; Grasso, V.; Leonardi, M.; Marucci, G.; Morandi, L.; Mostacci, B.; Palandri, G.; Pasini, E.; Pastore Trossello, M.; Pession, A.; Poggi, R.; Riguzzi, P.; Rinaldi, R.; Rizzi, S.; Romeo, G.; Spagnolli, F.; Tinuper, P.; Trocino, C.; Dall’Agata, M.; Frattarelli, M.; Gentili, G.; Giovannini, A.; Iorio, P.; Pasquini, U.; Galletti, G.; Guidi, C.; Neri, W.; Patuelli, A.; Strumia, S.; Casmiro, M.; Gamboni, A.; Rasi, F.; Cruciani, G.; Cenni, P.; Guidi, A. R.; Zumaglini, F.; Amadori, A.; Pasquinelli, M.; Pasquini, E.; Polselli, A.; Ravasio, A.; Viti, B.; Sintini, M.; Ariatti, A.; Bigliardi, G.; Carpeggiani, P.; Cavalleri, F.; Meletti, Stefano; Nichelli, Paolo Frigio; Pettorelli, E.; Pinna, G.; Zunarelli, E.; Artioli, F.; Bernardini, I.; Costa, M.; Greco, G.; Guerzoni, R.; Stucchi, C.; Iaccarino, C.; Ragazzi, M.; Rizzi, R.; Zuccoli, G.; Api, P.; Cartei, F.; Colella, M.; Fallica, E.; Farneti, M.; Frassoldati, A.; Granieri, E.; Latini, F.; Monetti, C.; Saletti, A.; Schivalocchi, R.; Sarubbo, S.; Seraceni, S.; Tola, M. R.; Zini, G.; Giorgi, C.; Montanari, E.; Cerasti, D.; Crafa, P.; Dascola, I.; Florindo, I.; Giombelli, E.; Mazza, S.; Ramponi, V.; Silini, E. M.; Torelli, P.; Immovilli, P.; Morelli, N.; Vanzo, C.; Nobile, C.
abstract

The role of temozolomide concurrent with and adjuvant to radiotherapy (RT/TMZ) in elderly patients with glioblastoma (GBM) remains unclear. We evaluated the outcome of patients &gt;70&nbsp;years in the context of the Project of Emilia-Romagna Region in Neuro-Oncology (PERNO), the first Italian prospective observational population-based study in neuro-oncology. For this analysis the criteria for selecting patients enrolled in the PERNO study were: age &gt;70&nbsp;years; PS 0–3; histologically confirmed GBM; postoperative radiotherapy (RT) after surgery with or without concomitant temozolomide (TMZ) or postsurgical TMZ alone. Between January 2009 and December 2010, 76 GBM elderly patients were identified in the prospective PERNO study. Twenty-three patients did not receive any treatment after surgery, and 53 patients received postsurgical treatments (25 patients received RT alone and 28 patients RT/TMZ). Median survival was 11.1&nbsp;months (95&nbsp;% CI 8.8–13.5), adding temozolomide concomitant and adjuvant to radiotherapy it was 11.6&nbsp;months (95&nbsp;% CI 8.6–14.6), and 9.3&nbsp;months (95&nbsp;% CI 8.1–10.6) in patients treated with RT alone (P&nbsp;=&nbsp;0.164). However, patients with MGMT methylated treated with RT/TMZ obtained a better survival (17.2&nbsp;months, 95&nbsp;% CI 11.5–22.9) (P&nbsp;=&nbsp;0.042). No difference in terms of survival were observed if patients with MGMT unmethylated tumor received RT alone, or RT/TMZ or, in MGMT methylated tumor, if patients received radiotherapy alone. In elderly patients RT/TMZ represent a widely used approach but it is effective with methylated MGMT tumors only.

2015 - A one-year prospective study of refractory status epilepticus in Modena, Italy [Articolo su rivista]
Giovannini, Giada; Monti, Giulia; Polisi, Michela M; Mirandola, Laura; Marudi, Andrea; Pinelli, Giovanni; Valzania, Franco; Girardis, Massimo; Nichelli, Paolo Frigio; Meletti, Stefano
abstract

Refractory status epilepticus (RSE) is a particular critical condition characterized by seizures that continue despite the use of first- and second-line therapies and by high mortality. To date, only one prospective study investigated clinical features and prognostic factors in RSE. In this study, we performed a one-year prospective survey to identify clinical features, outcomes, and variables associated with the development of RSE in the adolescent and adult population of Modena, northern Italy. We observed 83 episodes of SE in 83 patients. In 31% of the cases, third-line therapy (anesthetic drug) was needed. Among this group, 14% resolved and were classified as RSE, while, in 17%, seizures recurred at withdrawal of anesthetics and were classified as super-RSE. The development of RSE/super-RSE was associated with a stuporous/comatose state at presentation and with the absence of a previous history of epilepsy. Refractory status epilepticus/super-refractory status epilepticus showed a worse outcome compared with responsive SE: 54% versus 21% for 30-day mortality; 19% versus 56% for a return to baseline condition. This prospective study confirms stupor/coma at onset as a relevant clinical factor associated with SE refractoriness. We observed a rate of RSE comparable with previous reports, with high mortality and morbidity. Mortality in the observed RSE was higher than in previous studies; this result is probably related to the low rate of a previous epilepsy history in our population that reflects a high incidence of acute symptomatic etiologies, especially the inclusion of patients with postanoxic SE who have a bad prognosis per se. This article is part of a Special Issue entitled "Status Epilepticus".

2015 - An EEG-fMRI Study on the Termination of Generalized Spike-And-Wave Discharges in Absence Epilepsy [Articolo su rivista]
Benuzzi, Francesca; Ballotta, Daniela; Mirandola, Laura; Ruggieri, Andrea; Vaudano, Anna Elisabetta; Zucchelli, Micaela Maria; Ferrari, Elisabetta; Nichelli, Paolo Frigio; Meletti, Stefano
abstract

INTRODUCTION: Different studies have investigated by means of EEG-fMRI coregistration the brain networks related to generalized spike-and-wave discharges (GSWD) in patients with idiopathic generalized epilepsy (IGE). These studies revealed a widespread GSWD-related neural network that involves the thalamus and regions of the default mode network. In this study we investigated which brain regions are critically involved in the termination of absence seizures (AS) in a group of IGE patients. METHODS: Eighteen patients (6 male; mean age 25 years) with AS were included in the EEG-fMRI study. Functional data were acquired at 3T with continuous simultaneous video-EEG recording. Event-related analysis was performed with SPM8 software, using the following regressors: (1) GSWD onset and duration; (2) GSWD offset. Data were analyzed at single-subject and at group level with a second level random effect analysis. RESULTS: A mean of 17 events for patient was recorded (mean duration of 4.2 sec). Group-level analysis related to GSWD onset respect to rest confirmed previous findings revealing thalamic activation and a precuneus/posterior cingulate deactivation. At GSWD termination we observed a decrease in BOLD signal over the bilateral dorsolateral frontal cortex respect to the baseline (and respect to GSWD onset). The contrast GSWD offset versus onset showed a BOLD signal increase over the precuneus-posterior cingulate region bilaterally. Parametric correlations between electro-clinical variables and BOLD signal at GSWD offset did not reveal significant effects. CONCLUSION: The role of the decreased neural activity of lateral prefrontal cortex at GSWD termination deserve future investigations to ascertain if it has a role in promoting the discharge offset, as well as in the determination of the cognitive deficits often present in patients with AS. The increased BOLD signal at precuneal/posterior cingulate cortex might reflect the recovery of neural activity in regions that are "suspended" during spike and waves activity, as previously hypothesized.

2015 - Cerebrospinal fluid tau proteins in status epilepticus [Articolo su rivista]
Monti, Giulia; Tondelli, Manuela; Giovannini, Giada; Bedin, Roberta; Nichelli, Paolo Frigio; Trenti, Tommaso; Meletti, Stefano; Chiari, Annalisa
abstract

Tau protein is a phosphorylated microtubule-associated protein, principally localized at neuronal level in the central nervous system (CNS). Tau levels in the cerebrospinal fluid (CSF) are considered to index both axonal and neuronal damage. To date, however, no study has specifically evaluated the CSF levels of tau proteins in patients with status epilepticus (SE). We evaluated these established biomarkers of neuronal damage in patients with SE who received a lumbar puncture during SE between 2007 and 2014. Status epilepticus cases due to acute structural brain damage, including CNS infection, were excluded. Clinical, biological, therapeutic, and follow-up data were collected. Group comparison between patients stratified according to SE response to antiepileptic drugs (AEDs), disability, and epilepsy outcomes were performed. Twenty-eight patients were considered for the analyses (mean age 56years): 14 patients had abnormally high CSF t-tau level, six patients had abnormally high CSF p-tau level, and only three patients had abnormally low Aβ1-42 level. Cerebrospinal fluid t-tau value was higher in patients who developed a refractory SE compared to patients with seizures controlled by AED. Cerebrospinal fluid t-tau values were positively correlated with SE duration and were higher in patients treated with propofol anesthesia compared to patients that had not received this treatment. Patients with higher CSF t-tau had higher risk of developing disability (OR=32.5, p=0.004) and chronic epilepsy (OR=12; p=0.016) in comparison with patients with lower CSF t-tau level. Our results suggest that CSF t-tau level might be proposed as a biomarker of SE severity and prognosis. Prospective studies are needed to evaluate the effects of propofol on tau pathology in this setting. This article is part of a Special Issue entitled "Status Epilepticus".

2015 - Claustrum damage and refractory status epilepticus following febrile illness [Articolo su rivista]
Meletti, Stefano; Slonkova, Jana; Mareckova, Iva; Monti, Giulia; Specchio, Nicola; Hon, Petr; Giovannini, Giada; Marcian, Vaclav; Chiari, Annalisa; Krupa, Petr; Pietrafusa, Nicola; Berankova, Dagmar; Bar, Michal
abstract

BACKGROUND: To characterize the clinical, EEG, and brain imaging findings in an adult case series of patients with de novo refractory status epilepticus (SE) occurring after a febrile illness. METHODS: A retrospective study (2010-2013) was undertaken with the following inclusion criteria: (1) previously healthy adults with refractory SE; (2) seizure onset 0-21 days after a febrile illness; (3) lacking evidence of infectious agents in CSF; (4) no history of seizures (febrile or afebrile) or previous or concomitant neurologic disorder. RESULTS: Among 155 refractory SE cases observed in the study period, 6 patients (17-35 years old) fulfilled the inclusion criteria. Confusion and stupor were the most common symptoms at disease onset, followed after a few days by acute repeated seizures that were uncountable in all but one. Seizures consisted of focal motor/myoclonic phenomena with subsequent generalization. Antiepileptic drugs failed in every patient to control seizures, with all participants requiring intensive care unit admission. Barbiturate coma with burst-suppression pattern was applied in 4 out of 6 patients for 5-14 days. One participant died in the acute phase. In each patient, we observed a reversible bilateral claustrum MRI hyperintensity on T2-weighted sequences, without restricted diffusion, time-related with SE. All patients had negative multiple neural antibodies testing. Four out of 5 surviving patients developed chronic epilepsy. CONCLUSIONS: This is a hypothesis-generating study of a preliminary nature supporting the role of the claustrum in postfebrile de novo SE; future prospective studies are needed to delineate the specificity of this condition, its pathogenesis, and the etiology.

2015 - Comment on "Reflex epileptic mechanisms in humans: Lessons about natural ictogenesis" by Peter Wolf [Articolo su rivista]
Meletti, Stefano; Vaudano, Anna Elisabetta
abstract

We readwith great interest the review by PeterWolf who discusses extensively the most known reflex epileptic traits and the related hypotheses on their ictogenesis [1]. In particular, he presents the contribution provided by advanced neuroimaging techniques, especially ictal and interictal EEG-fMRI studies. Among the reflex epileptic traits, eye closure sensitivity (ECS) has been considered and discussed in light of a recent study by our group [2] in patients with Jeavons syndrome [or eyelid myoclonia with absences (EMA), which represents the archetypal of ECS]. Since several questions have been raised by Prof. Wolf in reference to our findings, we would like to take the opportunity to try to answer some of the raised questions and to better clarify our point of view about the ECS phenomenon.

2015 - Corrigendum to Expression of 19 microRNAs in glioblastoma and comparison with other brain neoplasia of grades I-III [Mol. Oncol. 8 (2) (2014) 417-30] [Articolo su rivista]
Visani, M.; de Biase, D.; Marucci, G.; Cerasoli, S.; Nigrisoli, E.; Bacchi Reggiani, M. L.; Albani, F.; Baruzzi, A.; Pession, A.; Agati, R.; Ambrosetto, G.; Bacci, A.; Baldin, E.; Baldrati, A.; Barbieri, E.; Bartolini, S.; Bellavista, E.; Bisulli, F.; Bonora, E.; Bunkheila, F.; Carelli, V.; Crisci, M.; Dall'Occa, P.; Ferro, S.; Franceschi, C.; Frezza, G.; Grasso, V.; Leonardi, M.; Morandi, L.; Mostacci, B.; Palandri, G.; Pasini, E.; Pastore Trossello, M.; Poggi, R.; Riguzzi, P.; Rinaldi, R.; Rizzi, S.; Romeo, G.; Spagnolli, F.; Tinuper, P.; Trocino, C.; Frattarelli, M.; Giovannini, A.; Iorio, P.; Pasquini, U.; Galletti, G.; Guidi, C.; Neri, W.; Patuelli, A.; Strumia, S.; Dall'Agata, M.; Faedi, M.; Gentili, G.; Zumaglini, F.; Casmiro, M.; Gamboni, A.; Rasi, F.; Cruciani, G.; Cenni, P.; Dazzi, C.; Guidi, A. R.; Amadori, A.; Pasini, G.; Pasquinelli, M.; Pasquini, E.; Polselli, A.; Ravasio, A.; Viti, B.; Sintini, M.; Ariatti, A.; Bertolini, F.; Bigliardi, G.; Carpeggiani, P.; Cavalleri, F.; Meletti, S.; Nichelli, P.; Pettorelli, E.; Pinna, G.; Zunarelli, E.; Artioli, F.; Bernardini, I.; Costa, M.; Greco, G.; Guerzoni, R.; Stucchi, C.; Ragazzi, M.; Iaccarino, C.; Rizzi, R.; Zuccoli, G.; Api, P.; Cartei, F.; Fallica, E.; Granieri, E.; Latini, F.; Lelli, G.; Monetti, C.; Saletti, A.; Schivalocchi, R.; Seraceni, S.; Tola, M. R.; Urbini, B.; Giorgi, C.; Montanari, E.; Cerasti, D.; Crafa, P.; Dascola, I.; Florindo, I.; Giombelli, E.; Mazza, S.; Ramponi, V.; Servadei, F.; Silini, E. M.; Torelli, P.; Immovilli, P.; Morelli, N.; Vanzo, C.; Nobile, C.
abstract

2015 - Emerging neuroimaging contribution to the diagnosis and management of the ring chromosome 20 syndrome [Articolo su rivista]
Vaudano, Anna Elisabetta; Ruggieri, Andrea; Vignoli, Aglaia; Canevini, Maria Paola; Meletti, Stefano
abstract

Ring chromosome 20 [r(20)] syndrome is an underdiagnosed chromosomal anomaly characterized by severe epilepsy, behavioral problems, and mild-to-moderate cognitive deficits. Since the cognitive and behavioral decline follows seizure onset, this syndrome has been proposed as an epileptic encephalopathy (EE). The recent overwhelming development of advanced neuroimaging techniques has opened a new era in the investigation of the brain networks subserving the EEs. In particular, functional neuroimaging tools are well suited to show alterations related to epileptiform discharges at the network level and to build hypotheses about the mechanisms underlying the cognitive disruption observed in these conditions. This paper reviews the brain circuits and their disruption as revealed by functional neuroimaging studies in patients with [r(20)] syndrome. It discusses the clinical consequences of the neuroimaging findings on the management of patients with [r(20)] syndrome, including their impact to an earlier diagnosis of this disorder. Based on the available lines of evidences, [r(20)] syndrome is characterized by interictal and ictal dysfunctions within basal ganglia-prefrontal lobe networks and by long-lasting effects of the peculiar theta-delta rhythm, which represents an EEG marker of the syndrome on integrated brain networks that subserve cognitive functions.

2015 - Emotion Recognition [Capitolo/Saggio]
Meletti, Stefano
abstract

The recognition of emotional signals from all sensory modalities is a critical component of human social interactions. It is through the understanding of the affective states of others that we can guide our own behavioral responses. Notably, facial expression provides the greatest amount of emotional cues that are useful in recognizing emotions, such as joy, anger, and fear. The temporal lobe – and the amygdala in particular – plays a crucial role in processing the appropriate autonomic and behavioral responses to relevant emotional stimuli. Only in the past decade, however, the role played by the antero-medial temporal lobe region has been demonstrated in decoding the emotions, mental states, and beliefs of others. In the fi eld of epilepsy, this knowledge has several clinical, as well as speculative, implications. Indeed, temporal lobe epilepsy (TLE) is the most common type of focal epilepsy. It is frequently characterized by lesions or gliosis/atrophy (hippocampal sclerosis) involving the medial temporal lobe region, and antero-medial temporal lobe resection is the standard treatment for drug-resistant medial TLE. Consequently, the investigation of emotional and social competence in TLE patients has been the focus of several studies. Such studies have extended the scope of neuropsychological evaluation in TLE beyond the traditional evaluation of memory, language, and executive functions.

2015 - Emotion recognition in temporal lobe epilepsy: A systematic review [Articolo su rivista]
Monti, Giulia; Meletti, Stefano
abstract

There is increasing interest in the understanding of emotion recognition deficits in temporal lobe epilepsy (TLE), the most common form of focal epilepsies. There are conflicting reports about impairments for different emotions in right and left temporal lobe epilepsy patients. A systematic review and a narrative synthesis was conducted for studies investigating emotion recognition (ER) in TLE. Embase, MEDLINE, PsychINFO and Pubmed were searched from 1990 to March 2015 and reference lists were reviewed. 996 citations were identified and 43 studies were finally included. ER deficits are consistently observed across studies. A fear recognition deficit is always reported, followed by deficits in sadness and disgust recognition. Deficits are observed across visual and auditory domains. Conflicting evidence is present concerning the severity of ER deficits in right and left TLE. Studies on anterior temporal lobectomy report data similar to that observed in pre-surgical patients. Current evidence supports the conclusion that recognition of negative emotions is commonly impaired in TLE, particularly for fear, and in the visual domain. Future work should focus on more ecologically valid test, on longitudinal studies to assess the role of anterior temporal lobectomy, and to correlate ER measures to social functioning in everyday life.

2015 - Erratum to: Survival prediction in high-grade gliomas using CT perfusion imaging [Articolo su rivista]
Yeung, Tp; Wang, Y; He, W; Urbini, B; Gafà, R; Ulazzi, L; Yartsev, S; Bauman, G; Lee TY, ; Fainardi, E; Project of Emilia-Romagna Region on Neuro-Oncology (PERNO) Study Group Participants :Agati, R.; Ambrosetto, G.; Bacci, A.; Baldin, E.; Baldrati, A.; Barbieri, E.; Bartolini, S.; Bellavista, E.; Bisulli, F.; Bonora, E.; Bunkheila, F.; Carelli, V.; Crisci, M.; Dall’Occa, P.; de Biase, D.; Ferro, S.; Franceschi, C.; Frezza, G.; Grasso, V.; Leonardi, M.; Marucci, G.; Morandi, L.; Mostacci, B.; Palandri, G.; Pasini, E.; Pastore Trossello, M.; Pession, A.; Poggi, R.; Riguzzi, P.; Rinaldi, R.; Rizzi, S.; Romeo, G.; Spagnolli, F.; Tinuper, P.; Trocino C., (Bologna); Dall’Agata, M.; Frattarelli, M.; Gentili, G.; Giovannini, A.; Iorio, P.; Pasquini, U.; Galletti, G.; Guidi, C.; Neri, W.; Patuelli, A.; Strumia S., (Forlı`-Cesena); Faedi, M.; (IRCCS Istituto Scientifico Romagnolo per lo Studio, e la Cura dei Tumori); Casmiro, M.; Gamboni, A.; Rasi, F. (Faenza R. A. ).; Cruciani G., (Lugo; RA), ; Cenni, P.; Dazzi, C.; Guidi, A. R.; Zumaglini F., (Ravenna); Amadori, A.; Pasini, G.; Pasquinelli, M.; Pasquini, E.; Polselli, A.; Ravasio, A.; Viti B., (Rimini); Sintini M., (Cattolica; RN), ; Ariatti, A.; Bertolini, F.; Bigliardi, G.; Carpeggiani, P.; Cavalleri, F.; Meletti, S.; Nichelli, P.; Pettorelli, E.; Pinna, G.; Zunarelli E., (Modena); Artioli, F.; Bernardini, I.; Costa, M.; Greco, G.; Guerzoni, R.; Stucchi, C. (Carpi M. O. ).; Iaccarino, C; Ragazzi, M.; Rizzi, R.; Zuccoli G., (Istituto di Ricovero e Cura a Carattere Scientifico; Reggio, Emilia); Api, P.; Cartei, F.; Colella, M.; Fallica, E.; Farneti, M.; Frassoldati, A.; Granieri, E.; Latini, F.; Monetti, C.; Saletti, A.; Schivalocchi, R.; Sarubbo, S.; Seraceni, S.; Tola, M. R.; Urbini, B.; Zini G., (Ferrara); Giorgi, C.; Montanari, E. (Fidenza P. R. ).; Cerasti, D.; Crafa, P.; Dascola, I.; Florindo, I.; Giombelli, E.; Mazza, S.; Ramponi, V.; Servadei, F.; Silini, Em.; Torelli P., (Parma); Immovilli, P.; Morelli, N.; Vanzo C., (Piacenza); Nobile, C. (Padova).
abstract

Erratum to: J Neurooncol (2015) 123:93–102 DOI 10.1007/s11060-015-1766-5 Three participants were missing in the Appendix (listing the members of the PERNO study group) in the original publication. They are included in the complete list in the Appendix below.

2015 - Integration of multimodal neuroimaging methods: a rationale for clinical applications of simultaneous EEG-fMRI [Articolo su rivista]
Vitali, Piera; Di Perri, C; Vaudano, Anna Elisabetta; Meletti, Stefano; Villani, F.
abstract

Functional magnetic resonance imaging (fMRI), which has high spatial resolution, is increasingly used to evaluate cerebral functions in neurological and psychiatric diseases. The main limitation of fMRI is that it detects neural activity indirectly, through the associated slow hemodynamic variations. Because neurovascular coupling can be regionally altered by pathological conditions or drugs, fMRI responses may not truly reflect neural activity. Electroencephalography (EEG) recordings, which directly detect neural activity with optimal temporal resolution, can now be obtained during fMRI data acquisition. Therefore, there is a growing interest in combining the techniques to obtain simultaneous EEG-fMRI recordings. The EEG-fMRI approach has several promising clinical applications. The first is the detection of cortical areas involved in interictal and ictal epileptic activity. Second, combining evoked potentials with fMRI could be an accurate way to study eloquent cortical areas for the planning of neurosurgery or rehabilitation, circumventing the above-mentioned limitation of fMRI. Finally, the use of this approach to evaluate the functional connectivity of resting-state networks would extend the applications of EEG-fMRI to uncooperative or unconscious patients. Integration of multimodal neuroimaging methods: a rationale for clinical applications of simultaneous EEG-fMRI.

2015 - Intracranial time–frequency correlates of seizure-related negative BOLD response in the sensory-motor network [Articolo su rivista]
Meletti, Stefano; Vaudano, ANNA ELISABETTA
abstract

The study evaluates the BOLD signal related to high and low frequency EEG changes related to focal seizures in the motor system

2015 - Ischemic-hypoxic mechanisms leading to hippocampal dysfunction as a consequence of status epilepticus [Articolo su rivista]
Lucchi, Chiara; Vinet, Jonathan; Meletti, Stefano; Biagini, Giuseppe
abstract

Status epilepticus (SE) is one of the recognized primary precipitating events that can lead to temporal lobe epilepsy (TLE) associated with hippocampal sclerosis. This type of epilepsy is characterized by poor response to drug treatment, often requiring surgical intervention to remove the mesial temporal regions involved in the seizure onset. However, even neurosurgery may not be completely successful. Thus, the prevention of hippocampal damage and epileptogenesis is currently evaluated as a possible alternative therapeutic approach to prevent the development of pharmacoresistant TLE. Lines of evidence suggest that ischemic-hypoxic lesions might occur in different brain regions, including the hippocampus, during SE. Especially in the hippocampal CA3 region, an ischemic-like lesion develops in the stratum lacunosum-moleculare and is mainly characterized by a loss of astrocytes and neuronal processes and increased immunostaining of pimonidazole which probes areas exposed to hypoxia. Interestingly, these mechanisms can contribute to neuronal cell loss and may be counteracted by drugs that can afford vascular protection, as in the case of ligands of the ghrelin receptor. Notably, some of the ghrelin receptor ligands possess a double edge effect, since they are anticonvulsant and vascular-protective, thus, potentially representing new tools to counteract the consequences of SE. This article is part of a Special Issue entitled Status Epilepticus.

2015 - Long-term surgery outcome for epilepsy and psychogenic nonepileptic seizures in a child with anterior cingulate gyrus dysplasia [Articolo su rivista]
Mirandola, Laura; Meletti, Stefano; Cantalupo, Gaetano
abstract

We present the case of a 13-year-old child with nocturnal frontal lobe epilepsy (NFLE) related to a right cingulate gyrus cortical dysplasia, who also presented with psychogenic nonepileptic seizures (PNES) and interictal antisocial behavior. The association of drug-resistant epilepsy with behavioral disorders is well established, but the role of epilepsy surgery in these patients is still controversial, especially in children. The key finding is represented by the excellent long-term outcome on both epilepsy and behavioral dysfunction after the surgical excision of the cingulate gyrus cortical dysplasia.

