Publications by authors named "Francesco Deleo"

35 Publications

Rage and aggressive behaviour in frontal lobe epilepsy: description of a case and review of the mechanisms of aggressive behaviour in epilepsy and dementia.

Epileptic Disord 2021 Apr 29. Epub 2021 Apr 29.

Epilepsy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy, Division of Clinical Neurophysiology and Epilepsy Center, IRCCS Ospedale Policlinico San Martino, Genova, Italy.

The study of dementia and epilepsy may provide particular insight into behavioural alterations. We describe a rare case of ictal aggressive behaviour in a patient with focal epilepsy associated with a non-dominant dorso-lateral prefrontal lesion. During focal seizures, our patient showed intense agitation and anger, for a long time misinterpreted as psychogenic attacks, which disappeared after epilepsy surgery. The defined anatomical origin of such ictal emotional behaviour is not fully understood, however, the dorso-lateral prefrontal area appears to correlate less frequently with aggressiveness compared to the antero-mesial area. We describe the electroclinical data of our patient and provide a brief review of the mechanisms underlying aggressive conduct in epilepsy and dementia. An understanding of this mechanism could help to clarify the neural basis and treatment of violence associated with these and other neurological disorders. [Published with video sequence].
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http://dx.doi.org/10.1684/epd.2021.1277DOI Listing
April 2021

Dendritic pathology, spine loss and synaptic reorganization in human cortex from epilepsy patients.

Brain 2021 02;144(1):251-265

Epilepsy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.

Neuronal dendritic arborizations and dendritic spines are crucial for a normal synaptic transmission and may be critically involved in the pathophysiology of epilepsy. Alterations in dendritic morphology and spine loss mainly in hippocampal neurons have been reported both in epilepsy animal models and in human brain tissues from patients with epilepsy. However, it is still unclear whether these dendritic abnormalities relate to the cause of epilepsy or are generated by seizure recurrence. We investigated fine neuronal structures at the level of dendritic and spine organization using Golgi impregnation, and analysed synaptic networks with immunohistochemical markers of glutamatergic (vGLUT1) and GABAergic (vGAT) axon terminals in human cerebral cortices derived from epilepsy surgery. Specimens were obtained from 28 patients with different neuropathologically defined aetiologies: type Ia and type II focal cortical dysplasia, cryptogenic (no lesion) and temporal lobe epilepsy with hippocampal sclerosis. Autoptic tissues were used for comparison. Three-dimensional reconstructions of Golgi-impregnated neurons revealed severe dendritic reshaping and spine alteration in the core of the type II focal cortical dysplasia. Dysmorphic neurons showed increased dendritic complexity, reduction of dendritic spines and occasional filopodia-like protrusions emerging from the soma. Surprisingly, the intermingled normal-looking pyramidal neurons also showed severe spine loss and simplified dendritic arborization. No changes were observed outside the dysplasia (perilesional tissue) or in neocortical postsurgical tissue obtained in the other patient groups. Immunoreactivities of vGLUT1 and vGAT showed synaptic reorganization in the core of type II dysplasia characterized by the presence of abnormal perisomatic baskets around dysmorphic neurons, in particular those with filopodia-like protrusions, and changes in vGLUT1/vGAT expression. Ultrastructural data in type II dysplasia highlighted the presence of altered neuropil engulfed by glial processes. Our data indicate that the fine morphological aspect of neurons and dendritic spines are normal in epileptogenic neocortex, with the exception of type II dysplastic lesions. The findings suggest that the mechanisms leading to this severe form of cortical malformation interfere with the normal dendritic arborization and synaptic network organization. The data argue against the concept that long-lasting epilepsy and seizure recurrence per se unavoidably produce a dendritic pathology.
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http://dx.doi.org/10.1093/brain/awaa387DOI Listing
February 2021

Epilepsy course during COVID-19 pandemic in three Italian epilepsy centers.

Epilepsy Behav 2020 11 25;112:107375. Epub 2020 Aug 25.

Division of Clinical Neurophysiology and Epilepsy Center, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, Genova, Italy.

During epidemic outbreaks, epilepsy course can be modified by different physical and psychological stressors and, most importantly, by irregular therapy intake. The effect of COVID-19 and quarantine isolation on the course of epilepsy and on incidence of new-onset seizures is still unclear. With the aim of managing epilepsy in quarantined patients, three Italian Epilepsy Centers set up telephone consultations using a semistructured interview, allowing a prospective collection of data on seizure course and other seizure-related problems during pandemic. The collected data on seizure course were compared with the analogous period of 2019. The level of patients' concern relating to the COVID-19 pandemic was also assessed using a numeric rating scale. To address the effect of COVID-19 pandemic on seizure incidence, data collection included the number of consultations for first seizures, relapse seizures, and status epilepticus (SE) in the emergency department of one of the participating centers. Clinical telephone interviews suggest the absence of quarantine effect on epilepsy course in our cohort. No differences in incidence of emergency consultations for seizures over a two-month period were also observed compared with a control period. As demonstrated in other infective outbreaks, good antiepileptic drug (AED) supplying, precise information, and reassurance are the most important factors in chronic conditions to minimize psychological and physical stress, and to avoid unplanned treatment interruptions.
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http://dx.doi.org/10.1016/j.yebeh.2020.107375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445187PMC
November 2020

Whole-brain multimodal MRI phenotyping of periventricular nodular heterotopia.

Neurology 2020 10 14;95(17):e2418-e2426. Epub 2020 Aug 14.

From the Neuroimaging of Epilepsy Laboratory (F.D., S.-J.H., F.F., B.C., S.K., N.B., A.B.), Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada; and Epilepsy Unit (F.D.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Objective: To test the hypothesis that in periventricular nodular heterotopia (PVNH) structure and function of cortical areas overlying the heterotopic gray matter are preferentially affected.

Methods: We studied a group of 40 patients with PVNH and normal-appearing cortex and compared their quantitative MRI markers of brain development, structure, and function to those of 43 age- and sex-matched healthy controls. Inspired by models of neocortical development suggesting that neuronal migration follows a curvilinear path to preserve topologic correspondence between the outer ventricular zone and the cortical surface, we computationally defined the overlying cortex using the Laplace equation and generated synthetic streamlines that link the ventricles, where nodules are located, and the neocortex.

Results: We found multilobar cortical thickening encompassing prefrontal, latero-basal temporal, and temporoparietal cortices largely corresponding with the PVNH group-averaged map of the overlying cortex, the latter colocalized with areas of abnormal function, as defined by resting-state fMRI. Patients also presented hippocampal functional hyperconnectivity and malrotation, the latter positively correlating with neocortical maldevelopment indexed by increased folding complexity of the parahippocampus. In clusters of thickness and curvature findings, there were no significant differences between unilateral and bilateral PVNH; contrasting brain-wide metrics between cohorts was also unrevealing. There was no relationship between imaging markers and disease duration except for positive correlation with functional anomalies.

Conclusion: Our quantitative image analysis demonstrates widespread structural and functional alterations in PVNH with differential interaction with the overlying cortex and the hippocampus. Right hemispheric predominance may be explained by an early insult, likely genetically determined, on brain morphogenesis.
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http://dx.doi.org/10.1212/WNL.0000000000010648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682914PMC
October 2020

Quality of life, psychiatric symptoms, and stigma perception in three groups of persons with epilepsy.

Epilepsy Behav 2020 09 5;110:107170. Epub 2020 Jun 5.

Epilepsy Unit, Neurological Institute C. Besta IRCCS Foundation, Via Celoria 11, 20133 Milan, Italy; Division of Clinical Neurophysiology and Epilepsy Center, IRCCS Ospedale San Martino, Largo R. Benzi 10, 16132 Genova, Italy.