2015 - Mapping (and modeling) physiological movements during EEG-fMRI recordings: the added value of the video acquired simultaneously [Articolo su rivista]
Ruggieri, Andrea; Vaudano, Anna Elisabetta; Benuzzi, Francesca; Serafini, Marco; Gessaroli, Giuliana; Farinelli, Valentina; Nichelli, Paolo Frigio; Meletti, Stefano
abstract

Background: During resting-state EEG-fMRI studies in epilepsy, patients' spontaneous head-face movements occur frequently. We tested the usefulness of synchronous video recording to identify and model the fMRI changes associated with non-epileptic movements to improve sensitivity and specificity of fMRI maps related to interictal epileptiform discharges (IED). New methods: Categorization of different facial/cranial movements during EEG-fMRI was obtained for 38 patients [with benign epilepsy with centro-temporal spikes (BECTS, n = 16); with idiopathic generalized epilepsy (IGE, n = 17); focal symptomatic/cryptogenic epilepsy (n = 5)]. We compared at single subject-and at group-level the IED-related fMRI maps obtained with and without additional regressors related to spontaneous movements. As secondary aim, we considered facial movements as events of interest to test the usefulness of video information to obtain fMRI maps of the following face movements: swallowing, mouth-tongue movements, and blinking. Results: Video information substantially improved the identification and classification of the artifacts with respect to the EEG observation alone (mean gain of 28 events per exam). Comparison with existing method: Inclusion of physiological activities as additional regressors in the GLM model demonstrated an increased Z-score and number of voxels of the global maxima and/or new BOLD clusters in around three quarters of the patients. Video-related fMRI maps for swallowing, mouth-tongue movements, and blinking were comparable to the ones obtained in previous task-based fMRI studies. Conclusions: Video acquisition during EEG-fMRI is a useful source of information. Modeling physiological movements in EEG-fMRI studies for epilepsy will lead to more informative IED-related fMRI maps in different epileptic conditions.

2015 - Neurosteroids as Endogenous Modulators of Epileptic Seizures [Abstract in Atti di Convegno]
Biagini, Giuseppe; Rustichelli, Cecilia; Lucchi, Chiara; Meletti, Stefano
abstract

Neurosteroids are a family of steroidal compounds which produce a variety of biological effects, mainly by interacting with the γ-aminobutyric acid receptor A (GABAA). Among neurosteroids, allopregnanolone and tetrahydrodeoxycorticosterone are positive modulators of GABAA receptors that were shown to counteract seizures in animal models. However, it is still to be defined the role of neurosteroids both in patients affected by epilepsy and in animal models based on spontaneously recurrent seizures. By using finasteride, an irreversible inhibitor of the enzyme 5α-reductase, we found that allopregnanolone cerebral levels were significantly decreased in rats treated with the convulsant pilocarpine. Interestingly, this decrease was followed by enhanced epileptogenesis. We also described a case of antiepileptic drug resistance in a patient that was maintained on finasteride to treat a dermatological disorder: seizures ceased by withdrawing finasteride. These findings point to a modulatory role of allopregnanalone and other neurosteroids on epileptic seizures.

2015 - Prevalence of nocturnal frontal lobe epilepsy in the adult population of Bologna and Modena, Emilia-Romagna region, Italy [Articolo su rivista]
Vignatelli, Luca; Bisulli, Francesca; Giovannini, Giada; Licchetta, Laura; Naldi, Ilaria; Mostacci, Barbara; Rubboli, Guido; Provini, Federica; Tinuper, Paolo; Meletti, Stefano
abstract

Study Objectives: To estimate the prevalence of nocturnal frontal lobe epilepsy (NFLE) in the adults of two areas of the Emilia-Romagna region (northeast Italy) and to describe the clinical features from a population-based perspective. Design: Population-based retrospective cohort study including adults with NFLE. Setting: Two areas of the Emilia-Romagna region: the city of Bologna (330,901 adult residents) and five districts of the province of Modena (424,007). Prevalence day: December 31, 2010. Participants: Patients with NFLE collected from multiple databases of neurologic hub centers of the districts involved. Diagnostic criteria: clinical history of sleep related bizarre motor attacks and videopolysomnographic recording confirming the typical features of NFLE. Inclusion criteria for prevalence calculation: residence in one of the two geographic areas on the prevalence day and an "active" or "in remission with treatment" form of NFLE. Measurements and Results: Six subjects from Bologna and eight from Modena were included. Crude prevalence (per 100,000 residents) was 1.8 (95% confidence interval 0.7-4.0) in Bologna and 1.9 (0.8-3.7) in Modena. Similarly, the main clinical features were consistent: onset during adolescence (median age 11-13 y), mainly hyperkinetic seizures, nonlesional form in more than two-thirds of cases, an active form of epilepsy in more than two-thirds of cases. A family history of epilepsy was reported only for two patients. Conclusions: This epidemiologic study establishes that nocturnal frontal lobe epilepsy is a rare epileptic condition, fulfilling the definition for rare disease. Because of methodological limitations of our case ascertainment, the estimates we disclose must be considered the minimum prevalence.

2015 - Survival prediction in high-grade gliomas using CT perfusion imaging [Articolo su rivista]
Yeung, T. P. C.; Wang, Y.; He, W.; Urbini, B.; Gafa, R.; Ulazzi, L.; Yartsev, S.; Bauman, G.; Lee, T. -Y.; Fainardi, E.; Franceschi, E.; Tosoni, A.; Cavallo, M.; Fiorica, F.; Valentini, A.; Depenni, R.; Mucciarini, C.; Crisi, G.; Sasso, E.; Biasini, C.; Cavanna, L.; Guidetti, D.; Marcello, N.; Pisanello, A.; Cremonini, A. M.; Guiducci, G.; de Pasqua, S.; Testoni, S.; Agati, R.; Ambrosetto, G.; Bacci, A.; Baldin, E.; Baldrati, A.; Barbieri, E.; Bartolini, S.; Bellavista, E.; Bisulli, F.; Bonora, E.; Bunkheila, F.; Carelli, V.; Crisci, M.; Dall'Occa, P.; Ferro, S.; Franceschi, C.; Frezza, G.; Grasso, V.; Leonardi, M.; Morandi, L.; Dall'Agata, M.; Frattarelli, M.; Gentili, G.; Giovannini, A.; Iorio, P.; Pasquini, U.; Galletti, G.; Guidi, C.; Neri, W.; Patuelli, A.; Strumia, S.; Faedi, M.; Casmiro, M.; Gamboni, A.; Rasi, F.; Cruciani, G.; Cenni, P.; Dazzi, C.; Guidi, A. R.; Zumaglini, F.; Amadori, A.; Pasini, G.; Pasquinelli, M.; Pasquini, E.; Polselli, A.; Ravasio, A.; Viti, B.; Sintini, M.; Ariatti, A.; Bertolini, F.; Bigliardi, G.; Carpeggiani, P.; Cavalleri, F.; Meletti, S.; Nichelli, P.; Pettorelli, E.; Pinna, G.; Zunarelli, E.; Artioli, F.; Bernardini, I.; Costa, M.; Greco, G.; Guerzoni, R.; Stucchi, C.; Iaccarino, C.; Ragazzi, M.; Rizzi, R.; Zuccoli, G.; Api, P.; Cartei, F.; Colella, M.; Fallica, E.; Farneti, M.; Frassoldati, A.; Granieri, E.; Latini, F.; Monetti, C.; Saletti, A.; Schivalocchi, R.; Sarubbo, S.; Seraceni, S.; Tola, M. R.; Urbini, B.; Zini, G.; Giorgi, C.; Montanari, E.; Cerasti, D.; Crafa, P.; Dascola, I.; Florindo, I.; Giombelli, E.; Mazza, S.; Ramponi, V.; Servadei, F.; Silini, E. M.; Torelli, P.; Immovilli, P.; Morelli, N.; Vanzo, C.; Nobile, C.
abstract

Patients with high-grade gliomas usually have heterogeneous response to surgery and chemoirradiation. The objectives of this study were (1) to evaluate serial changes in tumor volume and perfusion imaging parameters and (2) to determine the value of these data in predicting overall survival (OS). Twenty-nine patients with World Health Organization grades III and IV gliomas underwent magnetic resonance (MR) and computed tomography (CT) perfusion examinations before surgery, and 1, 3, 6, 9, and 12&nbsp;months after radiotherapy. Serial measurements of tumor volumes and perfusion parameters were evaluated by receiver operating characteristic analysis, Cox proportional hazards regression, and Kaplan–Meier survival analysis to determine their values in predicting OS. Higher trends in blood flow (BF), blood volume (BV), and permeability-surface area product in the contrast-enhancing lesions (CEL) and the non-enhancing lesions (NEL) were found in patients with OS&nbsp;&lt;&nbsp;18&nbsp;months compared to those with OS&nbsp;≥&nbsp;18&nbsp;months, and these values were significant at selected time points (P&nbsp;&lt;&nbsp;0.05). Only CT perfusion parameters yielded sensitivities and specificities of ≥70&nbsp;% in predicting 18 and 24&nbsp;months OS. Pre-surgery BF in the NEL and BV in the CEL and NEL 3&nbsp;months after radiotherapy had sensitivities and specificities &gt;80&nbsp;% in predicting 24&nbsp;months OS in patients with grade IV gliomas. Our study indicated that CT perfusion parameters were predictive of survival and could be useful in assessing early response and in selecting adjuvant treatment to prolong survival if verified in a larger cohort of patients.

2015 - Survival prediction in high-grade gliomas using CT perfusion imaging [Articolo su rivista]
Yeung, Timothy Pok Chi; Wang, Yong; He, Wenqing; Urbini, Benedetta; Gafà, Roberta; Ulazzi, Linda; Yartsev, Slav; Bauman, Glenn; Lee, Ting-Yim; Fainardi, Enrico; Meletti, S; Iaccarino, C
abstract

Patients with high-grade gliomas usually have heterogeneous response to surgery and chemoirradiation. The objectives of this study were (1) to evaluate serial changes in tumor volume and perfusion imaging parameters and (2) to determine the value of these data in predicting overall survival (OS). Twenty-nine patients with World Health Organization grades III and IV gliomas underwent magnetic resonance (MR) and computed tomography (CT) perfusion examinations before surgery, and 1, 3, 6, 9, and 12 months after radiotherapy. Serial measurements of tumor volumes and perfusion parameters were evaluated by receiver operating characteristic analysis, Cox proportional hazards regression, and Kaplan-Meier survival analysis to determine their values in predicting OS. Higher trends in blood flow (BF), blood volume (BV), and permeability-surface area product in the contrast-enhancing lesions (CEL) and the non-enhancing lesions (NEL) were found in patients with OS &lt; 18 months compared to those with OS ≥ 18 months, and these values were significant at selected time points (P &lt; 0.05). Only CT perfusion parameters yielded sensitivities and specificities of ≥ 70% in predicting 18 and 24 months OS. Pre-surgery BF in the NEL and BV in the CEL and NEL 3 months after radiotherapy had sensitivities and specificities &gt;80% in predicting 24 months OS in patients with grade IV gliomas. Our study indicated that CT perfusion parameters were predictive of survival and could be useful in assessing early response and in selecting adjuvant treatment to prolong survival if verified in a larger cohort of patients.

2015 - The Brain Correlates of Laugh and Cataplexy in Childhood Narcolepsy [Articolo su rivista]
Meletti, Stefano; Vaudano, Anna Elisabetta; Pizza, Fabio; Ruggieri, Andrea; Vandi, Stefano; Teggi, Alberto; Franceschini, Christian; Benuzzi, Francesca; Nichelli, Paolo Frigio; Plazzi, Giuseppe
abstract

The brain suprapontine mechanisms associated with human cataplexy have not been clarified. Animal data suggest that the amygdala and the ventromedial prefrontal cortex are key regions in promoting emotion-induced cataplectic attacks. Twenty-one drug-naive children/adolescent (13 males, mean age 11 years) with recent onset of narcolepsy type 1 (NT1) were studied with fMRI while viewing funny videos using a "naturalistic" paradigm. fMRI data were acquired synchronously with EEG, mylohyoid muscle activity, and the video of the patient's face. Whole-brain hemodynamic correlates of (1) a sign of fun and amusement (laughter) and of (2) cataplexy were analyzed and compared. Correlations analyses between these contrasts and disease-related variables and behavioral findings were performed.

2015 - Third International Congress on Epilepsy, Brain and Mind: Part 1 [Articolo su rivista]
Korczyn, Amos D.; Schachter, Steven C.; Amlerova, Jana; Bialer, Meir; van Emde Boas, Walter; Brázdil, Milan; Brodtkorb, Eylert; Engel, Jerome; Gotman, Jean; Komárek, Vladmir; Leppik, Ilo E.; Marusic, Petr; Meletti, Stefano; Metternich, Birgitta; Moulin, Chris J. A.; Muhlert, Nils; Mula, Marco; Nakken, Karl O.; Picard, Fabienne; Schulze Bonhage, Andreas; Theodore, William; Wolf, Peter; Zeman, Adam; Rektor, Ivan
abstract

Epilepsy is both a disease of the brain and the mind. Here, we present the first of two papers with extended summaries of selected presentations of the Third International Congress on Epilepsy, Brain and Mind (April 3-5, 2014; Brno, Czech Republic). Epilepsy in history and the arts and its relationships with religion were discussed, as were overviews of epilepsy and relevant aspects of social cognition, handedness, accelerated forgetting and autobiographical amnesia, and large-scale brain networks.

2014 - Epilepsy-related brain networks in ring chromosome 20 syndrome: An EEG-fMRI study [Articolo su rivista]
Vaudano, ANNA ELISABETTA; Ruggieri, Andrea; Aglaia, Vignoli; Avanzini, Pietro; Benuzzi, Francesca; Giuliana, Gessaroli; Nichelli, Paolo Frigio; Francesca, Darra; Gaetano, Cantalupo; Massimo, Mastrangelo; Bernardo Dalla Bernardina, ; Maria Paola Canevini, ; Meletti, Stefano
abstract

To identify the brain networks that are involved in the different electroencephalography (EEG) abnormalities in patients with ring chromosome 20 [r(20)] syndrome. We hypothesize the existence of both distinctive and common brain circuits for the paroxysmal high voltage sharp waves (hSWs), the seizures, and the slow-wave 3-7 Hz rhythm that characterize this condition. METHODS: Thirteen patients with [r(20)] syndrome were studied by means of EEG simultaneously recorded with functional magnetic resonance imaging (EEG-fMRI). EEG traces were reviewed in order to detect the pathologic interictal (hSWs) and ictal activities; the 3-7 Hz theta-delta power was derived using a fast Fourier transform. A group-level analysis was performed for each type of EEG abnormality separately using a fixed-effect model and a conjunction analysis. Finally, a second-level random-effect model was applied considering together the different EEG abnormalities, without distinction between hSW, seizures, or theta-delta rhythms. RESULTS: Subcontinuous theta-delta rhythm was recorded in seven patients, seizures in two, and hSWs in three patients. The main results are the following: (1) the slow-wave rhythm was related to blood oxygen level-dependent (BOLD) increases in the premotor, sensory-motor, and temporoparietal cortex, and to BOLD decrements involving the default mode (DMN) and the dorsal attention networks (DANs); (2) the ictal-related BOLD changes showed an early involvement of the prefrontal lobe; (3) increases in BOLD signal over the basal ganglia, either for interictal and ictal activities, were observed; (4) a common pattern of positive BOLD changes in the bilateral perisylvian regions was found across the different EEG abnormalities. SIGNIFICANCE: The BOLD increment in the perisylvian network and the decrease of the DMN and DAN could be the expression of the [r(20)] syndrome-related cognitive and behavioral deficits. The observed BOLD patterns are similar to the ones detected in other epileptic encephalopathies, suggesting that different epileptic disorders characterized by neurobehavioral regression are associated with dysfunction in similar brain networks. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

2014 - Expression of 19 microRNAs in glioblastoma and comparison with other brain neoplasia of grades I-III [Articolo su rivista]
Visani, M; de Biase, D; Marucci, G; Cerasoli, S; Nigrisoli, E; Bacchi Reggiani, Ml; Albani, F; Baruzzi, A; Pession, A; Baruzzi, A; Albani, F; Calbucci, F; D'Alessandro, R; Michelucci, R; Brandes, A; Eusebi, V; Ceruti, S; Fainardi, E; Tamarozzi, R; Emiliani, E; Cavallo, M; Franceschi, E; Tosoni, A; Cavallo, M; Fiorica, F; Valentini, A; Depenni, R; Mucciarini, C; Crisi, G; Sasso, E; Biasini, C; Cavanna, L; Guidetti, D; Marcello, N; Pisanello, A; Cremonini, Am; Guiducci, G; Agati, R; Ambrosetto, G; Bacci, A; Baldin, E; Baldrati, A; Barbieri, E; Bartolini, S; Bellavista, E; Bisulli, F; Bonora, E; Bunkheila, F; Carelli, V; Crisci, M; Dall'Occa, P; Ferro, S; Franceschi, C; Frezza, G; Grasso, V; Leonardi, M; Morandi, L; Mostacci, B; Palandri, G; Pasini, E; Pastore Trossello, M; Poggi, R; Riguzzi, P; Rinaldi, R; Rizzi, S; Romeo, G; Spagnolli, F; Tinuper, P; Trocino, C; Dall'Agata, M; Frattarelli, M; Gentili, G; Giovannini, A; Iorio, P; Pasquini, U; Galletti, G; Guidi, C; Neri, W; Patuelli, A; Strumia, S; Faedi, M; Casmiro, M; Gamboni, A; Rasi, F; Cruciani, G; Cenni, P; Dazzi, C; Guidi, Ar; Zumaglini, F; Amadori, A; Pasini, G; Pasquinelli, M; Pasquini, E; Polselli, A; Ravasio, A; Viti, B; Sintini, M; Ariatti, A; Bertolini, F; Bigliardi, G; Carpeggiani, P; Cavalleri, F; Meletti, S; Nichelli, P; Pettorelli, E; Pinna, G; Zunarelli, E; Artioli, F; Bernardini, I; Costa, M; Greco, G; Guerzoni, R; Stucchi, C; Iaccarino, C; Ragazzi, M; Rizzi, R; Zuccoli, G; Api, P; Cartei, F; Fallica, E; Granieri, E; Latini, F; Lelli, G; Monetti, C; Saletti, A; Schivalocchi, R; Seraceni, S; Tola, Mr; Urbini, B; Giorgi, C; Montanari, E; Cerasti, D; Crafa, P; Dascola, I; Florindo, I; Giombelli, E; Mazza, S; Ramponi, V; Servadei, F; Silini, Em; Torelli, P; Immovilli, P; Morelli, N; Vanzo, C; Nobile, C
abstract

Several biomarkers have been proposed as useful parameters to better specify the prognosis or to delineate new target therapy strategies for glioblastoma patients. MicroRNAs could represent putative target molecules, considering their role in tumorigenesis, cancer progression and their specific tissue expression. Although several studies have tried to identify microRNA signature for glioblastoma, a microRNA profile is still far from being well-defined. In this work the expression of 19 microRNAs (miR-7, miR-9, miR-9∗, miR-10a, miR-10b, miR-17, miR-20a, miR-21, miR-26a, miR-27a, miR-31, miR-34a, miR-101, miR-137, miR-182, miR-221, miR-222, miR-330, miR-519d) was evaluated in sixty formalin-fixed and paraffin-embedded glioblastoma samples using a locked nucleic acid real-time PCR. Moreover, a comparison of miRNA expressions was performed between primary brain neoplasias of different grades (grades IV-I). The analysis of 14 validated miRNA expression in the 60 glioblastomas, using three different non-neoplastic references as controls, revealed a putative miRNA signature: mir-10b and miR-21 were up-regulated, while miR-7, miR-31, miR-101, miR-137, miR-222 and miR-330 were down-regulated in glioblastomas. Comparing miRNA expression between glioblastoma group and gliomas of grades I-III, 3 miRNAs (miR-10b, mir-34a and miR-101) showed different regulation statuses between high-grade and low-grade tumors. miR-10b was up-regulated in high grade and significantly down-regulated in low-grade gliomas, suggesting that could be a candidate for a GBM target therapy. This study provides further data for the identification of a miRNA profile for glioblastoma and suggests that different-grade neoplasia could be characterized by different expression of specific miRNAs

2014 - Generalized Spike and Waves: Effect of Discharge Duration on Brain Networks as Revealed by BOLD fMRI. [Articolo su rivista]
Pugnaghi, M.; Carmichael, D. W.; Vaudano, A. E.; Chaudhary, U. J.; Benuzzi, Francesca; Bonaventura, C. D.; Giallonardo, A. T.; Rodionov, R.; Walker, M. C.; Duncan, J. S.; Meletti, Stefano; Lemieux, L.
abstract

In the past decade, the possibility of combining recordings of EEG and functional MRI (EEG-fMRI), has brought a new insight into the brain network underlying generalized spike wave discharges (GSWD). Nevertheless, how GSWD duration influences this network is not fully understood. In this study we aim to investigate whether GSWD duration had a threshold (non-linear) and/or a linear effect on the amplitude of the associated BOLD changes in any brain regions. This could help in elucidating if there is an hemodynamic background supporting the differentiation between interictal and ictal events. We studied a population of 42 patients with idiopathic generalized epilepsies (IGE) who underwent resting-state EEG-fMRI recordings in three centres (London, UK; Modena, Italy; Rome, Italy), applying a parametric analysis of the GSWD duration. Patients were classified as having Childhood Absence epilepsy, Juvenile Absence Epilepsy, or Juvenile Myoclonic Epilepsy. At the population level linear GSWD duration-related BOLD signal changes were found in a network of brain regions: mainly BOLD increase in thalami and cerebral ventricles, and BOLD decrease in posterior cingulate, precuneus and bilateral parietal regions. No region of significant BOLD change was found in the group analysis for the non-linear effect of GSWD duration. To explore the possible effect of both the different IGE sub-syndromes and the different protocols and scanning equipment used in the study, a full-factorial ANOVA design was performed revealing no significant differences. These findings support the idea that the amplitude of the BOLD changes is linearly related to the GSWD duration with no universal threshold effect of spike and wave duration on the brain network supporting this activity.

2014 - Ictal asystole as the first presentation of epilepsy: A case report and systematic literature review [Articolo su rivista]
Giovannini, Giada; Meletti, Stefano
abstract

We report the case of a 69-year-old woman who presented with recurring episodes of mental confusion/dizziness followed by loss of consciousness, intense pallor, and sweating. Cardiologic investigations were unremarkable. The electroencephalogram recorded during one typical episode allowed the demonstration of a right frontotemporal seizure with progressive bradycardia leading to a 9-second asystole. Following levetiracetam treatment up to 2500 mg/day, seizures with ictal asystole (IA) recurred. An MRI compatible pacemaker was then implanted. At 26-month follow-up, the patient has not had further episodes of loss of consciousness. A systematic review (1950-Apr 2014) searching for cases in which IA was an early manifestation of epilepsy led to the observation of 31 cases. The time lag between the first seizures and the correct diagnosis of IA was long (average: 27 months; median: 12 months). Clinical history alone was not sufficient to prompt a correct diagnosis of IA, and only 11 out of 31 cases presented with symptoms suggestive of a seizure disorder. The majority of patients had a frontotemporal epilepsy with a slight prevalence of left-side involvement (19 out of 31). Ictal bradycardia-asystole is an important condition that should be recognized by epileptologists, neurologists, as well as emergency department physicians. It is important to underscore that IA not only can occur in patients with drug-resistant epilepsy but also may be the first manifestation of the patient's epilepsy.

2014 - Low frequency mu-like activity characterizes cortical rhythms in epilepsy due to ring chromosome 20. [Articolo su rivista]
P., Avanzini; A. E., Vaudano; A., Vignoli; Ruggieri, Andrea; Benuzzi, Francesca; F., Darra; M., Mastrangelo; B. D., Bernardina; Nichelli, Paolo Frigio; M. P., Canevini; Meletti, Stefano
abstract

Objectives: To evaluate the spectral and spatial features of the cortical rhythms in patients affected by ring chromosome 20 - [r(20)]-syndrome. Methods: Twelve patients with [r(20)] syndrome were studied. As controls we enrolled 12 patients with idiopathic generalized epilepsy (IGE) and 12 healthy volunteers (HV). Blind source separation, spectral analyses and source reconstruction were applied in all cases in order to identify reliable spatio-temporal patterns of cortical activity. Results: A theta-delta EEG rhythm was identified in [r(20)] patients, with spectral peak ranging between 3 and 7 Hz and whose generators mapped over the sensory-motor cortices. A second peak laying at a frequency about double with respect to the first one was present in 6 cases. Analogue methodological approach in HV and IGE groups failed to show similar findings. Conclusions: EEG of [r(20)] patients reveals the existence of a highly reproducible EEG pattern arising from the sensory-motor system. Significance: The recognition of this peculiar EEG pattern could help the diagnostic work-up. Additionally, our findings supports the existence of a parallelism between this EEG trait and the physiological "mu" rhythm which is generate by the sensory-motor system. Such link suggests a sensory-motor system dysfunction in [r(20)] patients. (C) 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

2014 - Pattern of care and effectiveness of treatment for glioblastoma patients in the real world: Results from a prospective population-based registry. Could survival differ in a high-volume center? [Articolo su rivista]
Brandes, Alba A; Franceschi, Enrico; Ermani, Mario; Tosoni, Alicia; Albani, Fiorenzo; Depenni, Roberta; Faedi, Marina; Pisanello, Anna; Crisi, Girolamo; Urbini, Benedetta; Dazzi, Claudio; Cavanna, Luigi; Mucciarini, Claudia; Pasini, Giuseppe; Bartolini, Stefania; Marucci, Gianluca; Morandi, Luca; Zunarelli, Elena; Cerasoli, Serenella; Gardini, Giorgio; Lanza, Giovanni; Silini, Enrico Maria; Cavuto, Silvio; Baruzzi, Agostino; Baruzzi, A; Albani, F; Calbucci, F; D'Alessandro, R; Michelucci, R; Brandes, A; Eusebi, V; Ceruti, S; Fainardi, E; Tamarozzi, R; Emiliani, E; Cavallo, M; Franceschi, E; Tosoni, A; Cavallo, M; Fiorica, F; Valentini, A; Depenni, R; Mucciarini, C; Crisi, G; Sasso, E; Biasini, C; Cavanna, L; Guidetti, D; Marcello, N; Pisanello, A; Cremonini, A. M; Guiducci, G; de Pasqua, S; Testoni, S; Agati, R; Ambrosetto, G; Bacci, A; Baldin, E; Baldrati, A; Barbieri, E; Bartolini, S; Bellavista, E; Bisulli, F; Bonora, E; Bunkheila, F; Carelli, V; Crisci, M; Dall'Occa, P; de Biase, D; Ferro, S; Franceschi, C; Frezza, G; Grasso, V; Leonardi, M; Marucci, G; Mazzocchi, V; Morandi, L; Mostacci, B; Palandri, G; Pasini, E; Pastore Trossello, M; Pession, A; Ragazzi, M; Riguzzi, P; Rinaldi, R; Rizzi, S; Romeo, G; Spagnolli, F; Tinuper, P; Trocino, C; Cerasoli, S; Dall'Agata, M; Faedi, M; Frattarelli, M; Gentili, G; Giovannini, A; Iorio, P; Pasquini, U; Galletti, G; Guidi, C; Neri, W; Patuelli, A; Strumia, S; Casmiro, M; Gamboni, A; Rasi, F; Cruciani, G; Cenni, P; Dazzi, C; Guidi, Ar; Zumaglini, F; Amadori, A; Pasini, G; Pasquinelli, M; Pasquini, E; Polselli, A; Ravasio, A; Viti, B; Sintini, M; Ariatti, A; Bertolini, F; Bigliardi, G; Carpeggiani, P; Cavalleri, F; Meletti, Stefano; Nichelli, Paolo Frigio; Pettorelli, E; Pinna, G; Zunarelli, E; Artioli, F; Bernardini, I; Costa, M; Greco, G; Guerzoni, R; Stucchi, C; Iaccarino, C; Rizzi, R; Zuccoli, G; Api, P; Cartei, F; Fallica, E; Granieri, E; Latini, F; Lelli, G; Monetti, C; Ramponi, V; Saletti, A; Schivalocchi, R; Seraceni, S; Tola, M. R; Urbini, B; Giorgi, C; Montanari, E; Cerasti, D; Crafa, P; Dascola, I; Florindo, I; Mazza, S; Servadei, F; Silini, Em; Torelli, P; Immovilli, P; Morelli, N; Vanzo, C.
abstract

BACKGROUND:As yet, no population-based prospective studies have been conducted to investigate the incidence and clinical outcome of glioblastoma (GBM) or the diffusion and impact of the current standard therapeutic approach in newly diagnosed patients younger than aged 70 years. METHODS: Data on all new cases of primary brain tumors observed from January 1, 2009, to December 31, 2010, in adults residing within the Emilia-Romagna region were recorded in a prospective registry in the Project of Emilia Romagna on Neuro-Oncology (PERNO). Based on the data from this registry, a prospective evaluation was made of the treatment efficacy and outcome in GBM patients. RESULTS: Two hundred sixty-seven GBM patients (median age, 64 y; range, 29-84 y) were enrolled. The median overall survival (OS) was 10.7 months (95% CI, 9.2-12.4). The 139 patients ≤aged 70 years who were given standard temozolomide treatment concomitant with and adjuvant to radiotherapy had a median OS of 16.4 months (95% CI, 14.0-18.5). With multivariate analysis, OS correlated significantly with KPS (HR = 0.458; 95% CI, 0.248-0.847; P = .0127), MGMT methylation status (HR = 0.612; 95% CI, 0.388-0.966; P = .0350), and treatment received in a high versus low-volume center (HR = 0.56; 95% CI, 0.328-0.986; P = .0446). CONCLUSIONS: The median OS following standard temozolomide treatment concurrent with and adjuvant to radiotherapy given to (72.8% of) patients aged ≤70 years is consistent with findings reported from randomized phase III trials. The volume and expertise of the treatment center should be further investigated as a prognostic factor.

2014 - Recovery from Emotion Recognition Impairment after Temporal Lobectomy [Articolo su rivista]
Benuzzi, Francesca; Zamboni, Giovanna; Meletti, Stefano; Serafini, Marco; Lui, Fausta; Baraldi, Patrizia; Duzzi, Davide; Rubboli, Guido; Albertotassinari, Carlo; Nichelli, Paolo Frigio
abstract

Mesial temporal lobe epilepsy (MTLE) can be associated with emotion recognition impairment that can be particularly severe in patients with early onset seizures (1–3). Whereas, there is growing evidence that memory and language can improve in seizure-free patients after anterior temporal lobectomy (ATL) (4), the effects of surgery on emotional processing are still unknown. We used functional magnetic resonance imaging (fMRI) to investigate short-term reorganization of networks engaged in facial emotion recognition in MTLE patients. Behavioral and fMRI data were collected from six patients before and after ATL. During the fMRI scan, patientswere asked to make a gender decision on fearful and neutral faces. Behavioral data demonstrated that two patients with early onset right MTLE were impaired in fear recognition while fMRI results showed they lacked specific activations for fearful faces. Post-ATL behavioral data showed improved emotion recognition ability, while fMRI demonstrated the recruitment of a functional network for fearful face processing. Our results suggest that ATL elicited brain plasticity mechanisms allowing behavioral and fMRI improvement in emotion recognition.

2014 - Taking care of patients with brain tumor-related epilepsy: results from an Italian survey [Articolo su rivista]
Maschio, M.; Dinapoli, L.; Dispenza, S.; Mastroianni, S.; Scerrati, M.; Provinciali, L.; Iacoangeli, M.; Michelucci, R.; Melis, M.; Medda, A.; Merella, W.; Aste, L.; Melis, M.; Tosatto, L.; Zaccara, G.; Baglietto, M. G.; Prato, G.; Consales, A.; Striano, P.; Pezzella, M.; Aloisi, P.; Martella, F.; Napoleoni, L.; Salmaggi, A.; Basso, F.; Fiumani, A.; Avanzini, G.; Villani, F.; Casazza, M.; Didato, G.; Tringali, G.; Rizzi, M.; Meco, F. D.; Eoli, M.; Cuzzubbo, S.; Broggi, G.; Meletti, S.; Chiari, A.; Striano, S.; Gaudio, L. D.; Rossi, R.; Ticca, A.; Saladini, M.; Daniele, O.; Costa, C.; Siliquini, S.; Aguglia, U.; Vivalda, C. L.; Simone, R. D.; Vigevano, F.; Marras, C. E.; Buttinelli, C.; Tisei, P.; Colicchio, G.; Balducci, M.; Vernaleone, M.; Giallo-Nardo, A. T.; Bonaventura, C. D.; Fattouch, J.; Albini, M. R.; Terenzi, R.; Casellato, S.; Salis, B.; Vittorini, R.; Ricci, F.; Capizzi, G.; Monti, F.; Belluzzo, M.; Crichiutti, G.; Pauletto, G.; Eleopra, R.; Banfi, P.; Mariani, V.; Bono, G.; Dainese, F.; Palestini, C.; Paladin, F.
abstract

To date, no data have been published in literature regarding either a “model” or systematic approach to caring for patients with brain tumor-related epilepsy (BTRE). In Italy, there are numerous dedicated centers for epilepsy. Study aims: to investigate how many BTRE patients were followed by these specialized centers, independent of histological grade; to have a national snapshot of the range of care issues concerning these patients, with surveys completed by Italian centers adhering to the Italian League Against Epilepsy (LICE) study group for BTRE. Each participating Italian center received a survey requesting: description of organizational structure/service model for diagnosis and treatment of epilepsy; number of patients followed (from 1/2010 to 12/2011); services offered, within the same institution or in close proximity; degree of access to colleagues from other disciplines for discussion of cases, with indication of departments/areas of specialization were sought. Thirty out of the 35 centers adhering to LICE study group completed the survey indicating total of 2,528 patients with BTRE had been treated with 940 new patients/year. Data regarding the care model, service offerings, referral sources were collected. This study is a first collaborative project of epilepsy centers throughout Italy, aimed at collecting data on a national scale. Results indicate: (1) 2,528 patients had been followed by participating centers and account for 21&nbsp;% of estimated patients with BTRE in Italy (2) difficulties in organizing meetings with other specialists (e.g. for discussion of cases/patient briefings); (3) need for multidisciplinary integration with other specialists as a priority area for intervention.

2014 - Temporal lobe epilepsy and emotion recognition without amygdala: a case study of Urbach-Wiethe disease and review of the literature [Articolo su rivista]
Meletti, Stefano; Cantalupo, Gaetano; Santoro, Francesca; Benuzzi, Francesca; Marliani, Anna Federica; Tassinari, Carlo Alberto; Rubboli, Guido
abstract

We describe the epilepsy features and emotion recognition abilities (recognition of basic facial emotions and recognition of emotional prosody) in a patient with Urbach-Wiethe disease with bilateral amygdala calcifications. Our data, supported by ictal video-EEG recording, indicated that our patient suffered from mesial temporal lobe epilepsy. Emotion recognition abilities were compared to those of healthy controls and those of patients with bilateral mesial temporal lobe epilepsy. Our patient showed a selective impairment of the recognition of facial expression of fear, whereas recognition of emotional prosody was preserved, in contrast to bilateral mesial temporal lobe epilepsy patients that presented with deficits in both domains. We also reviewed the literature on epilepsy in Urbach-Wiethe disease (41 patients). Our findings suggest that in Urbach-Wiethe disease, the circumscribed damage of both amygdalae results in a selective dysfunction of fearful face processing, in contrast to bilateral mesial temporal lobe epilepsy patients who present with a widespread and multimodal impairment in the judgement of emotional stimuli.

2014 - The affective value of faces in patients achieving long-term seizure freedom after temporal lobectomy [Articolo su rivista]
Meletti, Stefano; Angelo, Picardi; Marco De, Risi; Monti, Giulia; Vincenzo, Esposito; Liliana G., Grammaldo; Giancarlo Di, Gennaro
abstract

We investigated different aspects of facial expression evaluation in a homogeneous cohort of 42 seizure-free patients with 5 or more years of follow-up after temporal lobectomy (TL), with the aim of further characterizing the impairment in emotion and social cognition among patients. A group of healthy subjects matched for sex, age, and education served as controls. Four tasks of facial expression evaluation were used: (a) facial expression recognition, (b) rating of the intensity of facial expression, and (c) rating of valence (pleasantness) and (d) rating of arousal induced by facial expressions. Patients had a worse performance in the recognition task for all negative emotions, while no differences in intensity ratings were found. They also reported lower arousal ratings than controls for faces showing fear, anger, disgust, and neutral expressions, as well as lower valence ratings for all facial expressions except those showing happiness. Longer epilepsy duration before TL was negatively associated with ratings of arousal and intensity and positively associated with valence ratings for fearful facial expressions. This study showed that patients who become seizure-free after TL present long-term deficits in several aspects of facial expression evaluation. Longitudinal, prospective studies are needed to evaluate if social cognition improves or declines after TL.

2014 - The visual system in eyelid myoclonia with absences [Articolo su rivista]
Vaudano, ANNA ELISABETTA; Ruggieri, Andrea; Tondelli, Manuela; Avanzini, Pietro; Benuzzi, Francesca; Giuliana, Gessaroli; Gaetano, Cantalupo; Massimo, Mastrangelo; Aglaia, Vignoli; Carlo Di Bonaventura, ; Maria Paola Canevini, ; Bernardo Dalla Bernardina, ; Nichelli, Paolo Frigio; Meletti, Stefano
abstract

OBJECTIVE: To investigate the functional and structural brain correlates of eyelid myoclonus and absence seizures triggered by eye closure (eye closure sensitivity [ECS]). METHODS: Fifteen patients with eyelid myoclonus with absences (EMA, Jeavons syndrome), 14 patients with idiopathic generalized epilepsies (IGE) without ECS, and 16 healthy controls (HC) underwent an electroencephalography (EEG)-correlated functional magnetic resonance imaging (fMRI) and voxel brain morphometry (VBM) protocol. The functional study consisted of 30-second epochs of eyes-open and eyes-closed conditions. The following EEG events were marked and the relative fMRI maps obtained: (1) eye closure times, (2) spontaneous blinking, and (3) spontaneous and eye closure-triggered spike and wave discharges (SWD; for EMA and IGE). Within-group and between-groups comparisons were performed for fMRI and VBM data as appropriate. RESULTS: In EMA compared to HC and IGE we found: (1) higher blood oxygenation level-dependent (BOLD) signal related to the eye closure over the visual cortex, the posterior thalamus, and the network implicated in the motor control of eye closure, saccades, and eye pursuit movements; and (2) increments in the gray matter concentration at the visual cortex and thalamic pulvinar, whereas decrements were observed at the bilateral frontal eye field area. No BOLD differences were detected when comparing SWD in EMA and IGE. INTERPRETATION: Results demonstrated altered anatomo-functional properties of the visual system in EMA. These abnormalities involve a circuit encompassing the occipital cortex and the cortical/subcortical systems physiologically involved in the motor control of eye closure and eye movements. Our work supports EMA as an epileptic condition with distinctive features and provides a contribution to its classification among epileptic syndromes.

2013 - Causality within the Epileptic Network: An EEG-fMRI Study Validated by Intracranial EEG [Articolo su rivista]
Anna Elisabetta, Vaudano; Avanzini, Pietro; Laura, Tassi; Ruggieri, Andrea; Gaetano, Cantalupo; Benuzzi, Francesca; Nichelli, Paolo Frigio; Louis, Lemieux; Meletti, Stefano
abstract

Accurate localization of the Seizure Onset Zone (SOZ) is crucial in patients with drug-resistance focal epilepsy. EEG with fMRI recording (EEG-fMRI) has been proposed as a complementary non-invasive tool, which can give useful additional information in the pre-surgical work-up. However, fMRI maps related to interictal epileptiform activities (IED) often show multiple regions of signal change, or "networks," rather than highly focal ones. Effective connectivity approaches like Dynamic Causal Modeling (DCM) applied to fMRI data potentially offers a framework to address which brain regions drives the generation of seizures and IED within an epileptic network. Here, we present a first attempt to validate DCM on EEG-fMRI data in one patient affected by frontal lobe epilepsy. Pre-surgical EEG-fMRI demonstrated two distinct clusters of blood oxygenation level dependent (BOLD) signal increases linked to IED, one located in the left frontal pole and the other in the ipsilateral dorso-lateral frontal cortex. DCM of the IED-related BOLD signal favored a model corresponding to the left dorso-lateral frontal cortex as driver of changes in the fronto-polar region. The validity of DCM was supported by: (a) the results of two different non-invasive analysis obtained on the same dataset: EEG source imaging (ESI), and "psycho-physiological interaction" analysis; (b) the failure of a first surgical intervention limited to the fronto-polar region; (c) the results of the intracranial EEG monitoring performed after the first surgical intervention confirming a SOZ located over the dorso-lateral frontal cortex. These results add evidence that EEG-fMRI together with advanced methods of BOLD signal analysis is a promising tool that can give relevant information within the epilepsy surgery diagnostic work-up.

2013 - Centrotemporal spikes during NREM sleep: The promoting action of thalamus revealed by simultaneous EEG and fMRI coregistration [Articolo su rivista]
Mirandola, Laura; Gaetano, Cantalupo; Vaudano, ANNA ELISABETTA; Pietro, Avanzini; Ruggieri, Andrea; Francesco, Pisani; Giuseppe, Cossu; Carlo Alberto, Tassinari; Nichelli, Paolo Frigio; Benuzzi, Francesca; Meletti, Stefano
abstract

Benign childhood epilepsy with centrotemporal spikes (BECTS) has been investigated through EEG–fMRI with the aim of localizing the generators of the epileptic activity, revealing, in most cases, the activation of the sensory–motor cortex ipsilateral to the centrotemporal spikes (CTS). In this case report, we investigated the brain circuits hemodynamically involved by CTS recorded during wakefulness and sleep in one boy with CTS and a language disorder but without epilepsy. For this purpose, the patient underwent EEG–fMRI coregistration. During the “awake session”, fMRI analysis of right-sided CTS showed increments of BOLD signal in the bilateral sensory–motor cortex. During the “sleep session”, BOLD increments related to right-sided CTS were observed in a widespread bilateral cortical–subcortical network involving the thalamus, basal ganglia, sensory–motor cortex, perisylvian cortex, and cerebellum. In this patient, who fulfilled neither the diagnostic criteria for BECTS nor that for electrical status epilepticus in sleep (ESES), the transition from wakefulness to sleep was related to the involvement of a widespread cortical–subcortical network related to CTS. In particular, the involvement of a thalamic–perisylvian neural network similar to the one previously observed in patients with ESES suggests a common sleep-related network dysfunction even in cases with milder phenotypes without seizures. This finding, if confirmed in a larger cohort of patients, could have relevant therapeutic implication.

2013 - Definition of miRNAs expression profile in glioblastoma samples: the relevance of non-neoplastic brain reference. [Articolo su rivista]
M., Visani; D. d., Biase; G., Marucci; C., Taccioli; A., Baruzzi; A., Pession; A., Ariatti; B., Bertolini; G., Bigliardi; P., Carpeggiani; F., Cavalleri; Meletti, Stefano; Nichelli, Paolo Frigio; G., Pinna; E., Zunarelli; A., Pession; PERNO study, Group
abstract

Glioblastoma is the most aggressive brain tumor that may occur in adults. Regardless of the huge improvements in surgery and molecular therapy, the outcome of neoplasia remains poor. MicroRNAs are small molecules involved in several cellular processes, and their expression is altered in the vast majority of tumors. Several studies reported the expression of different miRNAs in glioblastoma, but one of the most critical point in understanding glioblastoma miRNAs profile is the comparison of these studies. In this paper, we focused our attention on the non-neoplastic references used for determining miRNAs expression. The aim of this study was to investigate if using three different non-neoplastic brain references (normal adjacent the tumor, commercial total RNA, and epileptic specimens) could provide discrepant results. The analysis of 19 miRNAs was performed using Real-Time PCR, starting from the set of samples described above and the expression values compared. Moreover, the three different normal RNAs were used to determine the miRNAs profile in 30 glioblastomas. The data showed that different non-neoplastic controls could lead to different results and emphasize the importance of comparing miRNAs profiles obtained using the same experimental condition.

2013 - Epilepsy in primary cerebral tumors: The characteristics of epilepsy at the onset (results from the PERNO study - Project of Emilia Romagna Region on Neuro-Oncology). [Articolo su rivista]
R., Michelucci; E., Pasini; Meletti, Stefano; E., Fallica; R., Rizzi; I., Florindo; A., Chiari; C., Monetti; A. M., Cremonini; S., Forlivesi; F., Albani; A., Baruzzi; P. E., R.
abstract

Purpose: To present new information on the semiology and short-term evolution of seizures associated with primary brain tumors (PBTs) in a prospective study. Methods: This study is a section of the PERNO study - Project of Emilia Romagna Region on Neuro-Oncology, the main aim of which is to collect prospectively all cases of PBTs occurring in the Emilia-Romagna region, northeast Italy (3,983,346 population) from January 2009 to December 2011, to allow epidemiologic, clinical, and biomolecular studies. The epilepsy section of the PERNO study included all the patients who experienced seizures, either as first symptom of the tumor or appearing during the course of the disease. Each patient was interviewed by the referring neurologist with a specific interest in epilepsy. The patients who entered the study were followed up with visits on a quarterly basis. Key Findings: We collected 100 cases with full clinical, neuroradiologic, and pathologic data. The majority (79%) had high grade PBTs (glioblastoma in 50 cases), whereas the remaining patients had low-grade gliomas, mostly localized in the frontal (60%), temporal (38%), and parietal (28%) lobes. Seizures were the first symptom of the tumor in 72 cases. Overall, the initial seizures were tonic-clonic (48%) (without clear initial focal signs in more than half of the patients), focal motor (26%), complex partial (10%), and somatosensitive (8%). The majority of cases (60%) had isolated seizures or a low seizure frequency at the onset of the disease, whereas a high seizure frequency or status epilepticus was observed in 18% and 12% of cases, respectively. Ninety-two patients underwent surgical removal of the tumor, which was either radical (38%) or partial (53%). Seven patients underwent only cerebral biopsy. In the 72 patients in whom seizures were the first symptom, the mean time to the surgical treatment was 174days, with a significant difference between high grade (95days) and low grade (481days) gliomas. At the time of our first observation, the majority of patients (69%) had already undergone surgical removal, with a mean follow-up of 3months after the procedure. Overall, 39 patients (56%) were seizure free after tumor removal. The good outcome did not depend on presurgical seizure frequency or tumor type, although there was a trend for better results with low-grade PBTs. Significance: These data provide evidence that seizures are strictly linked to the tumoral lesion: They are the initial symptom of the tumor, reflect the tumor location and type, are usually resistant to antiepileptic treatment, and may disappear after the treatment of the lesion.

2013 - Epilepsy, cognition, and neuropsychiatry (Epilepsy, Brain, and Mind, part 2) [Articolo su rivista]
A. D., Korczyn; S. C., Schachter; M. J., Brodie; S. S., Dalal; J., Engel; A., Guekht; H., Hecimovic; K., Jerbi; A. M., Kanner; C. J., Landmark; P., Mares; P., Marusic; Meletti, Stefano; M., Mula; P. N., Patsalos; M., Reuber; P., Ryvlin; K., Štillová; R., Tuchman; I., Rektor
abstract

Epilepsy is, of course, not one disease but rather a huge number of disorders that can present with seizures. In common, they all reflect brain dysfunction. Moreover, they can affect the mind and, of course, behavior. While animals too may suffer from epilepsy, as far as we know, the electrical discharges are less likely to affect the mind and behavior, which is not surprising. While the epileptic seizures themselves are episodic, the mental and behavioral changes continue, in many cases, interictally. The episodic mental and behavioral manifestations are more dramatic, while the interictal ones are easier to study with anatomical and functional studies. The following extended summaries complement those presented in

2013 - Facial emotion recognition in childhood: the effects of febrile seizures in the developing brain. [Articolo su rivista]
G., Cantalupo; Meletti, Stefano; A., Miduri; S., Mazzotta; L., Rios Pohl; Benuzzi, Francesca; F., Pisani; C. A., Tassinari; G., Cossu
abstract

It has been documented that anteromedial temporal lobe dysfunction can cause impairment in emotional intelligence. In particular, medial temporal lobe epilepsy (MTLE) is associated with disorders in emotion recognition from facial expressions. About one-third of patients with MTLE experienced febrile seizures (FSs) during childhood. In the present study, we investigated facial emotion recognition ability in a group of 38 school-aged children with antecedent FSs and in an age- and sex-matched control group. Children with abnormal general visuoperceptual abilities were excluded. Children with FSs showed lower recognition scores versus controls in both matching (28.64 vs 33.47; p<.0001) and labeling (21.25 vs 23.03; p=.001) facial emotions. Our findings support the hypothesis that FSs can be associated during childhood with a dysfunction within the neural network subserving the processing of facial expressions of the basic emotions.

2013 - Generalized spike-and-wave discharges offset is related to precuneal-posterior cingulate activity. [Poster]
Benuzzi, Francesca; Zuccheli, M.; Ferrari, E.; Vaudano, A. E.; Ruggieri, Andrea; Mirandola, Laura; Nichelli, Paolo Frigio; Meletti, Stefano
abstract

Introduction: Recent EEG-fMRI studies revealed that a widespread neural network subserves the generation of ictal and interictal activity in patients with generalized epilepsy (1-4). Different studies investigated the hemodynamic changes related to the onset and duration of generalized spike-and-wave discharges (GSWD) in human epilepsy. Conversely, the BOLD signal changes related to GSWD termination has not been addressed to date. Few studies have focused the mechanisms that promote seizures stop at molecular and cellular level (6). In particular, a recent single neuron recording study in human focal epilepsy (7) revealed that neuronal firing patterns change homogeneously at seizure offset suggesting that seizure termination is marked by an abrupt homogeneous change in neuronal firing. These data support a mechanism that acts at the neural network level. The present EEG-fMRI study aimed at evaluating the neural correlates of seizure termination studying the BOLD variations at GSWD offset in a large sample of patients with Idiopathic generalized epilepsy (IGE). Materials and methods: eighteen patients (6 male; mean age 25 yrs.) with IGE were included. Scalp EEG was recorded by means of a 32 channels MRI-compatible EEG recording system. Functional data were acquired with a 3T Philips Intera System (TR=3000 ms) from 30 axial contiguous 4 mm slices (64 x 64 matrix) over two-three 10-min sessions per patient with continuous simultaneous video-EEG recording. Event-related analysis was performed with SPM8 software, using the following regressors: (1) GSWD onset and duration; (2) GSWD offset. Data were analyzed at a second level random effect analysis. Results: a mean of 17 events for each patient was recorded (mean duration= 4 s). Second-level random effect analysis related to onset and GSWD length confirmed previous findings (5) revealing a thalamus activation and a parietal and precuneus-posterior cingulate deactivation. GSWD onset respect to the offset showed BOLD increases in the prefrontal regions (inferior and middle frontal gyrus) mostly on the left side and in the bilateral primary visual cortex. Conversely, GSWD offset respect to the onset revealed significant hemodynamic changes over the precuneus-posterior cingulate region (Fig. 1). Conclusions: fMRI results showed that the neural network at GSWD termination involved precuneus-posterior cingulate region. These findings confirm an important role of this brain region in GSWD pathophysiology. Particularly, precuneal/posterior cingulate neuronal activity might participate actively to the GSWD termination or it might reflect the recovery of the awareness impaired during the pathological activity. BIBLIOGRAFY 1) Gotman J, Grova C, Bagshaw A, Kobayashi E, Aghakhani Y, Dubeau F. (2005) Generalized epileptic discharges show thalamocortical activation and suspension of the default state of the brain. Proc Natl Acad Sci USA, vol. 102, pp. 15236–15240. 2) Moeller F, Siebner HR, Wolff S, Muhle H, Boor R, Granert O, Jansen O, Stephani U, Siniatchkin M. (2008) Changes in activity of striato-thalamo- cortical network precede generalized spike wave discharges. Neuroimage vol. 39, pp. 1839–1849. 3) Vaudano AE, Laufs H, Kiebel SJ, Carmichael DW, Hamandi K, Guye M, Thornton R, Rodionov R, Friston KJ, Duncan JS, Lemieux L. (2009) Causal hierarchy within the thalamo-cortical network in spike and wave discharges. PLoS ONE vol. 4:e6475. 4) Carney PW, Masterton RA, Harvey AS, Scheffer IE, Berkovic SF, Jackson GD. (2010) The core network in absence epilepsy. Differences in cortical and thalamic BOLD response. Neurology vol. 75, pp. 904–911. 5) Benuzzi F, Mirandola L, Pugnaghi M, Farinelli V, Tassinari CA, Capovilla G, Cantalupo G, Beccaria F, Nichelli P, Meletti S (2012). Increased cortical BOLD signal anticipates generalized spike and wave discharges in adolescents and adults with idiopathic generalized epilepsies. Epilepsia, vol. 53(4

2013 - Hypoxia markers are expressed in interneurons exposed to recurrent seizures. [Articolo su rivista]
Gualtieri, Fabio; C., Marinelli; Longo, Daniela; Pugnaghi, Matteo; Nichelli, Paolo Frigio; Meletti, Stefano; Biagini, Giuseppe
abstract

An early but transient decrease in oxygen availability occurs during experimentally induced seizures. Using pimonidazole, which probes hypoxic insults, we found that by increasing the duration of pilocarpine-induced status epilepticus (SE) from 30 min to 120 min, counts of pimonidazole-immunoreactive neurons also increased (P < 0.01, 120 vs 60 and 30 min). All the animals exposed to SE were immunopositive to pimonidazole, but a different scenario emerged during epileptogenesis when a decrease in pimonidazole immunostained cells occurred from 7 to 14 days, so that only 1 out of 4 rats presented with pimonidazole-immunopositive cells. Pimonidazole-immunoreactive cells robustly reappeared at 21 days post-SE induction when all animals (7 out of 7) had developed spontaneous recurrent seizures. Specific neuronal markers revealed that immunopositivity to pimonidazole was present in cells identified by neuropeptide Y (NPY) or somatostatin antibodies. At variance, neurons immunopositive to parvalbumin or cholecystokinin were not immunopositive to pimonidazole. Pimonidazoleimmunopositive neurons expressed remarkable immunoreactivity to hypoxia-inducible factor 1α (HIF-1α). Interestingly, surgical samples obtained from pharmacoresistant patients showed neurons co-labeled by HIF-1α and NPY antibodies. These interneurons, along with parvalbumin-positive interneurons that were negative to HIF-1α, showed immunopositivity to markers of cell damage, such as high-mobility group box 1 in the cytoplasm and cleaved caspase-3 in the nucleus. These findings suggest that interneurons are continuously endangered in rodent and human epileptogenic tissue. The presence of hypoxia and cell damage markers in NPY interneurons of rats and patients presenting with recurrent seizures indicates a mechanism of selective vulnerability in a specific neuronal subpopulation.