Objective: The current study aimed to describe quality of life (QoL) levels, psychiatric symptoms prevalence, and perceived stigma levels in persons with either drug-resistant epilepsy (DRE) or drug-sensitive epilepsy (DSE) and in persons with epilepsy (PwE) with DRE that underwent epilepsy surgery (DREES).

Methods: Persons with epilepsy diagnosed as having DRE according to International League Against Epilepsy (ILAE) criteria, DSE, and DREES were enrolled at the Epilepsy Unit of the Neurological Institute Carlo Besta of Milan. Sociodemographic and clinical data, Quality of Life in Epilepsy Inventory (QOLIE-31), Symptom Checklist-90 (SCL-90), and the Epilepsy Stigma Scale (ESS) were collected based on self-reported information and on medical records.

Results: Sociodemographic, medical, and psychological data were obtained from 181 PwE: 80 with DRE, 31 with DSE, and 70 with DREES. We found that QoL is higher and psychiatric symptoms are lower in persons with DSE compared with DRE and that patients with DREES, who were drug-resistant before surgery, are in between DSE and DRE for both measures. Perceived stigma level is different in DSE and in DRE, that report the highest levels of stigma, and is between the other two groups in DREES.

Significance: This study suggests that low QoL levels and high psychiatric symptoms prevalence in drug-resistant PwE may be significantly improved after epilepsy surgery and suggests the importance of a biopsychosocial approach when planning therapeutic intervention.
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http://dx.doi.org/10.1016/j.yebeh.2020.107170DOI Listing
September 2020

Expanding clinical spectrum of Caspr2 antibody-associated disease: warning on brainstem involvement and respiratory failure.

J Neurol Sci 2020 06 28;413:116865. Epub 2020 Apr 28.

Epilepsy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; Division of Clinical Neurophysiology and Epilepsy Center, IRCCS Ospedale Policlinico San Martino, Genova, Italy.

We report the case of a 68-year-old man who presented with ataxia, insomnia, rapidly developing cognitive decline, seizures and small vessel vasculitis. Both serum and cerebro-spinal fluid samples showed positive titre of anti-CASPR2 antibodies. Limbic encephalitis was diagnosed and immunomodulatory therapy was started with benefit. After one-year follow-up, the patient relapsed with a difficult-to-treat respiratory failure, brainstem involvement, neuropathic pain and severe dysautonomia with esophageal dysfunction. We discuss here the occurrence of life-threating complication such as respiratory dysfunction in CASPR2 limbic encephalitis. Furthermore, we showed different phenotype and treatment response during disease onset compared to relapse. This case expands the clinical spectrum of anti-CASPR2 associated disease, underlying the need for respiratory and sleep evaluation.
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http://dx.doi.org/10.1016/j.jns.2020.116865DOI Listing
June 2020

How deep do we have to go? Recurrent episodes of aura continua with psychic symptoms may be misdiagnosed without intracranial recordings.

Clin Neurophysiol 2020 02 22;131(2):580-582. Epub 2019 Nov 22.

Epilepsy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133 Milan, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.clinph.2019.11.007DOI Listing
February 2020

Predictive value of high titer of GAD65 antibodies in a case of limbic encephalitis.

J Neuroimmunol 2019 12 10;337:577063. Epub 2019 Sep 10.

Epilepsy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; Division of Clinical Neurophysiology, Policlinico IRCCS San Martino, Genova, Italy. Electronic address:

We report the case of a 42-year-old woman who presented with vertigo and migraine and rapidly developed cognitive decline and seizures. Both serum and cerebro-spinal fluid samples showed high titer of anti-glutamic acid decarboxylase (anti-GAD65) antibodies (998,881 IU/ml and 54,687 IU/ml respectively). Limbic encephalitis was diagnosed and high dose steroids treatment started. During one-year follow-up, without further immunomodulatory therapy, the patient became seizure free, and cognitive functions returned to normal. Serum anti-GAD65 antibodies titer decreased significantly but remained elevated (192,680 IU/ml). We discuss the prognostic and pathogenic value of high titer anti-GAD65 antibodies and its variations in a case of autoimmune limbic encephalitis.
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http://dx.doi.org/10.1016/j.jneuroim.2019.577063DOI Listing
December 2019

The impact of perampanel treatment on quality of life and psychiatric symptoms in patients with drug-resistant focal epilepsy: An observational study in Italy.