2013 - Investigation of the brain networks underlying eye closure sensitivity in Jeavons syndrome and healthy subjects: an EEG-fMRI study [Abstract in Rivista]
Vaudano, Ae; Avanzini, P; Ruggieri, ; Cantalupo, G; Di Bonaventura, C; Nichelli, ; Benuzzi, F; Meletti, S.
abstract

2013 - Isolated paroxysmal dysarthria caused by a single demyelinating midbrain lesion [Articolo su rivista]
Codeluppi, Luca; G., Bigliardi; A., Chiari; Meletti, Stefano
abstract

Paroxysmal dysarthria is an unusual condition characterised by brief episodes of dysarthria with the sudden onset and frequent recurrence. It has been mainly reported in multiple sclerosis and an association with midbrain lesions has been claimed; however, most of the reported patients had multiple brain alterations so it was difficult to associate this symptom with a specific lesion site. We illustrate the cases of two patients with an isolated demyelinating midbrain lesion presenting paroxysmal dysarthria as the only symptom; both participants had oligoclonal bands in the cerebrospinal fluid and an unremarkable follow-up. Both patients had benefit from carbamazepine treatment, similarly to previously reported cases. Our report confirms that a demyelinating midbrain lesion is sufficient to provoke paroxysmal dysarthria. It is noteworthy that an erroneous diagnosis of psychogenic disorders was initially made in both cases, highlighting the importance not to underestimate isolated paroxysmal symptoms in clinical practice.

2013 - Neurosteroids And Epileptogenesis [Articolo su rivista]
Biagini, Giuseppe; Rustichelli, Cecilia; Curia, Giulia; Vinet, Jonathan; Lucchi, Chiara; Pugnaghi, Matteo; Meletti, Stefano
abstract

Epileptogenesis is defined as the latent period at the end of which spontaneous recurrent seizures occur. This concept has been recently re-evaluated to include exacerbation of clinically-manifested epilepsy. Thus, in patients affected by pharmacoresistant seizures, the progression toward a worse condition may be viewed as the result of a durable epileptogenic process. However, the mechanism potentially responsible for this progression remains unclear. Neuroinflammation has been consistently detected both in the latent period and in the chronic phase of epilepsy, especially when brain damage is present. This phenomenon is accompanied by glial cell reaction, leading to gliosis. We have previously described rats presenting an increased expression of the cytochrome P450 cholesterol side-chain cleavage (P450scc) enzyme, during the latent period, in glial cells of the hippocampus. The P450scc enzyme is critically involved in the synthesis of neurosteroids and its upregulation is associated with a delayed appearance of spontaneous recurrent seizures in rats that experienced status epilepticus (SE) induced by pilocarpine. Moreover, by decreasing the synthesis of neurosteroids able to promote inhibition, such as allopregnanolone, through administration of the 5α-reductase blocker finasteride, it is possible to terminate the latent period in pilocarpine-treated rats. Finasteride was also found to promote seizures in the chronic period of epileptic rats, suggesting that neurosteroids are continuously produced to counteract seizures. In humans, exacerbation of epilepsy has been also described in patients occasionally exposed to finasteride. Overall, these findings suggest a major role of neurosteroids in the progression of epilepsy and a possible antiepileptogenic role of allopregnanolone and cognate molecules.

2013 - Neurosteroids and epileptogenesis. [Abstract in Atti di Convegno]
Biagini, Giuseppe; Rustichelli, Cecilia; Curia, Giulia; Lucchi, Chiara; Pugnaghi, Matteo; Meletti, Stefano; Avoli, M.
abstract

Epileptogenesis is defined as the latent period at the end of which spontaneous recurrent seizures occur. This concept has been recently re-evaluated to include exacerbation of clinically-manifested epilepsy. Thus, in patients affected by pharmacoresistant seizures, the progression toward a worse condition may be viewed as the result of a durable epileptogenic process. However, the mechanism potentially responsible for this progression remains unclear. Neuroinflammation has been consistently detected both in the latent period and in the chronic phase of epilepsy, especially when brain damage is present. This phenomenon is accompanied by glial cell reaction, leading to gliosis. We have previously described rats presenting an increased expression of the cytochrome P450 cholesterol side-chain cleavage (P450scc) enzyme, during the latent period, in glial cells of the hippocampus. The P450scc enzyme is critically involved in the synthesis of neurosteroids and its up-regulation is associated with a delayed appearance of spontaneous recurrent seizures in rats that experienced status epilepticus induced by pilocarpine. Moreover, by decreasing the synthesis of neurosteroids able to promote inhibition, such as allopregnanolone, through the administration of the 5α-reductase blocker finasteride, it is possible to terminate the latent period in pilocarpine-treated rats. Finasteride was also found to promote seizures in the chronic period of epileptic rats, suggesting that neurosteroids are continuously produced to counteract seizures. In humans, exacerbation of epilepsy has been also described in patients occasionally exposed to finasteride. Overall, these findings suggest a major role of neurosteroids in the progression of epilepsy and a possible antiepileptogenic role of allopregnanolone and cognate molecules.

2013 - Sleep and centrotemporal spikes: Thalamic BOLD changes related to centrotemporal spikes during the wake-sleep transition [Articolo su rivista]
Mirandola, L.; Cantalupo, G.; Avanzini, P.; Pugnaghi, M.; Ruggieri, A.; Benuzzi, F.; Meletti, S.
abstract

A 13 years-old right-handed boy with centrotemporal spikes (CTS) heightened during NREM sleep and with language difficulties, underwent EEG-fMRI co-registration both during wake and sleep. Scalp EEG was recorded by means of a 32 channels MRI-compatible EEG recording system and MRI was 3T (3 sessions 10 minutes long; TR: 3 sec). EEG offline was analyzed with Brainvision software and processed with Independent Component Analysis (ICA), while EEG source-imaging analysis was conducted through sLORETA software. SPM5 was utilized for functional data. During the "wake session" 47 right CTS were recorded in 10 minutes and were associated to focal cortical signal in the sensory motor cortex: increments in fMRI BOLD signal were recorded bilaterally, while EEG-source imaging showed activation in the ipsilateral sensory-motor cortex. During the "sleep session" 191 right CTS were recorded in 20 minutes: while the EEG source-imaging analysis resulted identical to the "wake session" (activation of right sensory-motor cortex), EEG-fMRI during sleep showed a more widespread activation in a cotical-subcortical network involving thalamus bilaterally, sensory-motor cortex and perisilvian cortex bilaterally. These results confirm the importance of thalamic oscillations in the genesis of CTS. Moreover, in this single case of CTS accentuated during sleep the involvement of a neural network similar to the one previously observed in patients with ESES has been identified.

2013 - Temporal lobe epilepsy exacerbation during pharmacological inhibition of endogenous neurosteroid synthesis [Articolo su rivista]
Pugnaghi, Matteo; Monti, Giulia; Biagini, Giuseppe; Meletti, Stefano
abstract

We report the case of a woman who presented cryptogenic temporal lobe seizures from the age of 43 years. Antiepileptic drug (AED) treatment with carbamazepine was able to control seizures for 1 year, but seizures relapsed and an add-on treatment with lamotrigine was started without achieving seizures control. The patient's medical history was unremarkable except for a mild hirsutism for which she was taking finasteride since 45 years of age. In view of the possible relationship between finasteride, a known inhibitor of neurosteroids synthesis, and patient's seizures exacerbation, we stopped finasteride resulting in prompt recovery of seizures control. It is know that 5α-dihydrosteroids are precursors of powerful positive modulators of γ-aminobutyric acid-A inhibitory currents and exert antiseizure effects in animal epilepsy models. This case supports the hypothesis that endogenous neurosteroids can modulate seizure susceptibility and response to AEDs also in humans, suggesting their possible use as a new therapeutic option.

2012 - Drug-resistant epilepsy after a first unprovoked seizure in adolescence and adulthood: A prospective cohort study [Articolo su rivista]
Monti, G.; Giovannini, G.; Pugnaghi, M.; Mirandola, L.; Nichelli, P.; Meletti, S.
abstract

We present a monocentric prospective study performed on a population of 394 consecutive patients with a first unprovoked seizure evaluated from January 1st 2006 to December 31st 2009 with the purpose to identify the short-term frequency of drug-resistant epilepsy (DRE) in patients with a first seizure in adolescence or adulthood. Drug resistance was determined using two different definitions: (a) Berg, 20061; (b) ILAE, 20102. We identify 18 ILAE DRE patients (6,5%) and 10 (4,5%) Berg DRE patients. Fifteen patients have focal epilepsy (12 symptomatic, 3 cryptogenic); 2 patients have idiopathic generalized epilepsy, one had cryptogenic generalized epilepsy. Three DRE patients had at onset status epilepticus, and all DRE patients had the second seizure within three months from the onset. Conclusion: These results suggest that: (a) epilepsy onset in adolescence/adulthood is associated wit a low percentage (4-7%) of DRE; (b) these patients quickly became drug-resistant, supporting the concept of DRE as expression of intrinsic severity of the disease (Sillanpaa et al, 2009). Early detection of these patients can lead to early epilepsy surgery.

2012 - Emotional experience in mesial temporal lobe epilepsy patients [Articolo su rivista]
Bonora, A.; Benuzzi, F.; Tocchini, S.; Monti, G.; Mirandola, L.; Pugnaghi, M.; Nichelli, P.; Meletti, S.
abstract

Defective social abilities have been observed in patients with Mesial Temporal Lobe Epilepsy and Hippocampal Sclerosis (MTLE), particularly in facial expression recognition of negative emotions1-3. The aim of this study was to test the existence of a supramodal system for recognizing signals of fundamental emotions and whether these abilities are linked to the experience of the same emotions. A group of MTLE patients has performed two different tasks: 1) emotions recognition from facial expressions and prosody of five basic emotions (happiness, fear, disgust, anger and sadness); 2) evaluation of subjective experience of emotions of fear, anger and disgust. The results show a significant correlation between facial emotion and emotional prosody recognition tasks, whereas no correlation was found between subjective measures of fear, anger, disgust and the recognition of these emotions in the visual and auditory domain. These preliminary data suggest the existence of a supramodal system for recognizing fundamental emotions and that the neuronal systems involved in the recognition of the visual and prosodic expression of emotion may not be necessary for the subjective experience.

2012 - Epileptic falling seizures associated with seizure-induced cardiac asystole in drug-resistant temporal lobe epilepsy [Capitolo/Saggio]
Rubboli, G.; Meletti, S.; Giulioni, M.; Marliani, A. F.; Bartolini, Y.; Forlivesi, S.; Gardella, E.; Michelucci, R.
abstract

Clinical history: A 52-year-old gentleman with positive family history for epilepsy. At 1 year of age he suffered from prolonged febrile seizures. At 29 years, he started to present brief episodes of loss of contact, staring and psychomotor arrest, paleness, oro-alimentary and right-hand gestural automatisms; the episodes occurred usually once or twice per month. At 49 years, the episodes increased in frequency and about 50% of them started to be complicated by abrupt and sudden falls to the ground. Despite several antiepileptic treatments, his seizures were never completely controlled. The patient was admitted to undergo long-term video–EEG monitoring for presurgical evaluation. General history: Arterial hypertension; duodenal ulcer; chronic HVB hepatitis; deep venous thrombosis with pulmonary embolism; thrombophilia (heterozygous factor V Leiden mutation). Examination: Unremarkable. Right-handed (Oldfield score: +1). Brain MRI: Right mesial temporal sclerosis (Fig. 1). Interictal EEG: Sporadic theta activities occasionally associated with spikes during sleep in the right temporal leads. Long-term video-EEG monitoring: Three stereotyped seizures were recorded during a 10-day computerized video-EEG monitoring. All of them occurred while the patient was sitting, and displayed stereotyped electroclinical features: the clinical onset was characterized by psychomotor arrest, oscillations of the trunk, and then backward fall in two seizures, frontward in the third episode; then oro-alimentary and right-hand automatisms were observed. A very brief postictal state followed. Ictal EEG showed a brief flattening in the right fronto-temporal leads, followed by a rhythmic theta-delta discharge with phase reversal in F8-T4; then delta activity mainly confined to the right temporal leads appeared. The EKG lead showed periods of asystole whose durations ranged from 5 to 8 seconds, associated with the right temporal rhythmic theta activity (Fig. 2), then the heart rate progressively resumed to baseline. The fall of the patient occurred few seconds after the end of the asystole, when the heart rate was starting to recover.

2012 - Fear and happiness in the eyes: an intra-cerebral event-related potential study from the human amygdala. [Articolo su rivista]
Meletti, Stefano; G., Cantalupo; Benuzzi, Francesca; R., Mai; L., Tassi; Gasparini, Elisa; C. A., Tassinari; Nichelli, Paolo Frigio
abstract

We present the response pattern of intracranial event-related potentials (ERPs) recorded from depth-electrodes in the human amygdala (four patients) to faces or face parts encoding fearful, happy or neutral expressions. The amygdala showed increased amplitude ERPs (from 200 to 400ms post-stimulus) in response to the eye region of the face compared to whole faces and to the mouth region. In particular, a strong emotional valence effect was observed, both at group and at single-subject level, with a preferential response to fearful eyes respect to every other stimulus category from 200 to 400ms after stimulus presentation. A preferential response to smiling eyes compared to happy faces and smiling mouths was also observed at group level from 300 to 400ms post-stimulus presentation. A complementary time-frequency analysis was performed showing that an increase in the theta frequency band (4-7Hz) accounted for the main event-related band power (ERBP) change during the 200-500ms post stimulus interval. The analysis of the ERBPs changes according to their emotional valence showed a strong increase in theta ERBP to fearful eyes, which was higher respect to any other facial stimulus. Moreover, theta ERBP increase to "smiling eyes" was larger respect with that evoked by smiling mouths and whole happy faces. Minimal post-stimulus ERBPs changes were evoked by neutral stimuli. These data are consistent with a special role of the amygdala in processing facial signals, both with negative and positive valence, conveyed by the eye region of the face.

2012 - Ictal involvement of the nigrostriatal system in subtle seizures of ring chromosome 20 epilepsy. [Articolo su rivista]
Meletti, Stefano; Vignoli, A; Benuzzi, Francesca; Avanzini, P; Ruggieri, A; Pugnaghi, Matteo; Nichelli, Paolo Frigio; Canevini, M. P.
abstract

Studies in animal models and patients with epilepsy have suggested that basal ganglia circuits may control epileptic seizures and that striatal dopaminergic transmission may play a role in seizure modulation and interruption. Chromosome 20 [r(20)] syndrome is a well-defined chromosomal disorder characterized by epilepsy, mild-to-moderate mental retardation, and lack of recognizable dysmorphic features. Epilepsy is often the most important clinical manifestation of the syndrome, with prolonged episodes of nonconvulsive status epilepticus suggesting dysfunction in the seizure control system. We present the ictal blood oxygen level-dependent (BOLD) changes in brief seizures recorded by means of electroencephalography-functional magnetic resonance imaging (EEG-fMRI) coregistration in a patient with [r(20)] syndrome. We observed ictal BOLD increments in a cortical-subcortical network involving substantia nigrastriatum and frontal cortex. At present, this is the first functional neuroimaging evidence of the involvement of the nigrostriatal system during ictal EEG discharges in [r(20)] syndrome supporting a role of the basal ganglia circuits in human epileptic seizures.

2012 - Increased cortical BOLD signal anticipates generalized spike and wave discharges in adolescents and adults with idiopathic generalized epilepsies. [Articolo su rivista]
Benuzzi, Francesca; Mirandola, Laura; Pugnaghi, Matteo; Farinelli, Valentina; C. A., Tassinari; G., Capovilla; G., Cantalupo; F., Beccaria; Nichelli, Paolo Frigio; Meletti, Stefano
abstract

Purpose:  Electroencephalography-functional magnetic resonance imaging (EEG-fMRI) coregistration has recently revealed that several brain structures are involved in generalized spike and wave discharges (GSWDs) in idiopathic generalized epilepsies (IGEs). In particular, deactivations and activations have been observed within the so-called brain default mode network (DMN) and thalamus, respectively. In the present study we analyzed the dynamic time course of blood oxygen level-dependent (BOLD) changes preceding and following 3 Hz GSWDs in a group of adolescent and adult patients with IGE who presented with absence seizures (AS). Our aim was to evaluate cortical BOLD changes before, during, and after GSWD onset. Methods:  Twenty-one patients with IGE underwent EEG-fMRI coregistration. EEG-related analyses were run both at the single-subject and at group level (random effect). The time-course analysis was conducted for 3 s time windows before, during, and after GSWDs, and they were included until no further BOLD signal changes were observed. Key Findings:  Fifteen patients (nine female, mean age 28 years) had GSWDs during EEG-fMRI coregistration (262 total events, mean duration 4 s). Time-course group analysis showed BOLD increments starting approximately 10 s before GSWD onset located in frontal and parietal cortical areas, and especially in the precuneus-posterior cingulate region. At GSWD onset, BOLD increments were located in thalamus, cerebellum, and anterior cingulate gyrus, whereas BOLD decrements were observed in the DMN regions persisting until 9 s after onset. Significance:  Hemodynamic changes (BOLD increments) occurred in specific cortical areas, namely the precuneus/posterior cingulate, lateral parietal, and frontal cortices, several seconds before EEG onset of GSWD. A dysfunction of these brain regions, some of which belongs to the DMN, may be crucial in generating GSWDs in patients with IGE.

2012 - Oral Lacosamide as treatment option in a case of aphasic status epilepticus with continuous spike-and-wave discharges of the adult [Articolo su rivista]
Mirandola, L.; Monti, G.; Bonora, A.; Pugnaghi, M.; Benuzzi, F.; Vinceti, G.; Zucchelli, M.; Nichelli, P.; Meletti, S.
abstract

We present a case report of a 58 year-old man who suffered from simptomatic focal epilepsy due to artero-venous malformation localized in the left superior temporal gyrus. After the excision of the lesion he developed drugresistant epilepsy with temporal seizures characterized by behavioral arrest, automatisms, and aphasia. Despite numerous attempts with different AEDs (CBZ, PHT, LEV) the patient presented monthly seizures. He was admitted to our Department for non-convulsive status epilepticus, clinically characterized by aphasia and confusion, associated to continuous spikes and wave discharges over the fronto-temporal derivations of the left hemisphere. CBL and VPA were added to his therapy, while LEV was suspended for marked irritability. His language disturbance continued to be severe and he underwent neuropsychological evaluation and language fMRI, which documented complex language disorder. Only after gradually introducing oral Lacosamide the patient improved significantly. At 6 months follow-up he no longer experienced recurrent seizures, his EEG was free from epileptiform abnormalities and the aphasia was partially improved, too. We suggest that oral Lacosamide can be a therapeutic option for non convulsive status epilepticus.

2012 - Survival in patients with newly diagnosed conventional glioblastoma: a modified prognostic score based on a single-institution series. [Articolo su rivista]
F., Bertolini; E., Zunarelli; C., Baraldi; A., Valentini; C. D., Giovane; R., Depenni; A., Falasca; P., Giacobazzi; M., Malagoli; Meletti, Stefano; A., Fontana; P., Conte; G. N., Oncologico
abstract

Recursive partioning analysis (RPA) is commonly used to define the stratification of patients with glioblastoma. Epigenetic silencing of the O6-methylguanine methyltransferase (MGMT) gene by promoter methylation plays an important role in regulating MGMT expression in gliomas and this is an established independent prognostic factor. We tested a prognostic scoring system including all clinical variables used by RPA classification (age, ECOG performance status and type of surgery) and MGMT gene promoter methylation status.Seventy-eight consecutive patients with newly diagnosed, histopathologically confirmed conventional glioblastoma were included. Information about MGMT promoter methylation status was available for all of them. Based on the patients' age (&lt;50 vs ≥50 years), ECOG performance status (0 vs ≥1), type of surgery (gross tumor resection versus partial resection/biopsy) and MGMT promoter methylation status (methylated versus unmethylated), three classes of risk were generated where the prognostic score was defined assigning 1 point to every favorable parameter (Class I: ≥3; Class II: 2; Class III: 0-1). All classes were correlated with overall survival.The median survival times were 32.4, 8.6 and 8.8 months for Class I, II and III, respectively, corresponding to 2-year survival rates of 69\%, 13.5\% and &lt;1\%. The same analysis was performed on 54 patients treated with postoperative concomitant chemoradiotherapy. The median survival times were 32.5, 13.4 and 8.9 months for Class I, II and III, respectively, corresponding to 2-year survival rates of 68.6\%, 26.9\% and &lt;1\%. In both groups of 78 and 54 patients the differences in survival between Class I and III were statistically significant ( P &lt;0.0001).The proposed prognostic scoring system including clinical variables and MGMT promoter methylation status proved valuable in patients with primary conventional glioblastoma, especially those treated with postoperative chemoradiotherapy.

2012 - The effect of generalized spike and waves discharge duration and IGE sub-syndrome on brain networks as revelaed by EEG/fMRI [Abstract in Rivista]
Pugnaghi, M; Carmichael, Dw; Vaudano, Ae; Chaudhary, Uj; Benuzzi, F; DI BONAVENTURA, C; Giallonardo, At; Rodionov, R; Walker, Mc; Duncan, J; Meletti, S; Lemieux, L
abstract

2012 - The system epilepsies: a pathophysiological hypothesis. [Articolo su rivista]
Avanzini, G; Manganotti, P; Meletti, Stefano; Moshé, Sl; Panzica, F; Wolf, P; Capovilla, G.
abstract

We postulate that "system epilepsies" (SystE) are due to an enduring propensity to generate seizures of functionally characterized brain systems. Data supporting this hypothesis-that some types of epilepsy depend on the dysfunction of specific neural systems-are reviewed. The SystE hypothesis may drive pathophysiologic and clinical studies that can advance our understanding of epilepsies and can open up new therapeutic perspectives.

2012 - miRNAs expression analysis in paired fresh/frozen and dissected formalin fixed and paraffin embedded glioblastoma using real-time pCR [Articolo su rivista]
de Biase, D; Visani, M; Morandi, L; Marucci, G; Taccioli, C; Cerasoli, S; Baruzzi, A; Pession, A; Albani, F; Calbucci, F; D'Alessandro, R; Michelucci, R; Brandes, A; Eusebi, V; Ceruti, S; Fainardi, E; Tamarozzi, R; Emiliani, E; Cavallo, M; Franceschi, E; Tosoni, A; Cavallo, M; Fiorica, F; Valentini, A; Depenni, R; Mucciarini, C; Crisi, G; Sasso, E; Biasini, C; Cavanna, L; Guidetti, D; Marcello, N; Pisanello, A; Cremonini, Am; Guiducci, G; de Pasqua, S; Testoni, S; Agati, R; Ambrosetto, G; Bacci, A; Baldin, E; Baldrati, A; Barbieri, E; Bartolini, S; Bellavista, E; Bisulli, F; Bonora, E; Bunkheila, F; Carelli, V; Crisci, M; Dall'Occa, P; Ferro, S; Franceschi, C; Frezza, G; Grasso, V; Leonardi, M; Mostacci, B; Palandri, G; Pasini, E; Pastore Trossello, M; Poggi, R; Riguzzi, P; Rinaldi, R; Rizzi, S; Romeo, G; Spagnolli, F; Tinuper, P; Trocino, C; Dall'Agata, M; Faedi, M; Frattarelli, M; Gentili, G; Giovannini, A; Iorio, P; Pasquini, U; Galletti, G; Guidi, C; Neri, W; Patuelli, A; Strumia, S; Casmiro, M; Gamboni, A; Rasi, F; Cruciani, G; Cenni, P; Dazzi, C; Guidi, Ar; Zumaglini, F; Amadori, A; Pasini, G; Pasquinelli, M; Pasquini, E; Polselli, A; Ravasio, A; Viti, B; Sintini, M; Ariatti, A; Bertolini, F; Bigliardi, G; Carpeggiani, P; Cavalleri, F; Meletti, Stefano; Nichelli, Paolo Frigio; Pettorelli, E; Pinna, G; Zunarelli, E; Artioli, F; Bernardini, I; Costa, M; Greco, G; Guerzoni, R; Stucchi, C; Iaccarino, C; Ragazzi, M; Rizzi, R; Zuccoli, G; Api, P; Cartei, F; Fallica, E; Granieri, E; Latini, F; Lelli, G; Monetti, C; Saletti, A; Schivalocchi, R; Seraceni, S; Tola, Mr; Urbini, B; Giorgi, C; Montanari, E; Cerasti, D; Crafa, P; Dascola, I; Florindo, I; Giombelli, E; Mazza, S; Ramponi, V; Servadei, F; Silini, Em; Torelli, P; Immovilli, P; Morelli, N; Vanzo, C; Nobile C., PERNO Study Group
abstract

miRNAs are small molecules involved in gene regulation. Each tissue shows a characteristic miRNAs epression profile that could be altered during neoplastic transformation. Glioblastoma is the most aggressive brain tumour of the adult with a high rate of mortality. Recognizing a specific pattern of miRNAs for GBM could provide further boost for target therapy. The availability of fresh tissue for brain specimens is often limited and for this reason the possibility of starting from formalin fixed and paraffin embedded tissue (FFPE) could very helpful even in miRNAs expression analysis. We analysed a panel of 19 miRNAs in 30 paired samples starting both from FFPE and Fresh/Frozen material. Our data revealed that there is a good correlation in results obtained from FFPE in comparison with those obtained analysing miRNAs extracted from Fresh/Frozen specimen. In the few cases with a not good correlation value we noticed that the discrepancy could be due to dissection performed in FFPE samples. To the best of our knowledge this is the first paper demonstrating that the results obtained in miRNAs analysis using Real-Time PCR starting from FFPE specimens of glioblastoma are comparable with those obtained in Fresh/Frozen samples.

2011 - A case of late onset drug-resistant epilepsy associated with chronic Epstein-Barr virus encephalitis [Articolo su rivista]
Monti, G.; Pugnaghi, M.; Nichelli, P.; Meletti, S.
abstract

Drug resistant epilepsies represent 25% of epilepsies and lead to a debilitating prognosis with low quality of life. This requires a correct diagnosis in each patients to verify the real drug-resistance. We describe a case of a old woman that began presenting seizure at age of 70. For several years the patient was treated for a cryptogenic drug resistant epilepsy. She presented also a cognitive decline and loss of autonomy. After a prolonged post-ictal state the patient was admitted to our department and we investigated the possible causes with several tests. The EEG was characterized by spread slow waves. MRI excluded acute events. We found a CSF positivity for EBV PCR. We started Acyclovir and steroids with a rapid clinical and EEG improvement. After a follow up of 6 month the patient is seizure free.

2011 - DRUG-RESISTANT EPILEPSY AFTER A FIRST UNPROVOKED SEIZURE IN ADOLESCENCE AND ADULTHOOD: A PROSPECTIVE COHORT STUDY [Abstract in Rivista]
Monti, Giulia; Giovannini, Giada; Pugnaghi, Matteo; Mirandola, Laura; Nichelli, Paolo Frigio; Meletti, Stefano
abstract

2011 - EMOTIONAL EXPERIENCE AND EMOTION RECOGNITION IN MESIAL TEMPORAL LOBE EPILEPSY PATIENTS [Abstract in Rivista]
A., Bonora; Meletti, Stefano; S., Tocchini; Nichelli, Paolo Frigio; Benuzzi, Francesca
abstract

2011 - FIRST UNPROVOKED SEIZURE 1-YEAR MORTALITY: A MONOCENTRIC PROSPECTIVE COHORT STUDY [Abstract in Rivista]
Giovannini, Giada; Monti, Giulia; Mirandola, Laura; Pugnaghi, Matteo; Nichelli, Paolo Frigio; Meletti, Stefano
abstract

2011 - Features of somatosensory manifestations induced by intracranial electrical stimulations of the human insula. [Articolo su rivista]
Pugnaghi, Matteo; Meletti, Stefano; L., Castana; S., Francione; L., Nobili; R., Mai; L., Tassi
abstract

Objective: To study the clinical manifestations induced by intracranial electrical stimulation of the insular cortex in epileptic patients submitted to invasive stereo-electroencephalography (SEEG) recordings. Methods: We retrospectively studied the clinical manifestations induced by intracerebral electrical stimulations of the insular cortex in 96 patients. In order to precisely localize the position of the electrodes a postoperative 3D CT-scan or a 3D MRI was obtained and then the images were merged with the preoperative MRI in the same stereotactic referenced system. Results: A total of 341 electrical bipolar stimulations were performed. The most frequently induced symptom was a somatosensory manifestation (70%), mainly tingling and electric sensation involving the contralateral face and arm. Motor responses represented the 8% of the total amount, as well as auditory phenomena. Language dysfunction accounted for 2% of responses. Autonomic and gustatory phenomena represented respectively 1% of responses. Conclusion: we found a great prevalence of somatosensory manifestations whereas other types of clinical modifications were extremely infrequent. Significance: Our data support a prominent somatosensory role of the human insular cortex and provide a precise characterization of the different types of sensory manifestations induced by intracranial electrical stimulation of the human insula.

2011 - Incidence and predictors of acute symptomatic seizures after stroke [Articolo su rivista]
Beghi, E; D'Alessandro, R; Beretta, S; Consoli, D; Crespi, V; Delaj, L; Gandolfo, C; Greco, G; La Neve, A; Manfredi, M; Mattana, F; Musolino, R; Provinciali, L; Santangelo, M; Specchio, Lm; Zaccara, G; Epistroke, Group; Meletti, Stefano
abstract

OBJECTIVE: To assess incidence and predictors of acute symptomatic seizures in a prospective cohort of patients with first stroke.METHODS: Patients with first stroke hospitalized in 31 Italian centers were recruited. Relevant demographic data, disease characteristics, and risk factors were collected. Acute symptomatic seizures (≤7 days) were recorded and correlated to age, gender, family history of epilepsy, and vascular risk factors.RESULTS: A total of 714 patients (315 women, 399 men; age 27-97 years) were enrolled. A total of 609 (85.3%) had cerebral infarction (32 cerebral infarction with hemorrhagic transformation [CIHT]) and 105 (14.7%) primary intracerebral hemorrhage (PIH). A total of 141 (19.7%) had a large lesion (&gt;3 cm) and 296 (41.5%) cortical involvement. Twelve patients reported family history of seizures. Forty-five patients (6.3%) presented acute symptomatic seizures, 24 with cerebral infarction (4.2%), 4 with CIHT (12.5%), and 17 (16.2%) with PIH. In multivariate analysis, compared to cerebral infarction, PIH carried the highest risk (odds ratio [OR] 7.2; 95% confidence interval [CI] 3.5-14.9) followed by CIHT (OR 2.7; 95% CI 0.8-9.6). Cortical involvement was a risk factor for PIH (OR 6.0; 95% CI 1.8-20.8) and for CI (OR 3.1; 95% CI 1.3-7.8). Hyperlipidemia (OR 0.2; 95% CI 0.03-0.8) was a protective factor for IPH.CONCLUSION: The incidence of acute symptomatic seizures is the highest reported in patients with first stroke with prospective follow-up. Hemorrhagic stroke and cortical lesion were independent predictors of acute symptomatic seizures. Hyperlipidemia was a protective factor for hemorrhagic stroke.

2011 - Intracranial electrical stimulations of human insular cortex: A stereo-EEG study in patients with drug-resistant focal epilepsy [Articolo su rivista]
Pugnaghi, M.; Meletti, S.; Castana, L.; Francione, S.; Nobili, L.; Mai, R.; Tassi, L.
abstract

The insular lobe is the less known of human cerebral lobes and few researches have been performed in order to comprehend its function. Lesional and functional neuroimaging studies were initially performed suggesting different roles of the insular lobe. More recently intracranial stimulation studies had contributed to understand the functions of the human insula. We studied the clinical manifestations induced by intracerebral electrical stimulations performed during the pre-surgical work-out in 96 epileptic patients submitted to SEEG, with at least one electrode exploring the insular cortex. In order to precisely localize the position of the electrodes we carried out a postoperative 3D CT-scan or a 3D MRI, and then we fused the images with the preoperative MRI in the same stereotactic referenced system. Electrical bipolar stimulations were carried out at low frequency and high frequency. The most frequent induced symptom was a somatosensory manifestation (72%), mainly paresthesic sensation involving the contralateral face and upper limb, while other types of clinical modification were extremely infrequent. Our data provide evidence of a prominent somatosensory role of the human insular cortex. The fusion imaging methodology enabled us to precisely localize the stimulated contacts, excluding those that were not located into the insular cortex, probably explaining the higher amount of sensory manifestations respect to previous articles.

2011 - Kufs Disease, the Major Adult Form of Neuronal Ceroid Lipofuscinosis, Caused by Mutations in CLN6. [Articolo su rivista]
T., Arsov; K. R., Smith; J., Damiano; S., Franceschetti; L., Canafoglia; C. J., Bromhead; E., Andermann; D. F., Vears; P., Cossette; S., Rajagopalan; A., Mcdougall; V., Sofia; M., Farrell; U., Aguglia; A., Zini; Meletti, Stefano; M., Morbin; S., Mullen; F., Andermann; S. E., Mole; M., Bahlo; S. F., Berkovic
abstract

The molecular basis of Kufs disease is unknown, whereas a series of genes accounting for most of the childhood onset forms of neuronal ceroid lipofuscinosis (NCL) have been identified. Diagnosis of Kufs disease is difficult because the characteristic lipopigment is largely confined to neurons and may require brain biopsy or autopsy for final diagnosis. We mapped 4 families with Kufs disease where there was good evidence for autosomal recessive inheritance, and found two peaks on chromosome 15. Three of the families had type A Kufs disease (presenting with progressive myoclonus epilepsy) and one had type B (presenting with dementia and motor system features). Sequencing of a candidate gene in one peak shared by all four families was unrewarding but sequencing of CLN6, found in the second peak and shared only by the three type A pedigrees revealed pathogenic mutations in all three. We subsequently sequenced CLN6 in eight other families, three with recessive type A Kufs disease. Mutations in both CLN6 alleles were found in the three type A cases and in one family with unclassified Kufs disease. Mutations in CLN6 are the major cause of recessive type A Kufs disease. The phenotypic differences between variant late infantile NCL, previously found to be caused by CLN6, and type A Kufs disease are striking with a much later age of onset and lack of visual involvement in the latter. Sequencing of CLN6 will provide a simple diagnostic strategy in this disorder where definitive identification usually requires invasive biopsy.

2011 - Non convulsive status epilepticus of frontal origin as the first manifestation of Haschimoto's encephalopathy [Articolo su rivista]
Monti, Giulia; Pugnaghi, Matteo; A., Ariatti; Mirandola, Laura; Giovannini, Giada; S., Scacchetti; Nichelli, Paolo Frigio; Meletti, Stefano
abstract

Hashimoto's encephalopathy is an often misdiagnosed, life threatening, condition which improves promptly with steroid therapy. Since clinical manifestations are heterogeneous and non-specific, the diagnosis is often difficult. Several case reports of Hashimoto's encephalopathy presenting with partial or generalised seizures are described, but only a few have focused on status epilepticus as the first clinical manifestation. We report two patients presenting with repetitive and prolonged seizures characterised by progressive reduction in contact and reactivity associated with frontal/diffuse polyspike-and-wave activities. This condition, which can be interpreted as a form of non-convulsive status epilepticus (NCSE) of frontal origin, was refractory to antiepileptic drugs but responded promptly to high doses of intravenous steroid treatment. In cases of unexplained encephalopathy with EEG documentation of NCSE, the early recognition and treatment of Hashimoto's encephalopathy may lead to a favourable prognosis.

2011 - POSITIVE BOLD RESPONSE IN THE BRAIN'S DEFAULT MODE NETWORK ANTICIPATES SPIKE AND WAVE DISCHARGES IN IDIOPATHIC GENERALIZED EPILEPSY [Abstract in Rivista]
Mirandola, Laura; Benuzzi, Francesca; Pugnaghi, Matteo; V., Farinelli; Tassinari, C. A.; G., Capovilla; G., Cantalupo; F., Beccaria; Nichelli, Paolo Frigio; Meletti, Stefano
abstract

2011 - Recognition of emotions from faces and voices in medial temporal lobe epilepsy [Articolo su rivista]
A., Bonora; Benuzzi, Francesca; Monti, Giulia; L., Mirandola; Pugnaghi, Matteo; Nichelli, Paolo Frigio; Meletti, Stefano
abstract

Patients with chronic medial temporal lobe epilepsy (MTLE) can be impaired in different tasks that evaluate emotional or social abilities. In particular, the recognition of facial emotions can be affected (Meletti S, Benuzzi F, Rubboli G, et al. Neurology 2003;60:426-31. Meletti S, Benuzzi F, Cantalupo G, Rubboli G, Tassinari CA, Nichelli P. Epilepsia 2009;50:1547-59). To better understand the nature of emotion recognition deficits in MTLE we investigated the decoding of basic emotions in the visual (facial expression) and auditory (emotional prosody) domains in 41 patients. Results showed deficits in the recognition of both facial and vocal expression of emotions, with a strong correlation between performances across the two tasks. No correlation between emotion recognition and measures of IQ, quality of life (QOLIE-31), and depression (Beck Depression Inventory) was significant, except for a weak correlation between prosody recognition and IQ. These data suggest that emotion recognition impairment in MTLE is not dependent on the sensory channel through which the emotional stimulus is transmitted. Moreover, these findings support the notion that emotional processing is at least partly independent of measures of cognitive intelligence.

2010 - A PROMINENT SENSORY ROLE OF HUMAN INSULA: A STEREO-EEG STUDY [Abstract in Rivista]
Pugnaghi, Matteo; Meletti, Stefano; F., Cardinale; L., Castana; L., Tassi
abstract

2010 - Acute facial diplegia and paraesthesias following Parvovirus B19 (HPV-B19) infection [Abstract in Rivista]
Barbi, Filippo; Ariatti, Alessandra; K., Funakoshi; Meletti, Stefano; M., Meacci; M., Odaka; G., Galassi
abstract

2010 - Comment on myasthenia gravis associated with TNF-alpha receptor blockers: A multifaceted issue. [Articolo su rivista]
G., Galassi; A., Ariatti; L., Codeluppi; Meletti, Stefano
abstract

Fee and Kasarskis12 described a 66-yearold- diabetic man who developed facial weakness and bulbar signs after 6 years of etanercept therapy for rheumatoid arthritis. The patient had an elevated titer of acetylcholine receptor antibodies (AChR-Ab), and electrophysiologic studies suggested a disorder of neuromuscular transmission associated with axonal polyneuropathy. No immunomodulating therapy was given. After 3–8 months off etanercept his clinical and electrophysiologic features improved, but AChR-Ab titer remained elevated. We recently encountered a 68-year-old woman who experienced fluctuating fatigability 7–8 months after starting etanercept (Enbrel; Wyeth Lederle SpA) taken weekly (50 mg autoinjected subcutaneously) to treat psoriatic arthritis.

2010 - EMOTION RECOGNITION IN MEDIAL TEMPORAL LOBE EPILEPSY IN THE VISUAL AND AUDITORY DOMAIN [Abstract in Rivista]
Monti, Giulia; A., Bonora; Benuzzi, Francesca; E., Gasparini; Pugnaghi, Matteo; Nichelli, Paolo Frigio; Meletti, Stefano
abstract

2010 - FACIAL EMOTION RECOGNITION IN CHILDREN WITH HISTORY OF FEBRILE SEIZURES [Abstract in Rivista]
G., Cantalupo; Meletti, Stefano; A., Miduri; S., Mazzotta; L., Rios Pohl; S., Boria; Benuzzi, Francesca; F., Pisani; C. A., Tassinari; G., Cossu
abstract

2010 - Focal sensory-motor status epilepticus in multiple sclerosis due to a new cortical lesion. An EEG-fMRI co-registration study. [Articolo su rivista]
E., Gasparini; Benuzzi, Francesca; Pugnaghi, Matteo; A., Ariatti; P., Sola; Nichelli, Paolo Frigio; Meletti, Stefano
abstract

A case of focal inferior limb sensory-motor status epilepticus as the only manifestation of a multiple sclerosis (MS) relapse is described. To obtain evidence of the relationship between the seizures, the cortical plaque and the left foot motor area, an EEG-fMRI co-registration study was undertaken demonstrating that seizure-related BOLD signal substantially overlapped with the inflammatory lesion involving the foot sensory-motor cortex. Seizures did not respond to intravenous anti-epileptic drugs (AEDs) but were controlled by steroid therapy.

2010 - HYPERFAMILIARITY FOR UNKNOWN FACES: A RARE POSTICTAL SYMPTOM OF ACUTE SYMPTOMATIC FOCAL SEIZURES [Abstract in Rivista]
R., Michelucci; P., Riguzzi; G., Rubboli; L., Volpi; Meletti, Stefano; E., Pisani; F., Santoro; F., Pittau; Benuzzi, Francesca
abstract

2010 - MAKING PLANS AND DECISIONS IN PATIENTS WITH SLEEP-RELATED HYPERMOTOR SEIZURES [Abstract in Rivista]
A., Bonora; M. A., Molinari; Monti, Giulia; Benuzzi, Francesca; E., Gasparini; Pugnaghi, Matteo; Nichelli, Paolo Frigio; Meletti, Stefano
abstract

2010 - Myasthenia gravis associated with etanercept therapy [Abstract in Rivista]
Codeluppi, Luca; Ariatti, Alessandra; Meletti, Stefano; F., Valzania; Barbi, Filippo; G., Galassi
abstract

2010 - Postictal hyperfamiliarity for unknow faces [Articolo su rivista]
R., Michelucci; P., Riguzzi; G., Rubboli; L., Volpi; E., Pasini; F., Santoro; Meletti, Stefano; Benuzzi, Francesca; F., Pittau; F., Toni; A., Marliani
abstract

Hyperfamiliarity for unknown faces (HFUF) is a rare disorder in which unfamiliar people or faces appear familiar. Three young adults were admitted for acute symptomatic secondarily generalized tonic–clonic seizures (two) and psychomotor status (one). During the days following the seizures the patients continuously experienced a strong familiarity for unknown people, including other patients, visitors, and hospital staff. This disorder disappeared gradually, lasting a mean of 13 days. Brain MRI showed left amygdalohippocampal lesions, suggesting the etiology of encephalitis in two patients and multiple “active” demyelinating lesions in one patient. Interictal and ictal EEG findings showed left temporal epileptiform abnormalities. Two patients had a transitory defect of verbal memory. HFUF is a newly defined postictal symptom, more likely to arise from left temporal epileptic discharges. In our cases it was associated with acute lesions of the temporal areas, suggesting that its occurrence may also imply a structural etiology of epilepsy.

2009 - Facial emotion recognition impairment in chronic temporal lobe epilepsy [Articolo su rivista]
Meletti, Stefano; Benuzzi, Francesca; G., Cantalupo; G., Rubboli; C. A., Tassinari; Nichelli, Paolo Frigio
abstract

PURPOSE: To evaluate facial emotion recognition (FER) in a cohort of 176 patients with chronic temporal lobe epilepsy (TLE). METHODS: FER was tested by matching facial expressions with the verbal labels for the following basic emotions: happiness, sadness, fear, disgust, and anger. Emotion recognition performances were analyzed in medial (n = 140) and lateral (n = 36) TLE groups. Fifty healthy subjects served as controls. The clinical and neuroradiologic variables potentially affecting the ability to recognize facial expressions were taken into account. RESULTS: The medial TLE (MTLE) group showed impaired FER (86% correct recognition) compared to both the lateral TLE patients (FER = 93.5%) and the controls (FER = 96.4%), with 42% of MTLE patients recording rates of FER that were lower [by at least 2 standard deviations (SDs)] than the control mean. The MTLE group was impaired compared to the healthy controls in the recognition of all basic facial expressions except happiness. The patients with bilateral MTLE were the most severely impaired, followed by the right and then the left MTLE patients. FER was not affected by type of lesion, number of antiepileptic drugs (AEDs), aura semiology, or gender. Conversely, the early onset of seizures/epilepsy was related to FER deficits. These deficits were already established in young adulthood, with no evidence of progression in older MTLE patients. CONCLUSION: These results on a large cohort of TLE patients demonstrate that emotion recognition deficits are common in MTLE patients and widespread across negative emotions. We confirm that early onset seizures with right or bilateral medial temporal dysfunction lead to severe deficits in recognizing facial expressions of emotions.

2009 - GLIOMATOSIS CEREBRI: A SINGLE INSTITUTION REPORT [Abstract in Rivista]
Bertolini, Federica; Depenni, Roberta; A., Fontana; A., Falasca; Meletti, Stefano; A., Valentini; P., Giacobazzi; F., Cavalleri; E., Zunarelli; G. P., Pinna
abstract

2009 - Impairment in Decoding Eye-Region Emotional Content in Mesial Temporal Lobe Epilepsy [Abstract in Rivista]
G., Cantalupo; Benuzzi, Francesca; G., Rubboli; C. A., Tassinari; Nichelli, Paolo Frigio; Meletti, Stefano
abstract

2009 - Neuroethological approach to frontolimbic epileptic seizures and parasomnias: The same central pattern generators for the same behaviours [Articolo su rivista]
C. A., Tassinari; G., Cantalupo; B., Högl; P., Cortelli; L., Tassi; S., Francione; L., Nobili; Meletti, Stefano; G., Rubboli; E., Gardella
abstract

The aim of this report is not to make a differential diagnosis between epileptic nocturnal seizures and non-epileptic sleep-related movement disorders, or parasomnias. On the contrary, our goal is to emphasize the commonly shared semiological features of some epileptic seizures and parasomnias. Such similar features might be explained by the activation of the same neuronal networks (so-called 'central pattern generators' or CPG). These produce the stereotypical rhythmic motor sequences - in other words, behaviours - that are adaptive and species-specific (such as eating/alimentary, attractive/aversive, locomotor and nesting habits). CPG are located at the subcortical level (mainly in the brain stem and spinal cord) and, in humans, are under the control of the phylogenetically more recent neomammalian neocortical structures, according to a simplified Jacksonian model. Based on video-polygraphic recordings of sleep-related epileptic seizures and non-epileptic events (parasomnias), we have documented how a transient "neomammalian brain" dysfunction - whether epileptic or not - can 'release' (disinhibition?) the CPG responsible for involuntary motor behaviours. Thus, in both epileptic seizures and parasomnias, we can observe: (a) oroalimentary automatisms, bruxism and biting; (b) ambulatory behaviours, ranging from the classical bimanual-bipedal activity of 'frontal' hypermotor seizures, epileptic and non-epileptic wanderings, and somnambulism to periodic leg movements (PLM), alternating leg muscle activation (ALMA) and restless legs syndrome (RLS); and (c) various sleep-related events such as ictal fear, sleep terrors, nightmares and violent behaviour.

2008 - Absence status epilepticus as first manifestation of Hashimoto's encephalopathy | [Stato di male frontale a tipo "assenza" come sintomo di esordio nella encefalopatia di Hashimoto] [Articolo su rivista]
Monti, Giulia; Pugnaghi, Matteo; Tondelli, Manuela; A., Ariatti; Nichelli, Paolo Frigio; Meletti, Stefano
abstract

Hashimoto's Encephalopathy is an underecognized condition, life-threatening, but treatable, and with a fast clinical improvement after steroid therapy. The clinical manifestations are heterogeneous, so the diagnosis in often difficult, and necessarily a diagnosis of exclusion. Epileptic seizures are a frequent onset symptom of Hashimoto's encephalopathy. In medical literature are described case report of Hashimoto's encephalopathy manifested with partial seizures, generalized seizure, or absence. Moreover, there are described few case report about status epilepticus as the first clinical manifestation of Hashimoto's encephalopathy. We described here two cases in which two patients without history of epilepsy, presented absence status epilepticus associated with fluctuating levels of consciousness. Both patients had elevated TSH level and sierum antithyroid antibodies (anti-thyreoperoxydas antibodies and anti-thyreoglobulin antibodies). Neuroimaging, hematological tests, complete rheumatologic panel, tumor markers and cerebrospinal fluid (CSF) analysis were normal. We excluded vascular, metabolic, tumor, and toxic causes. Ictal EEG showed continuously generalized sharp and slow wave, more evident in frontal electrode. Clinically, the patients presented eye-lid mioclonus and absence status. The patient were unresponsive to antiepileptic drug therapy but responded to high intravenous steroid treatment. Screening of serum anti-thyroid antibodies for unexplained encephalopathy with absences is suggested, as early recognition and prompt steroid treatment may lead to a favorable prognosis.

2008 - Adult neuronal ceroid lipofuscinoses (Kufs disease): An atypical case with recurrent occipital status epilepticus | [Ceroido-lipofuscinosi dell'adulto (malattia di Kufs): Un caso atipico con stati di male occipitali ricorrenti] [Articolo su rivista]
Pugnaghi, Matteo; A., Zini; Monti, Giulia; A., Ariatti; A., Todeschini; Nichelli, Paolo Frigio; G., Cenacchi; Meletti, Stefano
abstract

Kufs disease is the rare, adult-onset form of the neuronal ceroid-lipofuscinoses, characterized by early-onset dementia, progressive myoclonic epilepsy, gait disturbances, cerebellar and extrapyramidal symptoms, due to intraneuronal/extraneuronal accumulation of lipopigments (ceroid and lipofuscin-like). We describe the clinical evolution of an atypical case clinically characterized by slow progressive dementia and occipital recurrent status epilepticus.

2008 - Bold temporal dynamics in absence seizures: An EEG-fMRI coregistration study [Articolo su rivista]
Benuzzi, F.; Pugnaghi, M.; Farinelli, V.; Nichelli, P.; Meletti, S.
abstract

Recent studies have demonstrated BOLD signal changes related to interictal generalized spike-wave discharge discharges in idiopathic generalized epilepsy (IGE) describing a cortical-subcortical network. Our objective is to describe BOLD dynamics and its temporal variations during absence seizures in patients with IGE. Method: We studied two patients with IGE and Juvenile Absence Epilepsy. Scalp EEG was recorded by means of a 32 channels MRI-compatible EEG recording system. Functional data were acquired with a 3T Philips Achieva MR system. Event-related analysis was performed using absence seizures as regressors convolved with seven standard hemodynamic response function (HRF) starting at: -9, -6, -3 second before EEG onset of absence seizures, time 0 (onset),and +3, +6, +9 second after it. Results: Temporal analysis showed pre-ictal activations in frontal and parieto-occipital cortex. At seizure onset, activations were evident in thalamus, basal ganglia and mesial temporal regions. Deactivations were observed in precuneus from 6 sec before to 9 sec after the seizure onset, and in brainstem, caudate nuclei, anterior cingulate until 6 sec after it. Conclusion: Temporal analysis of absence seizures showed pre-ictal involvement of cortical regions (frontal cortex and precuneus). Then we observed an extended cortical-subcortical network including thalamus,basal ganglia, temporal mesial regions and brainstem. The involvement of these regions started at seizure onset and persisted many seconds after its end.

2008 - Bold temporal dynamics in absence seizures: An EEG-fMRI coregistration study | [Dinamica temporale del segnale bold in corso di crisi di assenza: Uno studio di co-registrazione EEG-fMRI] [Articolo su rivista]
Benuzzi, Francesca; Pugnaghi, Matteo; Farinelli, Valentina; Nichelli, Paolo Frigio; Meletti, Stefano
abstract

Recent studies have demonstrated BOLD signal changes related to interictal generalized spike-wave discharge discharges in idiopathic generalized epilepsy (IGE) describing a cortical-subcortical network. Our objective is to describe BOLD dynamics and its temporal variations during absence seizures in patients with IGE. Method: We studied two patients with IGE and Juvenile Absence Epilepsy. Scalp EEG was recorded by means of a 32 channels MRI-compatible EEG recording system. Functional data were acquired with a 3T Philips Achieva MR system. Event-related analysis was performed using absence seizures as regressors convolved with seven standard hemodynamic response function (HRF) starting at: -9, -6, -3 second before EEG onset of absence seizures, time 0 (onset),and +3, +6, +9 second after it. Results: Temporal analysis showed pre-ictal activations in frontal and parieto-occipital cortex. At seizure onset, activations were evident in thalamus, basal ganglia and mesial temporal regions. Deactivations were observed in precuneus from 6 sec before to 9 sec after the seizure onset, and in brainstem, caudate nuclei, anterior cingulate until 6 sec after it. Conclusion: Temporal analysis of absence seizures showed pre-ictal involvement of cortical regions (frontal cortex and precuneus). Then we observed an extended cortical-subcortical network including thalamus,basal ganglia, temporal mesial regions and brainstem. The involvement of these regions started at seizure onset and persisted many seconds after its end.