Epilepsy Behav 2019 10 29;99:106391. Epub 2019 Jul 29.

Epilepsy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133 Milan, Italy.

An observational, prospective study has been conducted to evaluate the effects of adjunctive treatment with perampanel (PER) on psychological functioning and quality of life (QoL) in patients with drug-resistant focal epilepsy. Fifty-six adult patients treated with PER in addition to antiepileptic drugs (AEDs) were recruited in 2 Italian Epilepsy Centers. Irritability in Adult Patients with Epilepsy (I-EPI), Quality of Life in Epilepsy (QOLIE-31), Beck Depression Inventory II (BDI-II), and State-Trait Anxiety Inventory Y-1 and Y-2 (STAI) questionnaires were administered at baseline and 3 and 6 months after the treatment onset. Adverse events (AEs) were collected during the observational 6 months period. Retention rate of treatment with PER was 82.1% at 3 months and 64.3% at 6 months. Thirteen patients reported a significant seizure frequency reduction, and one seizure freedom case was observed after 4 months of PER treatment. Perampanel was stopped because of inefficacy or paradoxical effects in 28.6% of cases and because of AEs in 7.1%. The peak dose was not associated with discontinuation probability. Irritability, QoL, depression, trait, and state anxiety did not change significantly during the PER therapy. A tendency of association between higher level of irritability at baseline and PER discontinuation was found. The results of this observational study have shown that the addition of PER to AEDs may improve seizure control, does not increase levels of irritability, depression, and anxiety, and does not reduce patients' QoL. This study also confirms the importance of a comprehensive clinical assessment, including psychiatric symptoms evaluation before offering a new treatment, to improve therapy compliance.
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http://dx.doi.org/10.1016/j.yebeh.2019.06.034DOI Listing
October 2019

Proliferative cells in the rat developing neocortical grey matter: new insights into gliogenesis.

Brain Struct Funct 2018 Dec 21;223(9):4053-4066. Epub 2018 Aug 21.

Unit of Clinical and Experimental Epileptology, Fondazione I.R.C.C.S. Istituto Neurologico "C. Besta", Via Amadeo 42, 20133, Milan, Italy.

The postnatal brain development is characterized by a substantial gain in weight and size, ascribed to increasing neuronal size and branching, and to massive addition of glial cells. This occurs concomitantly to the shrinkage of VZ and SVZ, considered to be the main germinal zones, thus suggesting the existence of other germinative niches. The aim of this study is to characterize the cortical grey matter proliferating cells during postnatal development, providing their stereological quantification and identifying the nature of their cell lineage. We performed double immunolabeling for the proliferation marker Ki67 and three proteins which identify either astrocytes (S100β) or oligodendrocytes (Olig2 and NG2), in addition to a wider panel of markers apt to validate the former markers or to investigate other cell lineages. We found that proliferating cells increase in number during the first postnatal week until P10 and subsequently decreased until P21. Cell lineage characterization revealed that grey matter proliferating cells are prevalently oligodendrocytes and astrocytes along with endothelial and microglial cells, while no neurons have been detected. Our data showed that astrogliogenesis occurs prevalently during the first 10 days of postnatal development, whereas contrary to the expected peak of oligodendrogenesis at the second postnatal week, we found a permanent pool of proliferating oligodendrocytes enduring from birth until P21. These data support the relevance of glial proliferation within the grey matter and could be a point of departure for further investigations of this complex process.
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http://dx.doi.org/10.1007/s00429-018-1736-8DOI Listing
December 2018

Tracking the Re-organization of Motor Functions After Disconnective Surgery: A Longitudinal fMRI and DTI Study.

Front Neurol 2018 5;9:400. Epub 2018 Jun 5.

Health Department, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy.