2008 - EEG-fMRI coregistration of absence seizures in patients with juvenile absence epilepsy | [Coregistrazione EEG-fMRI delle crisi di assenza in pazienti con juvenile absence epilepsy] [Articolo su rivista]
Pugnaghi, Matteo; Benuzzi, Francesca; Monti, Giulia; Farinelli, Valentina; Nichelli, Paolo Frigio; Meletti, Stefano
abstract

Simultaneous coregistration of EEG and fMRI (EEG-fMRI) is a new methodology which enables to identify changes in cerebral blood oxygenation level-dependent (BOLD) signal related to specific EEG events. Our objective is to describe BOLD dynamics during absence seizures in patients with Juvenile Absence Epilepsy (JAE). Methods: we studied two patients with JAE, without antiepileptic drug at the time of scanning. Scalp EEG was recorded by means of a 32 channels MRI-compatible EEG recording system. Functional data were acquired with a 3T Philips Achieva system. Event-related analysis was performed on functional data with SPM2 software. Results: seven and 13 absence seizures were recorded in the two patients. BOLD temporal dynamics showed activations in thalamus, medial temporal regions and pre-frontal cortex. Furthermore we observed deactivations in brainstem, caudate nuclei and widespread cortical regions, including precuneus, posterior parietal areas and pre-frontal cortex. Conclusion: We found cortical-subcortical BOLD network mostly overlapping of what previously described in GSWD of IGE. In addition we observed BOLD variations in brainstem and medial temporal regions not previously reported. We speculate that these data could be in relation to occurrence of absence seizures rather than GSWD and/or to the presence of complex absences with post-ictal oral automatisms.

2008 - Early-onset dementia with prolonged occipital seizures: an atypical case of Kufs disease [Articolo su rivista]
A., Zini; G., Cenacchi; Nichelli, Paolo Frigio; E., Zunarelli; A., Todeschini; Meletti, Stefano
abstract

OBJECTIVE: Kufs disease is the adult-onset form of neuronal ceroid lipofuscinosis (NCL). Its two clinical phenotypes are type A (progressive myoclonus epilepsy with dementia) and type B (behavioral abnormalities and dementia, associated with pyramidal and extrapyramidal signs). METHODS: We describe the clinical evolution of an atypical case characterized by progressive dementia and focal occipital seizures. RESULTS: A healthy 37-year-old woman began showing memory deficits and behavioral disturbances (apathy, lack of inhibitions, untidiness). After 4 years, she developed rare clusters of tonic-clonic seizures, as well as focal seizures originating from the temporo-occipital regions, clinically associated with visual hallucinations, wandering, and agitation. When she was 44 years old, neuropsychological assessment revealed severe frontotemporal dementia. MRI showed cortical atrophy and, on T2-weighted images, hypointensity of the basal ganglia, and hyperintensity and reduction of the deep white matter. On the basis of these findings, a diagnosis of Kufs disease was hypothesized. A skin biopsy was negative, but electron microscopy examination of a right frontal lobe brain biopsy revealed the presence of typical storage material (fingerprint inclusions). The patient never developed myoclonus or extrapyramidal signs. DISCUSSION: Kufs disease is difficult to diagnose on account of its heterogeneous clinical pattern and pathologic features, and the lack of a specific genetic locus alteration. The neuropsychological pattern and MRI findings observed in patients with early-onset frontotemporal dementia and seizure disorder suggest that Kufs disease should be considered in their differential diagnosis. Extracerebral biopsy can be nondiagnostic, and when alternative diagnoses have been ruled out, cerebral biopsy should be considered.

2008 - PROMINENT BRAINSTEM, THALAMIC AND AMYGDALA INVOLVEMENT IN ABSENCE SEIZURES WITH PERIORAL AUTOMATISMS AS REVEALED BY EEG-fMRI [Abstract in Rivista]
Pugnaghi, Matteo; Benuzzi, Francesca; Monti, Giulia; Farinelli, Valentina; Nichelli, Paolo Frigio; Meletti, Stefano
abstract

2008 - RECOGNITION OF BASIC AND SOCIAL EMOTIONS THROUGH FACE AND VOICE IN PATIENTS WITH MEDIAL TEMPORAL LOBE EPILEPSY [Abstract in Rivista]
Monti, Giulia; Benuzzi, Francesca; Pugnaghi, Matteo; M., Molinari; Nichelli, Paolo Frigio; Meletti, Stefano
abstract

2008 - SEMIOLOGY AND COGNITIVE ASSESSMENT OF SEIZURES WITH INTENSE EMOTIONAL COMPONENT [Abstract in Rivista]
Meletti, Stefano
abstract

2008 - Social cognition in patients with temporal lobe epilepsy [Articolo su rivista]
Monti, G.; Benuzzi, F.; Pugnaghi, M.; Molinari, M.; Nichelli, P.; Meletti, S.
abstract

Several studies demonstrated the critical role on processing emotional stimuli of mesial temporal lobe structures, which is the common pathologic substrate of Temporal Lobe Epilepsy associated with Mesial Temporal Sclerosis (TLE-MTS). The present study evaluated the emotional processing in TLE-MTS requiring patients to recognise facial and prosodic expressions of both basic and social emotions. Subjects: 11 patients with TLE-MTS. 12 patients with Temporal Lobe Epilepsy associated with other etiology (TLE-les) and 30 normal controls were evaluated. TLE-MTS patients were impaired in recognition all negative basic emotions (fear, sadness, angry, disgust) both from facial and prosodic expressions. They also showed a generalized deficit in social emotions recognitions whereas TLE-les patients were impaired in recognition of one specific social emotion (guilty). Our findings could also account for difficulties in social interactions often found in patients with mesial temporal lobe epilepsy.

2008 - Social cognition in patients with temporal lobe epilepsy | [La cognizione sociale nei pazienti con epilessia del lobo temporale] [Articolo su rivista]
Monti, Giulia; Benuzzi, Francesca; Pugnaghi, Matteo; M., Molinari; Nichelli, Paolo Frigio; Meletti, Stefano
abstract

Several studies demonstrated the critical role on processing emotional stimuli of mesial temporal lobe structures, which is the common pathologic substrate of Temporal Lobe Epilepsy associated with Mesial Temporal Sclerosis (TLE-MTS). The present study evaluated the emotional processing in TLE-MTS requiring patients to recognise facial and prosodic expressions of both basic and social emotions. Subjects: 11 patients with TLE-MTS. 12 patients with Temporal Lobe Epilepsy associated with other etiology (TLE-les) and 30 normal controls were evaluated. TLE-MTS patients were impaired in recognition all negative basic emotions (fear, sadness, angry, disgust) both from facial and prosodic expressions. They also showed a generalized deficit in social emotions recognitions whereas TLE-les patients were impaired in recognition of one specific social emotion (guilty). Our findings could also account for difficulties in social interactions often found in patients with mesial temporal lobe epilepsy.

2008 - Sudden falls due to seizure-induced cardiac asystole in drug-resistant focal epilepsy [Articolo su rivista]
G., Rubboli; F., Bisulli; R., Michelucci; Meletti, Stefano; M. A., Ribani; P., Cortelli; I., Naldi; P., Riguzzi; C. A., Tassinari; P., Tinuper
abstract

Sudden, abrupt falls to the ground during focalseizures, without any associated major motormanifestations, are a well-known althoughpoorly investigated phenomenon. Pathophysiologicmechanisms may include bitemporal orfrontal involvement with subsequent bilateralspread of the epileptic discharge. Seizure relatedcardiac arrhythmias (i.e., bradycardia orasystole) may result in syncope but may not alwaysbe considered in the etiology of ictal suddenfalls. We describe three patients with drug-resistantfocal epilepsy undergoing presurgical evaluation inwhom sudden falls during focal seizures resultedfrom seizure-related cardiac asystole.

2008 - Temporal epilepsy and social cognition in a patient with Turner syndrome [Articolo su rivista]
Tondelli, M.; Benuzzi, F.; Molinari, M. A.; Ariatti, A.; Pugnaghi, M.; Monti, G.; Nichelli, P.; Meletti, S.
abstract

Turner syndrome (TS) is a genetic disorder arising from X-monosomy or mosaicism. This genetic condition is associated with specific cognitive deficits and variations in brain volumes, especially in temporal lobes. Epilepsy is unusual in TS and only few cases have been reported, frequently associated with cerebral development abnormalities. In our report, we described the case of focal left temporal epilepsy without cerebral malformations in a woman with TS mosaicism.

2008 - Temporal epilepsy and social cognition in a patient with Turner syndrome | [Epilessia temporale e cognizione sociale in una paziente con sindrome di Turner] [Articolo su rivista]
Tondelli, Manuela; Benuzzi, Francesca; M. A., Molinari; A., Ariatti; Pugnaghi, Matteo; Monti, Giulia; Nichelli, Paolo Frigio; Meletti, Stefano
abstract

Turner syndrome (TS) is a genetic disorder arising from X-monosomy or mosaicism. This genetic condition is associated with specific cognitive deficits and variations in brain volumes, especially in temporal lobes. Epilepsy is unusual in TS and only few cases have been reported, frequently associated with cerebral development abnormalities. In our report, we described the case of focal left temporal epilepsy without cerebral malformations in a woman with TS mosaicism.

2008 - Temporal lobe epilepsy and social cognition assessment in a case of Urbach-Wiethe disease | [Epilessia temporale e cognizione sociale in una paziente affetta da malattia di Urbach-Wiethe] [Articolo su rivista]
G., Cantalupo; Meletti, Stefano; Benuzzi, Francesca; R., Michelucci; A. F., Marliani; S., Silipo; Nichelli, Paolo Frigio; G., Rubboli
abstract

We describe anatomo-electro-clinical features of temporal lobe epilepsy and social cognition skills in a 38 years old woman affected by Urbach-Wiethe disease. Patient's clinical history had typical features beginning in early infancy with low-pitched cry and hoarseness, due to vocal cords thickening, associated with cutaneous scar-like lesions and moniliform blepharosis. At age 13 genetic diagnosis was obtained finding mutation in extracellular matrix protein 1 gene. Since 8 years of age temporal-lobe seizures occurred. The patient underwent long-term video-EEG showing interictal slight bi-temporal theta rhythm and ictal EEG revealing rhythmic theta sequence on right temporal region during a subjective episode, without impairment of consciousness. Neuroimaging demonstrated bilateral comma-shaped calcifications involving amygdala, with mild abnormal signal in surrounding parenchyma. Social cognition assessment revealed only moderate deficit in recognition of facial expression of fear. Characteristic selective bilateral amygdala calcifications, frequently observed in Urbach-Wiethe disease, served as a model to prove the critical role of human amygdala in facial emotion recognition. Moderate and selective fear recognition deficit in our patient confirms the neuropsychological variability observed in these patients, probably related to damage timing.

2008 - Video-EEG in functional MRI | [Video-EEG-fMRI] [Articolo su rivista]
Farinelli, Valentina; Benuzzi, Francesca; Meletti, Stefano; Pugnaghi, Matteo; Nichelli, Paolo Frigio; M., Serafini
abstract

Combined EEG-fMRI is a methodology which enables to identify regional blood flow variations (BOLD contrast) associated with specific EEG events. We aimed to develop a technique allowing to acquire video images during EEG-fMRI recordings. We used a magnet compatible EEG recordings system (Micromed, S.P.A, Italy) designed to minimize interferences due to magnetic fields. In order to record video images we used a shielded video-camera with a flexible arm secured to the Radio Frequency coil. Video signals were synchronized with neurophysiological data in order to achieve a real video-EEG recording. Although some decay of the EEG signal due to magnetic field artefacts,we obtained satisfactory results allowing a real video-EEG recording with video monitoring of the patient's face. Integration of EEG-fMRI data with video images permit to widen our knowledge of clinical events which may appear during the EEG recording.

2007 - Automatisms as fixed action patterns in an ethological perspective: The role of central pattern generators [Abstract in Rivista]
C. A., Tassinari; G., Cantalupo; Meletti, Stefano; E., Gardella; F., Rondelli; M., Stanzani Maserati; G., Rubboli
abstract

2007 - Biting behavior as a model of aggression associated with seizures [Capitolo/Saggio]
M., Stanzani Maserati; Meletti, Stefano; G., Cantalupo; F., Pinardi; G., Rubboli; A. V., Delgado Escueta; C. A., Tassinari
abstract

2007 - Clinical features of epileptic negative myoclonus: Personal data and review of the literature [Abstract in Rivista]
G., Rubboli; M., Stanzani Maserati; G., Cantalupo; F., Rondelli; E., Gardella; Meletti, Stefano; F., Pinardi; L., Volpi; P., Riguzzi; R., Michelucci; C. A., Tassinari
abstract

2007 - Processing the socially relevant parts of faces [Articolo su rivista]
Benuzzi, Francesca; Pugnaghi, Matteo; Meletti, Stefano; Lui, Fausta; M., Serafini; Baraldi, Patrizia; Nichelli, Paolo Frigio
abstract

Faces are processed by a distributed neural system in the visual as well as in the non-visual cortex [the “core” and the “extended” systems, J.V. Haxby, E.A. Hoffman, M.I. Gobbini, The distributed human neural system for face perception, Trends Cogn. Sci. 4 (2000) 223–233]. Yet, the functions of the different brain regions included in the face processing system are far from clear. On the basis of the case study of a patient unable to recognize fearful faces, Adolphs et al. [R. Adolphs, F. Gosselin, T.W. Buchanan, D. Tranel, P. Schyns, A.R. Damasio, A mechanism for impaired fear recognition after amygdala damage, Nature 433 (2005) 68–72] suggested that the amygdala might play a role in orienting attention towards the eyes, i.e. towards the region of face conveying most information about fear. In a functional magnetic resonance (fMRI) study comparing patterns of activation during observation of whole faces and parts of faces displaying neutral expressions, we evaluated the neural systems for face processing when only partial information is provided, as well as those involved in processing two socially relevant facial areas (the eyes and the mouth).Twenty-four subjects were asked to perform a gender decision task on pictures showing whole faces, upper faces (eyes and eyebrows), and lower faces (mouth). Our results showed that the amygdala was activated more in response to the whole faces than to parts of faces, indicating that the amygdala is involved in orienting attention toward eye and mouth. Processing of parts of faces in isolation was found to activate other regions within both the “core” and the “extended” systems, as well as structures outside this network, thus suggesting that these structures are involved in building up the representation of the whole face from its parts.

2007 - Stiff-Person syndrome mimicking motor neuron disease: a case report [Abstract in Atti di Convegno]
Girolami, F; Zini, A; Meletti, S; Sola, P; Mandrioli, J
abstract

2006 - Emergence de comportements moteurs innés communs aux crises frontales nocturnes et aux parasomnies: approche éthologique et role des "central pattern generators" [Capitolo/Saggio]
C. A., Tassinari; Meletti, Stefano; E., Gardella; G., Cantalupo; M., Stanzani Maserati; G., Rubboli
abstract

2006 - Emotions induced by intracerebral electrical stimulation of the temporal lobe [Articolo su rivista]
Meletti, Stefano; L., Tassi; R., Mai; N., Fini; C. A., Tassinari; G. L., Russo
abstract

Purpose: To assess the quality and frequency ofemotions induced by intracerebral electrical stimulation of thetemporal lobe.Methods: Behavioral responses were obtained by electricalstimulation in 74 patients undergoing presurgical video-stereo-EEG monitoring for drug-resistant epilepsy. Intracerebral electricalstimulationwas performed by delivering trains of electricalstimuli of alternating polarity; the intensity could vary from 0.2to 3 mA. Stimulation frequencywas 1Hz or 50 Hz. Nine hundredthirty-eight stimulation procedures were performed.Results: Seventy-nine emotional responses (ERs) were obtained(8.4%). Of these, 67 were “’fear responses.” Sad feelingswere evoked 3 times, happy-pleasant feelings 9 times. Anger anddisgust were never observed. The following variables affectedthe incidence of ER: (a) Anatomical site of stimulation. ERs (always fear) were maximal at the amygdala (12%) and minimalfor lateral neocortical stimulation (3%, p &lt; 0.01). (b) Pathology.Stimulation of a temporal lobe with hippocampal sclerosiswas associated with a lower frequency of ERs compared withstimulation of a temporal lobe with no evidence of atrophy inthe medial temporal structures. (c) Stimulation frequency. ERswere 12% at 50 Hz versus 6.0% at 1 Hz (p &lt; 0.01). (d) Gender.In women fear responses were 16% compared with 3% in men(p &lt; 0.01). There were no gender differences when analyzingnonemotional responses.Conclusions: These data confirm the role of the medial temporallobe region in the expression of emotions, especiallyfear-related behaviors. Fear was observed more frequently inthe absence of medial temporal sclerosis, supporting the hypothesis that emotional behaviors induced by stimulation arepositive phenomena, strictly related to the physiological functionof these regions. Further investigations should addresswhy women express fear behaviors more frequently than men.

2006 - Negative myoclonus induced by cortical electrical stimulation in epileptic patients [Articolo su rivista]
G., Rubboli; R., Mai; Meletti, Stefano; S., Francione; F., Cardinale; L., Tassi; G., Lo Russo; M., Stanzani Maserati; G., Cantalupo; C. A., Tassinari
abstract

Negative myoclonus (NM) is a motor disorder characterized by a sudden and abrupt interruption of muscular activity. The EMG correlate of NM is a brief (<500 ms) silent period (SP) not preceded by any enhancement of EMG activity (i.e. myoclonus). This study investigated the role of premotor cortex (PMC), primary motor cortex (MI), primary somatosensory area (SI) and supplementary motor area (SMA) in the pathophysiology ofcortical NM by means of intracerebral low frequency (1 Hz) electrical stimulation. In three drug-resistant epileptic patients undergoing presurgical evaluation, we delivered single electric pulses (stimulus duration: 3 ms; stimulus intensity ranging from 0.4 to 3 mA) to PMC (2 patients), MI (1 patient), SI and SMA through stereo-EEG electrodes; surface EMG was collected from both deltoids. The results showed that (i) the stimulation ofPMC or MI could evoke a motor evoked potential (MEP) either at rest or during contraction, in this latter case followed by an SP; however, in two patients, at the lowest stimulus intensities (0.4 mA), 50% of stimuli could induce a pure SP, i.e. not preceded by an MEP; raising the intensity of stimulation (0.6 mA), the SPs showed an antecedent MEP in >80% of stimuli; (ii) the stimulation of SI at low stimulus intensities (from 0.4 to 0.8 mA) induced in two patients only SPs, never associated with an antecedent MEP, whereas in the third subject the SPs could be inconstantly preceded by an MEP; by incrementing the stimulus intensity (up to 3 mA), in all three patients the SPs tended to be preceded, although not constantly, by an MEP; stimulus intensity affected SPduration (i.e. the higher the intensity, the longer the SP), without influencing the latency of onset of the SPs; (iii) the stimulation of SMA induced only pure SPs, at all stimulus intensities up to 3 mA; as for SI, increment of stimulus intensity was paralleled by an increase in SP duration, without influencing the onset latency of SPs.We conclude that single electric pulse stimulation of PMC, MI, SI and SMA through stereo-EEG electrodes can induce pure SPs, not preceded by an MEP, which clinically appear as NM, suggesting therefore that these cortical areas may be involved in the genesis of this motor phenomenon. However, it must be pointed out that SMA stimulation induced only pure SPs, regardless of the stimulus intensity, whereas occurrence of pure SPs following stimulation of PMC, MI, and SI depended mainly on the intensity of stimulation.

2005 - Biting behavior, aggression, and seizures [Articolo su rivista]
C. A., Tassinari; L., Tassi; G., Calandra Buonaura; M., Stanzani Maserati; N., Fini; F., Pizza; I., Sartori; R., Michelucci; G., Lo Russo; Meletti, Stefano
abstract

Purpose: to describe the semiological features of aggressive behaviours observed in human epileptic seizures with particular reference to the act of biting a conspecific. Methods: we analysed the biting behaviour (BB) and other aggressive gestures occurring in a group of eleven patients retrospectively selected out of more 1000 patients subjected to video-EEG/SEEG monitoring for pre-surgical evaluation of drug-resistant seizures. Results: patients displaying BB showed: (i) a male sex predominance; (ii) heterogeneous aetiologies and lesion locations; (iii) seizures involving the fronto-temporal regions of both hemispheres. The act of biting was a rapid motor action, lasting about 600 ms, occurring in the context of strong emotional arousal, fear, anger with various bodily gestures with aggressive connotation. BB was mainly a ‘reflexive’ behaviour in that biting acts were evoked (both during and after seizures) by actions of people in close contact with the patient. The sole intrusion of the examiner’s hand in the space near the patient’s face was effective in triggering BB. Rarely self-directed or object-directed biting acts were not triggered by external stimuli. Intracranial data (SEEG) obtained in one subject showed that the amygdala/hippocampal region plus the orbital-medial prefrontal cortex had to be involved by ictal activity in order to observe BB.Conclusions: anatomical and electrophysiological data in our patients suggest that a model of dual – temporal and frontal – dysfunction could account for the occurrence of ictal/postictal BB. Behavioural data suggest also that BB and related aggressive gestures can be considered as the emergence of instinctive behaviours with an adaptative significance of defence of the peripersonal space.

2005 - Bradicardia critica e asistolia cardiaca durante crisi focali. Documentazione video-eeg di due casi. [Articolo su rivista]
Riguzzi, P.; Rubboli, G.; Michelucci, R.; Meletti, Stefano; Ribani, M. A.; Contardi, S.; Volpi, L.; Fini, N.; DI STASI, V.; Tassinari, C. A.
abstract

[ATTO DI CONVEGNO]

2005 - Central Pattern Generators for a common semiology in fronto-limbic seizures and in parasomnias. A neuroethologic approach [Articolo su rivista]
C. A., Tassinari; G., Rubboli; E., Gardella; G., Cantalupo; G., Calandra Buonaura; M., Vedovello; M., Alessandria; G., Gandini; S., Cinotti; N., Zamponi; Meletti, Stefano
abstract

Central pattern generators (CPGs) are geneticallydetermined neuronal aggregates in the mesencephalon,pons and spinal cord subserving innate motor behavioursessential for survival (feeding, locomotion, reproductionetc.). In higher primates CPGs are largely under neocorticalcontrol. We describe how certain motor events observedin parasomnias and epileptic seizures could have similarfeatures and resemble motor behaviours, which can be theexpression of the same CPG. Both epilepsy and sleep canlead to a temporary loss of control of neomammalian cortexthat facilitates through a common platform (arousal) theemergences of stereotyped inborn fixed action patterns.Therefore we suggest that, independently from the natureof the trigger, be it a seizure or a parasomnia, the sameCPGs can be involved, “caught up”, leading to a commonmotor semiology (the “Carillon theory”).

2005 - Emotions evoked by intracerebral electrical stimulation of the temporal lobe [Articolo su rivista]
Meletti, S.; Tassi, L.; Mai, R.; Tassinari, C. A.; Lo Russo, G.
abstract

The expression of emotions induced by temporal lobe stimulation was analysed in 74 patients undergonig presurgical video-Stereo-EEG monitoring for drug-resistant epilepsy. 79 emotional responses were obtained in more than 900 stimulations. 67 out of 79 ER were 'fear responses'. Sad feelings were evoked 3 times, happy-pleasant feelings were obtained 9 times. Anger and disgust were never observed. Expression of fear was preferentially evoked by mesial temporal lobe stimulation. The most effective stimulation parameters for inducing emotional responses were high frequency (50 Hz) stimuli with 2mA intensity.

2005 - Emotions evoked by intracerebral electrical stimulation of the temporal lobe [Emozioni evocate dalla stimolazione elettrica intracerebrale del lobo temporale] [Articolo su rivista]
Meletti, Stefano; L., Tassi; R., Mai; C. A., Tassinari; G., Lo Russo
abstract

The expression of emotions induced by temporal lobe stimulation was analysed in 74 patients undergonig presurgical video-Stereo-EEG monitoring for drug-resistant epilepsy. 79 emotional responses were obtained in more than 900 stimulations. 67 out of 79 ER were 'fear responses'. Sad feelings were evoked 3 times, happy-pleasant feelings were obtained 9 times. Anger and disgust were never observed. Expression of fear was preferentially evoked by mesial temporal lobe stimulation. The most effective stimulation parameters for inducing emotional responses were high frequency (50 Hz) stimuli with 2mA intensity.

2005 - Emotions induced by intracerebral electrical stimulation of the temporal lobe [Abstract in Rivista]
Meletti, Stefano; L., Tassi; R., Mai; C. A., Tassinari; G., Lo Russo
abstract

2005 - Esperienze emozionali evocate dalla stimolazione elettrica intracerebrale del lobo temporale. [Articolo su rivista]
Meletti, Stefano; Tassi, L.; Mai, R.; Tassinari, C. A.; LO RUSSO, G.
abstract

[ATTO DI CONVEGNO]

2005 - Ethological approach to epileptic 'automatisms' viewed as fixed action patterns induced by a release of central pattern generators [Abstract in Rivista]
C. A., Tassinari; Meletti, Stefano; E., Gardella; G., Calandra Buonaura; P., Riguzzi; L., Volpi; R., Michelucci; G., Rubboli
abstract

2005 - Ictal bradycardia and cardiac asystole during temporal lobe seizures: A Video-EEG documentation [Abstract in Rivista]
G., Rubboli; R., Michelucci; P., Riguzzi; Meletti, Stefano; Ribani, M. A.; S., Contardi; N., Fini; L., Volpi; C. A., Tassinari
abstract

2005 - Recognition of facial expressions of emotions in MTLE: Analysis of 122 consecutive patients [Abstract in Rivista]
Meletti, Stefano; Benuzzi, Francesca; M., Alessandria; G., Calandra Buonaura; G., Rubboli; M., Vedovello; P., Tinuper; Nichelli, Paolo Frigio; C. A., Tassinari
abstract

2005 - Withdrawal-approach behaviours during epileptic seizures [Abstract in Rivista]
G., Calandra Buonaura; Meletti, Stefano; E., Gardella; R., Michelucci; P., Riguzzi; G., Rubboli; L., Volpi; C. A., Tassinari
abstract

2004 - Biting behaviour and other displays of aggression evoked by epilepsy seizures [Abstract in Rivista]
G., Calandra Buonaura; Meletti, Stefano; M., Stanzani Maserati; G., Cantalupo; G., Rubboli; L., Volpi; N., Fini; C. A., Tassinari
abstract

2004 - Disruption of a neural network subserving facial expression processing in right mesial temporal lobe epilepsy [Abstract in Rivista]
Meletti, Stefano; Benuzzi, Francesca; G., Calandra Buonaura; G., Rubboli; M., Serafin; Lui, Fausta; Nichelli, Paolo Frigio; C. A., Tassinari
abstract

2004 - Espressione facciale delle emozioni nelle crisi epilettiche del lobo temporale e frontale nell'uomo. [Articolo su rivista]
Tassinari, C. A.; Gardella, E.; Rubbioli, G.; Meletti, Stefano; Volpi, L.; Costa, M.; RICCI BITTI, P. E.
abstract

[ARTICOLO]

2004 - Impaired fear processing in right mesial temporal sclerosis: a fMRI study [Articolo su rivista]
Benuzzi, Francesca; Meletti, Stefano; Zamboni, Giovanna; G., Calandra Buonaura; M., Serafini; Lui, Fausta; Baraldi, Patrizia; G., Rubboli; C. A., Tassinari; Nichelli, Paolo Frigio
abstract

Lesion and neuroimaging studies have demonstrated that the mesial temporal lobe is crucial for recognizing emotions from facial expressions. In humans, bilateral amygdala damage is followed by impaired recognition of facial expressions of fear. To evaluate the influence of unilateral mesial temporal lobe damage we examined recognition of facial expressions and functional magnetic resonance (fMRI) brain activation associated with incidental processing of fearful faces in thirteen mesial temporal lobe epilepsy (MTLE) patients (eight with right MTLE, five with left MTLE). We also examined the effect of early versus later damage, comparing subjects with hippocampal-amygdalar sclerosis (MTS) and seizures occurring before five years of age to epilepsy patients with late onset seizures. Fourteen healthy volunteers participated as controls. Neuropsychological testing demonstrated that the ability of right MTLE patients to recognize fearful facial expressions is impaired. Patients with early onset of seizures were the most severely impaired. This deficit was associated with defective activation of a neural network involved in the processing of fearful expressions, which in controls and left MTLE included the left inferior frontal cortex and several occipito-temporal structures of both hemispheres.

2004 - Pathophysiology of cortical negative myoclonus: an intracerebral electrical stimulation study [Abstract in Rivista]
G., Rubboli; R., Mai; Meletti, Stefano; M., Stanzani Maserati; G., Cantalupo; L., Tassi; S., Francione; G., Lo Russo; C. A., Tassinari
abstract

2004 - Rhythmic teeth grinding induced by temporal lobe seizures [Articolo su rivista]
Meletti, Stefano; G., Cantalupo; L., Volpi; G., Rubboli; A., Magaudda; C. A., Tassinari
abstract

The authors report the clinical and polygraphic features of rhythmic teeth grinding observed in a patient asthe predominant symptom related to temporal lobe seizures during sleep and wakefulness. This observation demonstratesthat exceptionally a teeth-grinding event can be not only a parasomnia (sleep bruxism) but also an epileptic-related motorevent. Electromyographic and autonomic features of seizure-related teeth grinding support the interpretation of thismotor phenomenon as a particular form of masticatory activity.

2003 - Atypical familial motor neuropathy in patients with mutant TTR Ile68Leu [Articolo su rivista]
F., Salvi; C., Scaglione; R., Michelucci; R. P., Linke; L., Obici; A., Ravani; P., Rimessi; A., Ferlini; Meletti, Stefano; T., Cavallaro; C. A., Tassinari; P., Martinelli
abstract

The article describes the clinical and genetic findings in a group of patients with familial motor neuropathy due to amyloid accumulation.

2003 - Damage to the right hippocampal-amygdala formation during early infancy and recognition of fearful faces: neuropsychological and fMRI evidence in subjects with temporal lobe epilepsy [Articolo su rivista]
Meletti, Stefano; Benuzzi, Francesca; Nichelli, Paolo Frigio; C. A., Tassinari
abstract

The article describes the deficits in emotion recognition observed in patients with early damage (during the first years of life) to the amygdala.

2003 - Early ictal speech and motor inhibition in fronto-mesial epileptic seizures: a polygraphic study in one patient [Articolo su rivista]
Meletti, Stefano; G., Rubboli; S., Testoni; R., Michelucci; G., Cantalupo; M., Stanzani Maserati; F., Calbucci; C. A., Tassinari
abstract

Objective: To investigate ictal motor inhibition occurring during seizures in a patient with a tumor located in the left fronto-mesial precentral cortex.Methods: Awake and sleep video-polygraphic monitoring, recording scalp EEG and EMG activities from several cranial, trunk and limbs muscles, was performed in a patient with drug-resistant recurrent focal motor seizures before surgical treatment. Speech/motor tasks were repeatedly administered to the patient during the recording sessions in order to evaluate the occurrence of early ictal motor inhibition.Results: Thirty-four seizures were recorded during wakefulness showing a stereotyped pattern of inhibition of speech and voluntary movements followed by sequential activation of upper limb–trunk–lower limb muscles contralateral to the tumor. Polygraphic recordings showed that: (1) initial speech and motor arrest were associated with the EMG evidence of progressive muscle tone suppression in cranial and right distal upper limb muscles; (2) tonic contraction of right deltoid, biceps brachii, intercostalis and paraspinalis muscles appeared aftermotor inhibition; (3) tonic-clonic activity in the right tibialis anterior muscle occurred at the end of seizures. Eleven subclinical seizures were recorded during sleep showing mild focal tonic EMG activity in right side trunk muscles.Conclusions: Our findings evidenced early and somatotopically organized inhibition of voluntary movement at the beginning of epileptic seizures with fronto-mesial onset. The demonstration that speech and motor arrest were associated with progressive EMG suppression in cranial and limb muscles supports the hypothesis of motor inhibitory seizures originating in the mesial aspect of pre-motor frontal cortex.

2003 - Facial expression of emotion in human frontal and temporal lobe epileptic seizures [Articolo su rivista]
C. A., Tassinari; E., Gardella; G., Rubboli; Meletti, Stefano; L., Volpi; M., Costa; Ricci Bitti, P. E.
abstract

The article analyze the patterns of facial expressions observed during human epileptic seizures.

2003 - Impaired facial emotion recognition in early-onset right mesial temporal lobe epilepsy. [Articolo su rivista]
Meletti, Stefano; Benuzzi, Francesca; G., Rubboli; G., Cantalupo; M., Stanzani Maserati; Nichelli, Paolo Frigio; C. A., Tassinari
abstract

BACKGROUND: Anteromedial temporal lobe regions, particularly the amygdala, participate in the recognition of emotions from facial expressions. The authors studied the ability of facial emotion recognition (ER) in subjects with symptomatic epilepsy, evaluating whether mesial temporal lobe damage is related to an impairment in the recognition of specific emotions and whether the onset of seizures in a critical period of life could prevent the development of ER. METHODS: Groups included patients with temporal lobe epilepsy (TLE) with MRI evidence of mesial temporal sclerosis (MTS) (n = 33); patients with TLE with MRI evidence of temporal lobe lesions other than MTS (n = 30); and patients with extratemporal epilepsy (n = 33). Healthy volunteers (n = 50) served as controls. ER was tested by matching a facial expression with the name of one of the following basic emotions: happiness, sadness, fear, disgust, and anger. A face-matching task was used to control visuoperceptual abilities with face stimuli. RESULTS: No subject showed deficits in the face-matching task. ER was impaired in patients with right MTS, especially for fearful faces. Patients presenting left MTS, right or left temporal lobe lesions other than MTS, or extratemporal seizure foci showed ER performances similar to controls. In all subjects with right TLE, the degree of emotion recognition impairment was related to age at first seizure (febrile or afebrile) and age at epilepsy onset. CONCLUSIONS: Early-onset right-sided mesial temporal lobe epilepsy is the key substrate determining a severe deficit in recognizing emotional facial expressions, especially fear.

2003 - Rasmussen's syndrome as a cause of intractable epilepsy in adults: A clinical and neurophysiological study of two patients [Abstract in Rivista]
R., Michelucci; G., Rubboli; Meletti, Stefano; A., Sabetta; P., Riguzzi; R., Ricci; C. A., Tassinari
abstract

2003 - Reorganization of neural circuit for fear recognition after anterior temporal lobectomy (selected for oral presentation). [Relazione in Atti di Convegno]
Benuzzi, Francesca; Meletti, Stefano; Zamboni, Giovanna; G., Calandra Buonaura; M., Serafini; Lui, Fausta; G., Rubboli; C. A., Tassinari; Nichelli, Paolo Frigio
abstract

Introduction: Several studies demonstrate the critical role on processing emotional stimuli of mesial temporal lobe structures, which are the common pathologic substrate of Temporal Lobe Epilepsy (TLE). We used fMRI to examine the reorganization of neural circuits underlying fear recognition after anterior temporal lobectomy in a group of TLE patients. Methods: Seven right-handed patients with a history of drug-resistant TLE (three with right and four with left TLE), were evaluated before and six months after lobectomy. Six right-handed healthy volunteers were tested as controls and re-tested after six months. Subjects were asked to make a gender decision task on fearful (F) and neutral faces (N). In a control condition (C) subjects were asked to detect a white square within scrambled faces. EPI data were acquired using a GE Signa HHS77 system at 1.5 Tesla (TR=3380 ms; TE=40 ms) across 16 axial 5 mm slices (64 x 64 matrix) and were analysed using SPM99. Before scanning, patients underwent a neuropsychological evaluation to assess their facial emotion recognition abilities. Results: Controls: A conjunction analysis (F and N) showed increased signal in occipito-temporal regions and mesial temporal lobe structures bilaterally, consistently with the activation of a specific face-selective network. This pattern of responses was similar at re-testing. Fearful expressions evoked activations in the inferior frontal and posterior cortex (fusiform gyrus and temporal lobe) bilaterally; re-test data showed activations reduced in extent and restricted to the left hemisphere. Patients: Preoperative and postoperative data showed regions of increased signal for faces similar to those found in controls. The activation of distinct regions for processing fearful faces was present in five of the seven patients; it was missing only in the two patients with right TLE and early amygdala damage. These two patients also failed in explicit recognition of fearful expressions. After surgery, they improved their performance at neuropsychological testing, and their fMRI data showed activation areas partially resembling the fearful activations found in controls and in left preoperative TLE patients. In the other patients the pattern of responses to fearful faces was not consistent on re-testing. Conclusions: In control subjects the neural network activated by faces (either neutral or fearful) did not vary on re-testing. Neither TLE nor anterior temporal lobectomy affected the response of this network. On the contrary, right early amygdala damage impaired explicit recognition of fearful expressions and it was associated with lack of fMRI activations during incidental processing of fearful faces. Re-test data showed that the selective pattern of activation to fearful expressions varied with the re-presentation of the emotional faces in controls and according to the side and the nature of the preoperative damage in TLE patients. Indeed, anterior temporal lobectomy improved emotional recognition in patients with early right amygdala damage and was associated with activation of a neural network for incidental processing of fearful faces. We suggest that an early discharging right mesial temporal lobe damage can prevent the brain from undergoing functional reorganization. Right anterior lobectomy, removing the discharging tissue, can release brain plasticity mechanisms, leading to recovery of emotion recognition.

2003 - The expression of interictal, preictal, and postictal facial-wiping behavior in temporal lobe epilepsy: a neuro-ethological analysis and interpretation [Articolo su rivista]
Meletti, Stefano; G., Cantalupo; M., Stanzani Maserati; G., Rubboli; C. A., Tassinari
abstract

By videotape recordings analysis we investigated the frequencies of interictal, preictal, and postictal wiping or rubbing movementstargeting the face region (face wiping, FW) in 17 right and 13 left mesial temporal lobe epilepsy (MTLE) patients. Patientsdata were compared with FW frequencies obtained in 22 healthy controls listening to a presentation. Results showed that: (1) FWmovements were present in both controls and patients; however, the patient groups showed lower interictal and preictal FW ratesrelative than controls; (2) right and left temporal lobe seizures were followed by a marked increase in the expression of wipingactivities directed to the nose as well as to other face regions with respect to the interictal–preictal period; (3) during the first 5 minpostictal FW was performed preferentially with the hand ipsilateral to the seizure focus; (4) postictal examination of the patient byan observer, especially if of the opposite sex, resulted in a higher incidence of FW acts. After temporal lobe seizures there is anexaggerated expression of movements targeting the face region, and not exclusively directed to the nose. According to an ethological interpretation of the FW behavior as a motor behavior present throughout the phylogenetic scale, from rodents to primates, we suggest the postictal emergence of an innate action pattern modulated by external emotional–cognitive stimuli.

2003 - The neuroethological interpretation of motor behaviors in “Nocturnal-Hyperkynetic-Frontal Seizures”: emergence of ‘innate’ motor behaviors and role of central pattern generators [Capitolo/Saggio]
C. A., Tassinari; E., Gardella; Meletti, Stefano; G., Rubboli
abstract

A neuroethological interpretation of motor behaviors observed in nocturnal-hyperkynetic seizures. We speculate that seizure semiology represents the emergence of ‘innate’ motor behaviors encoded in subcortical central pattern generators.

2002 - "Hand to face": A behaviour modulated by epileptic seizures | ["La mano al viso": Un comportamento modulato dalle crisi epilettiche] [Articolo su rivista]
G., Cantalupo; Meletti, Stefano; F., Rondelli; M., Stanzani Maserati; C. A., Tassinari
abstract

Postictal nosewiping is commonly observed in temporal lobe epilepsy and is highly predictive of seizure onset ipsilateral to the hand used. Our aim was to quantify by videotape analysis all hand movements directed toward either the nose or mouth, eye, ear, front and scalp in the preictal, postictal, and interictal periods. We found that these movements represent a unique pattern of behaviour, facilitated in the postictal period, and not necessarily reflex movements triggered by ictal-related vegetative modifications.

2002 - Encephalopathy with electrical status epilepticus during slow sleep [Capitolo/Saggio]
C. A., Tassinari; G., Rubboli; L., Volpi; Meletti, Stefano; E., Gardella; G., D’Orsi; A., Zaniboni; F., Rondelli; C., Cagnetti; R., Michelucci
abstract

2002 - Hypomaniac confusional state in a patient with drug-resistant partial epilepsy: Ictal or post-ictal origin? | [Stato confusionale ipomaniacale in paziente con epilessia parziale farmaco-resistente: Origine critica o post-critica?] [Articolo su rivista]
F., Rondelli; G., Rubboli; L., Volpi; R., Pantieri; O., Odorici; Meletti, Stefano; C., Cagnetti; C. A., Tassinari
abstract

Introduction. Behavioural manifestations with psychiatric features can be observed in patients with focal epilepsy in the ictal and/or past-ictal period. We report a 46-year-old female patient with right mesial temporal sclerosis suffering from seizures that started at the age of 23, characterized by epigastric aura, early oroalimentary automatisms, and possible secondary generalisation. From the age of 25, recurring anxious-depressive episodes and persecutory aspects appeared, requiring repeated hospital admissions. Intercritical EEG showed paroxysmal activities in the right-temporal leads; ictal EEG showed and initial discharge in the right-temporal derivations, them omo- and controrolateral spread. The ictal SPECT indicated a right temporal focus. During a drug reduction for recording seizures, the patient presented, after a cluster of seizures, an episode of dysphoric behaviour, extreme agitation, preserved consciousness, continuous verbal production. No concomitant paroxismal EEG activity was evident. At first, this episode was transitorily interrupted by a typical seizure, then it was stopped by lorazepam e.v. administration. A psychiatric evaluation of the video-EEG recording of the episode diagnosed a "hypomaniac confusional state". Conclusions. The behavioural manifestations observed during the confusional state in our patient were extremely peculiar. The interruption of the episode, at first following a seizure, than after benzodiazepine administration might suggest a possible ictal nature.

2002 - Ictal pattern of EEG and muscular activation in symptomatic infantile spasms: a videopolygraphic and computer analysis [Articolo su rivista]
F., Bisulli; L., Volpi; Meletti, Stefano; G., Rubboli; E., Franzoni; M., Moscano; G., D'Orsi; C. A., Tassinari
abstract

PURPOSE: To investigate ictal muscular phenomena characterizing symptomatic infantile spasms (ISs) and their relation to ictal EEG. METHODS: Four children with severe encephalopathy, neurologic impairment, and refractory ISs related to different dysplastic lesions, underwent videopolygraphic recordings collecting surface electromyogram (EMG) activity from several cranial and limb muscles to evaluate the pattern of muscular recruitment, duration, and side-to-side asymmetry of ISs. Acquired data were stored for off-line analysis by a computerized polygraphic system. RESULTS: Spasms were characterized by a complex pattern of muscular activation. A constant or rostrocaudal propagation pattern was lacking in all patients. Intervals between the onset of EMG activity in different muscles in each spasm were very long: </=100-200 ms. Two patients, with hemispheric cortical dysplasia and agenesis of the corpus callosum, had asymmetric and asynchronous spasms in which the EMG onset of the muscles contralateral to the affected hemisphere constantly anticipated that of the ipsilateral ones. Backaveraging of EEG activity disclosed a high-amplitude EEG complex on the same side as the dysplastic lesion, preceding or succeeding the contralateral muscle activity onset. In the other two patients with diffuse cortical dysplasia, no EEG transient was related to EMG activity onset. CONCLUSIONS: Despite clinical similarity between spasms in the same patient, our data demonstrate the complexity and heterogeneity of these motor phenomena. Our findings cannot be explained simply in terms of cortical or reticular generators like other motor phenomena such as cortical myoclonus or startle reflex.

2002 - Impaired recognition of facial expression of emotion in epileptic subjects with mesial temporal sclerosis [Abstract in Rivista]
Meletti, Stefano; Benuzzi, Francesca; G., Rubboli; E., Gardella; G., Cantalupo; Nichelli, Paolo Frigio; C. A., Tassinari
abstract

2002 - Motor pattern of periodic limb movements in sleep in idiopathic RLS patients [Articolo su rivista]
G., Plazzi; R., Vetrugno; Meletti, Stefano; F., Provini
abstract

Objective: Periodic limb movements in sleep (PLMS) are recurrent sleep-related movements that often occur in association with restless legs syndrome (RLS). The purpose of the present study was to examine the pathophysiology of PLMS in patients with idiopathic RLS.Methods: Ten patients with idiopathic RLS who were medication-free or who had withdrawn from medication at least 2 weeks prior to the study underwent an extensive neurophysiological investigation that included nocturnal video-polysomnographic recording (VPSG), EMG recording, and the Multiple Sleep Latency Test (MSLT). Sleep efficiency and PLMS index were calculated during VPSG.Results: All patients had an increased PLMS index, decreased sleep efficiency, and a pathological MSLT score. Leg muscles were the first to be activated, often with alternation of side, and no constant recruitment pattern could be found from one episode of PLMS to another, even in the same patient. No ordinate caudal or rostral spread of the EMG activity was observed.Conclusions: The results suggest that there are different, independent, and unsynchronized generators for PLMS. The direct participation of the cerebral cortex in the origin of PLMS is unlikely, suggesting that abnormal spinal cord hyperexcitability may act as the primary cause of PLMS, triggered by unidentified sleep-related factors.

2002 - Polysomnographic study of sleeplessness and oneiricisms in the alcohol withdrawal syndrome [Articolo su rivista]
Plazzi, G.; Montagna, P.; Meletti, Stefano; Lugaresi, E.
abstract

We describe a polysomnographic observation of the acute phase of the alcohol withdrawal syndrome, characterized by an alteration of the sleep–wake cycle and by the absence of non-rapid eye movement sleep. An atypical transitional state between rapid eye movement sleep and wake with hallucinations and enacting-dream behaviors represented the sole sleep pattern. Analogies of alcohol withdrawal syndrome with fatal familial insomnia and Morvan’s fibrillary chorea suggest a common pathophysiological mechanism in these conditions.

2002 - Recognition of facial expressions of emotion in subjects with epilepsy and mesial temporal sclerosis | [Riconoscimento delle espressioni facciali emozionali in pazienti con epilessia e sclerosi temporo-mesiale] [Articolo su rivista]
Meletti, Stefano; Benuzzi, Francesca; G., Cantalupo; G., Rubboli; M., Stanzani Maserati; Nichelli, Paolo Frigio; C. A., Tassinari
abstract

The effect of unilateral amygdala damage on processing emotional stimuli is not clear. Since amygdala complex may be damaged unilaterally in subjects with Temporal Lobe Epilepsy (TLE), we examined the processing of emotional facial expression in TLE patients with MRI evidence of mesial temporal sclerosis (MTS). Emotion recognition was impaired in patients with right TLE and MTS at variance with epileptic subjects with other localization related epilepsy. The deficit in recognition was maximum for fearful faces. Moreover, during functional MRI patients with right MTS lacked the activation of separable mesial-temporal and frontal regions for the processing of fearful faces.

2001 - Acquired Epileptic Aphasia [Capitolo/Saggio]
C. A., Tassinari; Meletti, Stefano; G., Rubboli; R., Michelucci; L., Volpi; H., Brunnschweiler
abstract

The chapter describes the clinical, EEG, and cognitive consequences of continuous epileptic activity in sleep, or electrical status epilepticus during sleep (ESES).

2001 - Cortical myoclonus in Janz syndrome [Articolo su rivista]
F., Panzica; G., Rubboli; S., Franceschetti; G., Avanzini; Meletti, Stefano; A., Pozzi; C. A., Tassinari
abstract

OBJECTIVE: To evaluate the characteristics of EEG paroxysms and the relationship between EEG spikes and ictal myoclonic jerks in patients with juvenile myoclonic epilepsy (JME). METHODS: Six patients with a typical form of JME entered the study and underwent computerized polygraphic recordings. In each patient, the inter-peak spike interval was measured on repeated EEG bursts, and jerk-locked back averaging was performed on ictal epochs using a time window including the 100 ms before and the 100-200 ms after the point at which the jerk-related EMG potential diverged from baseline. RESULTS: In all cases, the myoclonic jerks were associated with polyspike waves (PSW) complexes. The frequency of repeated spikes within the PSW complex ranged from 16 to 27 Hz. Jerk-locked averaging revealed a positive-negative EEG transient with maximal amplitude on the frontal leads, which preceded the myoclonic jerk by 10.25+/-0.96 ms. A delay of 9.50+/-1.73 ms was measured between the jerk-locked positive peak detected on the frontal EEG leads of the two hemispheres; a comparable time lag was observed between the onset of myoclonic jerks in the two deltoid muscles. CONCLUSIONS: Our data suggest that the ultimate mechanism responsible for ictal myoclonic jerks in JME is largely similar to that sustaining cortical myoclonus in more severe pathological conditions such as progressive myoclonus epilepsies, despite the different pathogenic substrate and triggering mechanisms.

2001 - Electrical Status Epilepticus of Sleep [Capitolo/Saggio]
C. A., Tassinari; Meletti, Stefano; L., Volpi; G., Rubboli; R., Michelucci; H., Brunnschweiler
abstract

The chapter describes the EEG features of electrical status epilepticus during sleep in children.

2001 - Epileptic intermittent snoring [Articolo su rivista]
G., Rubboli; M., Zamagni; R., Michelucci; E., Gardella; A., Zaniboni; G., D'Orsi; Meletti, Stefano; M., Franca; A. R., Sabetta; C. A., Tassinari
abstract

Snoring is an inspiratory noise, from airflow-induced vibration ofthe oropharyngeal soft tissues during sleep.1 This vibration resultsfrom a narrowing of the upper airways, caused by a disequilibriumbetween two forces: the inspiratory increment of the intrathoracicpressure and the phasic activation of oropharyngealdilator muscles.1 Intermittent snoring (IS) is the result of interruptions due to apneas and hypopneas.1We report two epileptic patients whose polysomnographic(PSG) monitoring suggested that their IS was of epileptic origin.Recording parameters included EEG, electromyogram (EMG)from the mylohyoideus and both deltoids, electro-oculogram, EKG,oronasal and thoracic respiration (monitored with a thermistorand a strain gauge, respectively), and microphone. Both patientshad normal brain CT and MRI. Their seizures were incompletelycontrolled despite antiepileptic polytherapy.

2001 - Leber's hereditary optic neuropathy (LHON/11778) with myoclonus: report of two cases [Articolo su rivista]
V., Carelli; M. L., Valentino; R., Liguori; Meletti, Stefano; R., Vetrugno; F., Provini; G. L., Mancardi; F., Bandini; A., Baruzzi; P., Montagna
abstract

The previously unrecognised association of myoclonus in two patients with LHON with the 11778/ND4 pathogenic mutationis described. EEG failed to disclose epileptic figures, and a back averaging study suggested that myoclonus was cortical inorigin in both patients.

2001 - Motor pattern of periodic limb movements during sleep [Articolo su rivista]
Provini, F.; Vetrugno, R.; Meletti, Stefano; Plazzi, G.; Solieri, L.; Lugaresi, E.; Coccagna, G.; Montagna, P.
abstract

Background: The pathophysiology of periodic limb movements in sleep (PLMS) in restless legs syndrome (RLS) is unclear. Objective: The authors neurophysiologically investigated PLMS in patients with idiopathic RLS in order to obtain information on the origin and pathophysiology of the movements. Methods: Ten patients with idiopathic RLS underwent electromyography with nerve conduction velocity (EMG-CV), somatosensory evoked potentials (SEPs), transcranial magnetic stimulation (TMS), nocturnal videopolysomnography, and multiple sleep latency test. The authors analyzed 100 consecutive PLMS for each patient to determine how frequently each muscle was involved in the PLMS; how frequently EMG activity started in a given muscle; and the time delay and pattern of activation between the first and theother activated muscles. Results: EMG-CV, SEPs, and TMS findings were all normal; in PLMS, leg muscles were thosemore frequently involved, often with alternation of side. Axial muscles were rarely and upper limb muscles sometimesinvolved. The tibialis anterior was the most frequent starting muscle. There was no constant recruitment pattern from onePLMS episode to another, even in the same patient. There was no ordinate caudal or rostral spread of the EMG activity.Conclusion: The recruitment pattern indicates the engagement of different, independent, and sometimes unsynchronizedgenerators for each PLMS. The authors hypothesize an abnormal hyperexcitability along the entire spinal cord, especiallyits lumbosacral and cervical segments, as the primary cause of PLMS, triggered by sleep-related factors located at asupraspinal but still unresolved level.

2001 - Propriospinal myoclonus at the sleep-wake transition: a new type of parasomnia [Articolo su rivista]
R., Vetrugno; F., Provini; Meletti, Stefano; G., Plazzi; R., Liguori; P., Cortelli; E., Lugaresi; P., Montagna
abstract

STUDY OBJECTIVES: To describe the clinical, neurophysiological, and polysomnographic characteristics of propriospinal myoclonus (PSM) at the sleep-wake transition. DESIGN: Patients referred for insomnia due to myoclonic activity arising during relaxed wakefulness preceding sleep, or complaining of muscular jerks also during intrasleep wakefulness and upon awakening in the morning were considered. SETTING: All patients underwent EEG-EMG recordings during wakefulness and night sleep. Back-averaging of the EEG activity preceding the jerks was performed. Somatosensory evoked potentials (SEPs), transcranial magnetic stimulation (TMS) and spinal and cranial MRI were also done. PARTICIPANTS: Four patients were studied all affected with involuntary jerks arising when falling asleep, and one with jerks also during sleep and upon awakening in the morning. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Polysomnographic investigations revealed jerks arising during the sleep-wake transition period. Myoclonic activity was neurophysiologically documented to be of the propriospinal type. SEPs, TMS and MRI were normal CONCLUSIONS: PSM may have a peculiar relationship with the state of vigilance and represent a sleep-wake transition disorder. In this regard we consider PSM a new type of parasomnia.