Mechanisms of motor plasticity are critical to maintain motor functions after cerebral damage. This study explores the mechanisms of motor reorganization occurring before and after surgery in four patients with drug-refractory epilepsy candidate to disconnective surgery. We studied four patients with early damage, who underwent tailored hemispheric surgery in adulthood, removing the cortical motor areas and disconnecting the corticospinal tract (CST) from the affected hemisphere. Motor functions were assessed clinically, with functional MRI (fMRI) tasks of arm and leg movement and Diffusion Tensor Imaging (DTI) before and after surgery with assessments of up to 3 years. Quantifications of fMRI motor activations and DTI fractional anisotropy (FA) color maps were performed to assess the lateralization of motor network. We hypothesized that lateralization of motor circuits assessed preoperatively with fMRI and DTI was useful to evaluate the motor outcome in these patients. In two cases preoperative DTI-tractography did not reconstruct the CST, and FA-maps were strongly asymmetric. In the other two cases, the affected CST appeared reduced compared to the contralateral one, with modest asymmetry in the FA-maps. fMRI showed different degrees of lateralization of the motor network and the SMA of the intact hemisphere was mostly engaged in all cases. After surgery, patients with a strongly lateralized motor network showed a stable performance. By contrast, a patient with a more bilateral pattern showed worsening of the upper limb function. For all cases, fMRI activations shifted to the intact hemisphere. Structural alterations of motor circuits, observed with FA values, continued beyond 1 year after surgery. In our case series fMRI and DTI could track the longitudinal reorganization of motor functions. In these four patients the more the paretic limbs recruited the intact hemisphere in primary motor and associative areas, the greater the chances were of maintaining elementary motor functions after adult surgery. In particular, DTI-tractography and quantification of FA-maps were useful to assess the lateralization of motor network. In these cases reorganization of motor connectivity continued for long time periods after surgery.
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http://dx.doi.org/10.3389/fneur.2018.00400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5996100PMC
June 2018

Histological and MRI markers of white matter damage in focal epilepsy.

Epilepsy Res 2018 02 23;140:29-38. Epub 2017 Nov 23.

NeuroImaging of Epilepsy Laboratory, Montreal Neurological Institute, McGill University, Canada. Electronic address:

Growing evidence highlights the importance of white matter in the pathogenesis of focal epilepsy. Ex vivo and post-mortem studies show pathological changes in epileptic patients in white matter myelination, axonal integrity, and cellular composition. Diffusion-weighted MRI and its analytical extensions, particularly diffusion tensor imaging (DTI), have been the most widely used technique to image the white matter in vivo for the last two decades, and have shown microstructural alterations in multiple tracts both in the vicinity and at distance from the epileptogenic focus. These techniques have also shown promising ability to predict cognitive status and response to pharmacological or surgical treatments. More recently, the hypothesis that focal epilepsy may be more adequately described as a system-level disorder has motivated a shift towards the study of macroscale brain connectivity. This review will cover emerging findings contributing to our understanding of white matter alterations in focal epilepsy, studied by means of histological and ultrastructural analyses, diffusion MRI, and large-scale network analysis. Focus is put on temporal lobe epilepsy and focal cortical dysplasia. This topic was addressed in a special interest group on neuroimaging at the 70th annual meeting of the American Epilepsy Society, held in Houston December 2-6, 2016.
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http://dx.doi.org/10.1016/j.eplepsyres.2017.11.010DOI Listing
February 2018

Seizure activity per se does not induce tissue damage markers in human neocortical focal epilepsy.

Ann Neurol 2017 Sep 30;82(3):331-341. Epub 2017 Aug 30.

Epilepsy Unit, C. Besta Neurological Institute Foundation.

Objective: The contribution of recurring seizures to the progression of epileptogenesis is debated. Seizure-induced brain damage is not conclusively demonstrated either in humans or in animal models of epilepsy. We evaluated the expression of brain injury biomarkers on postsurgical brain tissue obtained from 20 patients with frequent seizures and a long history of drug-resistant focal epilepsy.