2000 - A video-polygraphic analysis of the cataplectic attack [Articolo su rivista]
G., Rubboli; G., D'Orsi; A., Zaniboni; E., Gardella; M., Zamagni; R., Rizzi; Meletti, Stefano; F., Valzania; A., Tropeani; C. A., Tassinari
abstract

Objectives and methods: To perform a video-polygraphic analysis of 11 cataplectic attacks in a 39-year-old narcoleptic patient,correlating clinical manifestations with polygraphic fndings. Polygraphic recordings monitored EEG, EMG activity from several cranial, trunk, upper and lower limbs muscles, eye movements, EKG, thoracic respiration.Results: Eleven attacks were recorded, all of them lasting less than 1 min and ending with the fall of the patient to the ground. We identifed, based on the video-polygraphic analysis of the episodes, 3 phases: initial phase, characterized essentially by arrest of eye movements and phasic, massive, inhibitory muscular events; falling phase, characterized by a rhythmic pattern of suppressions and enhancements of muscular activity, leading to the fall; atonic phase, characterized by complete muscle atonia. Six episodes out of 11 were associated with bradycardia, that was maximal during the atonic phase.Conclusions: Analysis of the muscular phenomena that characterize cataplectic attacks in a standing patient suggests that the cataplectic fall occurs with a pattern that might result from the interaction between neuronal networks mediating muscular atonia of REM sleep and neural structures subserving postural control.

2000 - Encephalopathy with electrical status epilepticus during slow sleep or ESES syndrome including the acquired aphasia [Articolo su rivista]
C. A., Tassinari; G., Rubboli; L., Volpi; Meletti, Stefano; G., D'Orsi; M., Franca; A. R., Sabetta; P., Riguzzi; E., Gardella; A., Zaniboni; R., Michelucci
abstract

Encephalopathy with electrical status epilepticus during sleep or ESES is an age-dependent and self-limited syndrome whose distinctive features include a characteristic age of onset (with a peak around 4±5 years), heterogeneous seizures types (mostly partial motor or unilateral seizures during sleep and absences or falls while awake), a typical EEG pattern (with continuous and diffuse paroxysms occupying at least 85% of slow wave sleep) and a variable neuropsychological regression consisting of IQ decrease, reduction of language (as in acquired aphasia or Landau±Kleffner syndrome), disturbance of behaviour (psychotic states) and motor impairment (in the form of ataxia, dyspraxia,dystonia or unilateral defcit). Despite the long-term favourable outcome of epilepsy and status epilepticus during sleep (SES), the prognosis is guarded because of the persistence of severe neuropsychological and/or motor defcits in approximately half of the patients. No specifctreatment has been advocated for this syndrome, but valproate sodium, benzodiazepines and ACTH have been shown to control the seizuresand the SES pattern in many cases, although often only temporarily. Subpial transection is proposed in some instances as in non-regressiveacquired aphasia. Recent data support the concept that ESES syndrome may include a large subset of developmental or acquired regressiveconditions of infancy

2000 - Epileptic negative myoclonus and brief asymmetric tonic seizures. A supplementary sensorimotor area involvement for both negative and positive motor phenomena [Articolo su rivista]
Meletti, Stefano; P., Tinuper; F., Bisulli; M., Santucci
abstract

Epileptic negative myoclonus (ENM) is an epileptic motor dysfunction characterised by brief lapses of postural tone provoked by paroxysmal cortical discharges. We report the electrophysiological and video-polygraphic findings in a patient presenting with the unusual association of ENM and brief asymmetric tonic-postural seizures of cryptogenetic origin. Focal EMG silent periods in the left deltoid muscle (mean duration 81.2 +/- 16.4 ms), time-locked with vertex spikes were present. The time lag between spikes and ENM was 33.1 +/- 4.6 ms. We suggest the involvement of mesial frontal areas in the genesis of both negative and positive motor phenomena.

2000 - Hypertension, hyperekplexia, and pyramidal paresis due to vascular compression of the medulla [Articolo su rivista]
F., Salvi; M., Mascalchi; C., Bortolotti; Meletti, Stefano; R., Plasmati; G., Rubboli; S., Stecchi; N., Villari; F., Calbucci; C. A., Tassinari
abstract

MRI showed impingement of the vertebral artery on theleft lateral medulla in two patients with arterial hypertension, exaggerated startle reflexes (hyperekplexia), and progressive spastic paresis. One patient underwent microvascular decompression with normalization of arterial hypertension,disappearance of hyperekplexia, and improvement of spastic paresis. The combination of arterial hypertension, hyperekplexia, and progressive spastic paresis should arouse suspicion of neurovascular compression of the lateral medulla.

2000 - Intermittent falls and fecal incontinence as a manifestation of epileptic negative myoclonus in idiopathic partial epilepsy of childhood [Articolo su rivista]
G., Capovilla; G., Rubboli; F., Beccaria; S., Meregalli; P., Veggiotti; P. N., Giambelli; Meletti, Stefano; C. A., Tassinari
abstract

We report two children, suffering from idiopathic partialepilepsy, who started to present, in the same period of time,with epileptic negative myoclonus (ENM) in one lower limb andfecal incontinence (FI). Polygraphic recordings showed thatENM was associated with paroxysmal activities distributed overthe vertex region. Both ENM and FI disappeared when ethosuximide treatment was started. We hypothesize that, in our patients, ENM in one lower limb and FI depended on a transitoryimpairment, caused by epileptic activity that altered the functionality of nearby cortical areas, located in fronto-mesial regions, involved in the control of the muscular tone of the lowerlimbs and of the pelvic floor muscles.

1999 - 'Progressive Myoclonus Epilepsy' in a Down Syndrome patient with Alzheimer's Disease | ['Epilessia Mioclonica Progressiva' in paziente affetta da Sindrome di Down con Malattia di Alzheimer] [Articolo su rivista]
L., Vignatelli; Meletti, Stefano; G., Ambrosetto
abstract

Progressive Myoclonus Epilepsy (PME) has been reported to be an unusual manifestation of early-onset Alzheimer's Disease. We describe the case of a 46-year-old woman with Down Syndrome (47, XX +21), who developed a PME-like epilepsy together with an Alzheimer type deterioration. Our neurophysiological findings seem to confirm the peculiarity of this association also in Down Syndrome.

1999 - Bilateral centrotemporal spikes triggered by blinking: an unusual form of sensory input with related cortical EEG activity [Articolo su rivista]
Vetrugno, R.; Meletti, Stefano; Plazzi, G.; Posar, A.; Santucci, M.; Rossi, P. G.; Lugaresi, E.; Liguori, R.
abstract

Objective: To investigate the morphology, scalp topography and temporal relationship with orbicularis oculi muscle contraction ofbilateral blink related spikes (BRS) in a 7-year-old boy with chromosomopathy, mild mental retardation and left spontaneous centrotemporal spikes (SS).Methods: The patient underwent video-polygraphic recordings with off-line analysis of SS and BRS by means of spike-averaging and orbicularis oculi contraction-locked averaging techniques respectively. EEG activity related to reflex blinking (evoked by glabellar tapping) was also studied.Results: SS and BRS presented the same morphology, characterised by four peaks (P1, N1, P2, N2). SS were located over the left centroparietal regions, while BRS were placed over both left and right centrotemporoparietal regions and constantly followed the contraction of orbicularis oculi with overlapping peak latencies over C3 and C4 electrodes (P1 72 ms; N1 115 ms; P2 164 ms; N2 236 ms). Refex blinking evoked a small waveform with the same features as BRS.Conclusions: Our fndings suggest that both involuntary and reflex blinking can act as a form of sensory stimulation probably engaging similar nervous pathways and cortical sources in generating EEG abnormalities: the trigeminal system.

1999 - Correlations of perioral myoclonia and paroxysmal EEG activity: A neurophysiological study | [Correlazioni tra anomalie EEG parossistiche e mioclonie peribuccali: Studio neurofisiologico] [Articolo su rivista]
E., Gardella; G., Rubboll; G., D'Orsi; Meletti, Stefano; L., Volpi; A., Zaniboni; S., Testoni; C. A., Tassinari
abstract

We studied 3 patients, 2 with Myoclonic Absences Epilepsy (MAE) and 1 with Rolandic Epilepsy (RE), presenting with perioral myoclonia associated with EEG paroxysmal activity. Neurophysiological investigations showed a correlation between the positive transient (PT) encompassed in the generalized (MAE patients) or centro-temporal predominant (RE patient) spike and wave complex and myoclonia in orbicularis oris muscle. In MAE patients PT of one side preceded the contralateral with alternating driving side, whereas in RE patient PT in the right region constantly preceded the contralatera

1999 - Ethosuximide is effective in the treatment of epileptic negative myoclonus in childhood partial epilepsy [Articolo su rivista]
G., Capovilla; F., Beccaria; P., Veggiotti; G., Rubboli; Meletti, Stefano; C. A., Tassinari
abstract

The aim of our study was to evaluate the effectiveness of ethosuximide in the treatment of epileptic negative myoclonus, a motor disorder that can occur in childhood partial epilepsy. We introduced ethosuximide in nine patients with partial epilepsy of varying etiology (idiopathic, cryptogenic, symptomatic) who presented with epileptic negative myoclonus. The drug was added to the patients' preexisting antiepileptic drugs, which were maintained unchanged for the following 6 months. Epileptic negative myoclonus disappeared in all patients 15 to 30 days after ethosuximide was started. Plasma ethosuximide levels ranged from 55 to 89 micrograms/mL. The clinical response was not influenced by the patients' preexisting treatment or by the etiology of the epilepsy. No side effects were observed, and none of the patients presented a recurrence of epileptic negative myoclonus during follow-up. Furthermore, in five patients we observed the disappearance of partial seizures; in the remaining patients seizures were reduced by more than 75%. Electroencephalograms showed a decrement or disappearance of focal paroxysmal abnormalities. Our results suggest that ethosuximide is effective in the treatment of epileptic negative myoclonus and that it should be considered as a first-choice drug in the treatment of this motor disorder.

1999 - Interictal and ictal EEG-SPECT correlations in a patient with partial seizures and mesial temporal sclerosis [Articolo su rivista]
Meletti, S.; D'Orsi, G.; Rubboli, G.; Michelucci, R.; Dondi, M.; Bernardi, B.; Zaniboni, A.; Gardella, E.; Testoni, S.; Bisulli, A.; Tassinari, C. A.
abstract

We studied a 26 year-old patient with partial seizures and right mesial temporal sclerosis by means of computerized video-EEG monitoring and SPECT. Ictal seizures semiology was compatible with mesial temporal seizures. Dipole modeling of interictal and ictal paroxysmal activities and peri-postictal SPECT were consistent with involvement of the anterior-middle portion of the right temporal lobe, in accordance with MRI findings. These results show the usefulness of a multimodal approach, combining neuroimaging and neurophysiological techniques to obtain non-invasive information on the epileptogenic area.

1999 - Interictal and ictal EEG-SPECT correlations in a patient with partial seizures and mesial temporal sclerosis | [Correlazioni EEG-SPECT intercritiche e critiche in un paziente con sclerosi temporale mesiale] [Articolo su rivista]
Meletti, Stefano; G., D'Orsi; G., Rubboli; R., Michelucci; M., Dondi; B., Bernardi; A., Zaniboni; C. A., Tassinari
abstract

We studied a 26 year-old patient with partial seizures and right mesial temporal sclerosis by means of computerized video-EEG monitoring and SPECT. Ictal seizures semiology was compatible with mesial temporal seizures. Dipole modeling of interictal and ictal paroxysmal activities and peri-postictal SPECT were consistent with involvement of the anterior-middle portion of the right temporal lobe, in accordance with MRI findings. These results show the usefulness of a multimodal approach, combining neuroimaging and neurophysiological techniques to obtain non-invasive information on the epileptogenic area.

1999 - Late onset myoclonic epilepsy in a patient with mitochondrial encephalomyopathy: A clinical, polygraphic and biochemical study | [Epilessia mioclonica a esordio tardivo in un caso di encefalopatia mitocondriale: Studio clinico, poligrafico e biochimico] [Articolo su rivista]
P., Riguzzi; G., D'Orsi; Meletti, Stefano; R., Rizzi; G., Rubboll; L., Monari; A., Zaniboni; C. A., Tassinari
abstract

We describe a 60 years-old patient presenting with late onset myoclonic seizures, progressive neurological impairment and mental deterioration. Neurophysiological investigations showed marked photosensitivity, a startle reaction, a cortical-subcortical myoclonus. Biochemical study on muscle and skin biopsy was consistent with mitochondrial encephalomyopathy.

1999 - Neurological and neurophysiological follow-up in patients with Crigler-Najjar syndrome type I and possible implications for the timing of liver transplantation [Articolo su rivista]
Rubboli, G.; Ronchi, F.; Cecchi, P.; Meletti, S.; Gardella, E.; Zaniboni, A.; D'Orsi, G.; Testoni, S.; Bisulli, A.; Tassinari, C. A.
abstract

In children and adolescents suffering from Crigler-Najjar syndrome type I, the most worrisome complication is the possible appearance of neurological disorders with aging. We report the results of a neurological and neurophysiological assessment in 6 patients (age range 5-26 years) suffering from Crigler-Najjar syndrome type I. Our results indicate that, in children and adolescents with Crigler-Najjar syndrome type I, neurophysiological tests, such as EEG-polygraphic recordings, are sensitive techniques to demonstrate the involvement of the central nervous system and to evaluate the efficacy of the treatment (i.e., liver transplantation in one of our patients), therefore suggesting a possible usefulness of these neurophysiological techniques for the timing of liver transplantation.

1999 - Neurophysiological features of epileptic negative myoclonus in a patient with partial epileptic seizures and centro-parietal dysplastic lesion | [Caratteristiche neurofisiologiche nel mioclono epilettico negativo in un paziente con crisi parziali motorie e lesione centro-parietale] [Articolo su rivista]
A., Zaniboni; Meletti, Stefano; P., Riguzzi; G., Rubboli; E., Gardella; G., D'Orsi; A., Bisulli; C. A., Tassinari
abstract

We report the neurophysiological features of epileptic negative myoclonus (ENM) involving the right upper limb in a patient with partial seizures and left centro-parietal dysplasic lesion. Our findings suggest a role of the lesion or/and the sensori-motor cortex in its in the generation of ENM.

1999 - Photic reflex myoclonus: a neurophysiological study in progressive myoclonus epilepsies [Articolo su rivista]
G., Rubboli; Meletti, Stefano; E., Gardella; A., Zaniboni; G., D'Orsi; C., Dravet; C. A., Tassinari
abstract

PURPOSE: To investigate the neurophysiological features of photic reflex myoclonus (PRM) in patients with progressive myoclonus epilepsies (PMEs) of different types (Unverricht-Lundborg disease, Lafora's disease, cryptogenic). METHODS: All patients underwent computerized video-polygraphic recordings, collecting electromyographic (EMG) activity from several cranial and limb muscles. PRM was elicited by intermittent photic stimulation (IPS). RESULTS: IPS could evoke PRM with a 1:1 relation at frequencies up to 12 Hz. Back-average of the EEG, triggered from the onset of PRM at the upper limbs, showed a contralateral positive-negative transient in central region, preceded by approximately 10 ms by a similar, ipsilateral occipital wave. When IPS induced bilateral jerking, a time lag of approximately 10 ms between the homologous muscles of the two sides was observed, paralleled by a similar delay between the associated contralateral EEG transients in the two central regions, suggesting spread of cortical myoclonic activity from one hemisphere to the other via transcallosal fibers. PRM propagated in different cranial and limb muscles according to a rostrocaudal pattern, with latencies compatible with a transmission along fast-conducting corticospinal motor pathways. CONCLUSIONS: In our PME patients, PRM presented uniform neurophysiological features, indicating the participation of both occipital and motor cortices, with bilateral spread presumably mediated by transcallosal connections and propagation down the spinal cord via fast-conducting corticospinal pathways.

1999 - Right mesial temporal sclerosis and left temporal seizures? Description of a case [Abstract in Rivista]
R., Pamieri; Meletti, Stefano; A., Zanihoni; G., D'Orsi; E., Gardella; A., Bisulli; S., Testoni; C. A., Tassinari
abstract

Objective To report the diagnostic problems in the non-invasive presurgical evaluation of a patient with temporal lobe epilepsy. Materials and methods We studied a 34-year-old woman who presented prolonged febrile convulsions at 2 years of age, suffering from daily automotor seizures since the age of 3. The patient underwent sleep and awake EEG recordings, prolonged video-EEG monitoring and cranial MRI. Results MRI disclosed right mesial temporal sclerosis. Interjetai EEG showed paroxysmal activities over the right temporal region and less frequent independent left temporal spikes. We recorded by means of videoEEG five seizures. Clinical ictal semiology was characterized by an epigastric aura followed by right head and eye deviation, oro-alimentary and right arm automatisms together with a distonic posturing of the left arm and finally a right hand nose-wiping. These findings suggested a right temporal lobe involvement. Ictal EEG was characterized by a rhythmic sharp theta activity on the left temporal regions. Conclusions Ictal seizure semiology and neuroradiological data in accordance suggested right temporal lobe involvement. On the contrary ictal EEG suggested a left temporal seizure onset. With such a discrepancy, are deep electrode studies mandatory to localize the epileptogenic area?

1999 - Right mesial temporal sclerosis and left temporal seizures? Description of a case | [Sclerosi temporale mesiale (STM) destra e crisi temporali sinistre: Epilessia sintomatica a destra e criptogenetica a sinistra? Discussione di un caso] [Articolo su rivista]
R., Pantieri; Meletti, Stefano; A., Zaniboni; G., D'Orsi; E., Gardella; F., Bisulli; S., Testoni; C. A., Tassinari
abstract

We studied a patient suffering from partial seizures whose both seizures semiology and neuroradiological data suggested a right temporal lobe focus. However, ictal EEG may suggest a left temporal seizures onset. This example case is discussed rising the issues whether, in circumstances like this it is mandatory the use of depth electrode studies.

1998 - A video-polygraphic study of the cataplectic attack | [Studio video-poligrafico della caduta cataplettica] [Articolo su rivista]
G., Rubboli; G., D'Orsi; A., Zaniboni; E., Gardella; M., Zamagni; Meletti, Stefano; R., Rizzi; C., Tassinari
abstract

We studied, by means of video-polygraphic techniques, the clinical and polygraphic features of 7 cataplectic attacks in a patient with narcolepsy. Clinically, the cataplectic attacks were characterized by progressively increasing losses of the postural tone of cranial and limb muscles, that corresponded, in the polygraphic tracing, to a pattern of rhythmic suppression and enhancement of EMG activity. These findings suggests that the cataplectic fit occurs through a complex modulation, with inhibitory and excitatory phenomena, of the postural control system.

1998 - Blink induced epileptiform EEG activity in a patient with chromosomopathy | [Anomalie EEG indotte da ammiccamento palpebrale in paziente con cromosomopatia] [Articolo su rivista]
M., Santucci; A., Posar; R., Vetrugno; Meletti, Stefano; A., Baroncini; A., Cassetti; P., Giovanardi Rossi
abstract

We describe a 7 year old boy, who presented centro-temporal (C-T) spikes triggered by blinking. The clinical picture was characterized by mild mental retardation and dysmorphisms; epileptic seizures were absent. Karyotype revealed a 13q deletion. EEG showed independent bilateral C-T paroxysmal abnormalities, very increased during sleep. From the age of 5.5 years blinking triggered C-T spikes: neither eye closure nor elimination of visual fixation induced this phenomenon. Rare similar cases are described in literature

1997 - A neurophysiological study in children and adolescents with Crigler-Najjar syndrome type I [Articolo su rivista]
G., Rubboli; F., Ronchi; P., Cecchi; R., Rizzi; E., Gardella; Meletti, Stefano; A., Zaniboni; L., Volpi; C. A., Tassinari
abstract

We studied the neurophysiological features of five patients (age range: 4-20 years) suffering from Crigler-Najjar syndrome type I (CNsI) by means of multimodal (brainstem, somatosensory, motor) evoked potentials and periodic EEG-polygraphic recordings (follow-up: 3 months-4.5 years). Two patients presented with neurological disturbances, consisting mainly of mental slowing, motor impairment and seizures. Both of them presented an abnormal EEG, characterized by slowing of background activity associated with paroxysmal discharges. Liver transplantation was performed in one of these two patients and was followed by improvement of both the neurological picture and EEG activity. In a third patient, clinically normal, after two years of follow-up, the EEG started to show paroxysmal activity during sleep or when evoked by intermittent photic stimulation. In these three patients, multimodal evoked potentials were unremarkable. The remaining two younger subjects did not show any clinical or EEG abnormality. Our findings suggest that, whereas in newborns and infants evoked potentials have been demonstrated as reliable techniques to monitor bilirubin neurotoxicity, in children and adolescents with CNsI, EEG seems to be more sensitive in evaluating patients for neurological damage and effectiveness of therapeutic strategies adopted.

1997 - Clinical and Neurophysiological features of different forms of epileptic falls [Relazione in Atti di Convegno]
G., Rubboli; R., Michelucci; F., Valzania; L., Parmeggiani; Meletti, Stefano; E., Gardella; R., Rizzi; A., Zaniboni; C. A., Tassinari
abstract

Falling seizures are a heterogeneous group of epileptic seizures in which the fail represents the main or only clinical manifestation. In this chapter, we discuss the clinical and neurophysiological characteristics of focal atonic epileptic events, such as epileptic negative myoclonus, and of different types of epileptic falling seizures, occurring in generalized and partial epilepsies. Pathophysiological hypotheses on epileptic negative myoclonus indicate the involvement of frontal areas with inhibitory effect on the motor system. Current knowledge on basic mechanisms of epileptic falling seizures is still limited; subcortical as well as cortical mechanisms have been suggested to play a role in the origin of these types of seizures. Appropriate neurophysiological investigations, particularly video-polygraphic recordings, have been, so far, extremely useful to describe the electroclinical characteristics of these phenomena, and it is conceivable that a more diffuse application of these techniques will provide further insights on the different types of falling seizures and their pathophysiological mechanisms.

1997 - Dipole source estimation suggests similar generators for spontaneous spikes, tapping evoked spikes and N60 SEP component in benign rolandic epilepsy | [Il calcolo delle sorgenti suggerisce generatori simili per le punte spontanee, le punte evocate da tapping e la componente N60 dei PES nell'epilessia benigna a punte rolandiche] [Articolo su rivista]
G., Rubboli; R., Plasmati; L., Parmeggiani; Meletti, Stefano; E., Gardella; F., Pastorelli; G., D'Orsi; C. A., Tassinari
abstract

We used dipole source localization methods to model the generators of spontaneous spikes, hand tapping evoked spikes and giant N60 component of somatosensory evoked potentials in children with benign epilepsy with rolandic spikes. We obtained similar dipole solutions for spontaneous and hand tapping evoked spikes, and for the N60 component, suggesting that these phenomena might result from the activation of similar hyperexcitable cortical regions, including somatosensory cortex

1997 - Neurophysiological mechanisms of paroxysmal motor manifestation, induced by visual stimulation, in photosensitive epilepsies | [Meccanismi neurofisiologici delle manifestazioni motorie nelle epilessie fotosensibili] [Articolo su rivista]
G., Rubboli; Meletti, Stefano; A., Strafella; A., Zaniboni; F., Pastorelli; F., Valzania; C. A., Tassinari
abstract

Myoclonus is the most common motor clinical manifestation of photosensitivity. We investigated, by means of computerized video-polygraphic techniques, the neurophysiological characteristics of photic-induced myoclonia in four patients with progressive myoclonus epilepsies and marked photosensitivity. In all four patients, intermittent photic stimulation induced either focal or massive myoclonic jerks. Myoclonic jerks at the limbs were associated with a contralateral cortical potential, whose peak preceded the onset of the myoclonic potential by a latency compatible with a conduction along direct cortico-spinal pathways. Propagation of photic- induced myoclonia in different cranial and limb muscles followed a rostro- caudal pattern. Our findings indicate a cortical origin of photic-induced myoclonia in PME, with neurophysiological features similar to those described in photic cortical reflex myoclonus.

1997 - Propriospinal myoclonus: Clinical and polygraphic features in 5 cases [Articolo su rivista]
Montagna, P.; Plazzi, G.; Liguori, R.; Meletti, Stefano; Provmi, F.; Cevoli, S.; Lugaresi, E.
abstract

Propriospinal Myoclonus (PSM) is characterized by jerks arising within the cord and propagating rostrally and caudally at low velocity, probably along propnospmal pathways intrinsic to the cord. In the last years we have encountered 5 males aged between 41 to 73 years displaying the clinical and polygraphic features of PSM PSM had set in all without any recognizable trigger, and neurological examination and MRI of cord and brain were normal in all except one patient who had an arachnoid cyst at the level of the T9 left root. EMG showed that the jerks arose in spinally innervated muscles, usually the thoracic or lumbar segments; the jerks were thereafter propagated to rostral and caudal muscles at velocities of 3 to 16 m/s, according to a propriospinal pattern of propagation. Polygraphic studies showed that in 4 cases the jerks occurred quasirhythmically only during periods of relaxed wakefulness, when EEG alpha activity spread to anterior regions. Any mental activation and sleep inhibited the PSM. In the 5th case, some features of the restless legs syndrome were found, and the jerks lasted into light sleep. PSM responded partially to clonazepam or tramadol. PSM is a peculiar movement disorder arising in the spinal cord but subjected to supraspinal influences during the various wake and sleep stages. It may represent a cause of severe insomnia.

1996 - Neurophysiological study of paroxysmal EEG activity during 'electrical status epilepticus during sleep' in a patient with Landau-Kleffner syndrome | [Studio neurofisiologico delle attivita parossistiche durante 'stato di male elettrico durante il sonno' in un paziente con sindrome di Landau- Kleffner] [Articolo su rivista]
G., Rubboli; L., Volpi; L., Parmeggiani; Meletti, Stefano; E., Gardella; M., Zamagni; F., Pastoralli; F., Bisulli; A., Zaniboni; P., Riguzzi; R., Rizzi; C. A., Tassinari
abstract

We have investigated paroxysmal activity during 'Electrical Status Epilepticus during Slow Sleep' in a patient with Landau-Kleffner syndrome by means of computerized EEG techniques. Our findings showed that, despite the diffuse distribution of the EEG paroxysms during ESES, a left fronto-temporal focus drove bilateral epileptic activity with a time lag between the two hemispheres of about 35-40 msec

1995 - Epileptic negative myoclonus [Articolo su rivista]
C. A., Tassinari; G., Rubboli; L., Parmeggiani; F., Valzania; R., Plasmati; P., Riguzzi; R., Michelucci; L., Volpi; D., Passarelli; Meletti, Stefano
abstract

The article describes and define the clinical and neurophysiological features of epileptic negative myoclonus in different epilepsy syndromes. The techniques of investigation are described, from EEG to transcranial magnetic stimulation.