Methods: The expression patterns of specific glial, neuronal, and inflammatory molecules were evaluated by immunohistochemistry in the core of type II focal cortical dysplasias (FCD-II), at the FCD boundary (perilesion), and in the adjacent normal-appearing area included in the epileptogenic region. We also analyzed surgical specimens from cryptogenic patients not presenting structural alterations at imaging.

Results: Astroglial and microglial activation, reduced neuronal density, perivascular CD3-positive T-lymphocyte clustering, and fibrinogen extravasation were demonstrated in the core of FCD-II lesions. No pathological immunoreactivity was observed outside the FCD-II or in cryptogenetic specimens, where the occurrence of interictal and ictal epileptiform activity was confirmed by either stereo-electroencephalography or intraoperative electrocorticography.

Interpretation: Recurrent seizures do not induce the expression of brain damage markers in nonlesional epileptogenic cortex studied in postsurgical tissue from cryptogenic and FCD patients. This evidence argues against the hypothesis that epileptiform activity per se contributes to focal brain injury, at least in the neocortical epilepsies considered here. Ann Neurol 2017;82:331-341.
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http://dx.doi.org/10.1002/ana.25005DOI Listing
September 2017

Surgical outcomes in two different age groups with Focal Cortical Dysplasia type II: Any real difference?

Epilepsy Behav 2017 05 11;70(Pt A):45-49. Epub 2017 Apr 11.

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

Objective: Focal Cortical Dysplasias (FCDs) represent a common architectural cortical disorder underlying drug-resistant focal epilepsy. So far, studies aimed at evaluating whether age at surgery is a factor influencing surgical outcome are lacking, so that data on the comparison between patients harboring Type II FCD operated at younger age and those operated at adult age are still scarce. We compared presurgical clinical features and surgical outcomes of patients with histopathologically diagnosed Type II FCD undergoing surgery at an earlier age with those operated after 20 years of age.

Methods: We retrospectively analyzed 1660 consecutive patients operated at the "Claudio Munari" Epilepsy Surgery Centre. There were 289 patients (17.4%) with a neuropathological diagnosis of Type II FCD. We included two different groups of patients, the first one including patients operated on at less than 6years, the second sharing the same seizure onset age but with delayed surgery, carried out after the age of 20. Seizure characteristics and, neuropsychological and postoperative seizure outcomes were evaluated by study group.

Results: Forty patients underwent surgery before the age of 6 and 66 patients after the age of 20. Surgical outcome was favorable in the whole population (72.6% were classified in Engel's Class Ia+Ic), independently from age at surgery. In the children group, 32 patients were classified in Class I, including 30 (75%) children in classes Ia and Ic. In the adult group, 53 belonged to Class I of whom 47 (71%) were in classes Ia and Ic. The percentage of permanent complications, the surgical outcomes, and AED withdrawal did not significantly differ by study group.

Conclusion: Our results indicate that there is no difference between the groups, suggesting that outcome depends mainly on the histological findings and not on timing of surgery.
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http://dx.doi.org/10.1016/j.yebeh.2017.02.031DOI Listing
May 2017

Early and late epilepsy surgery in focal epilepsies associated with long-term epilepsy-associated tumors.

J Neurosurg 2017 Nov 13;127(5):1147-1152. Epub 2017 Jan 13.

"Claudio Murani" Epilepsy Surgery Centre, Niguarda Hospital, Milan, Italy; and.

OBJECTIVE Epilepsy surgery is an effective means of treating focal epilepsy associated with long-term epilepsy-associated tumors. This study evaluated a large population of surgically treated patients with childhood onset of epilepsy and a histologically confirmed diagnosis of long-term epilepsy-associated tumors. The authors analyzed long-term seizure outcomes to establish whether the time of surgery and patients' ages were determinant factors. METHODS The authors separately investigated several presurgical, surgical, and postsurgical variables in patients operated on before (pediatric group) and at or after (adult group) the age of 18 years. Patients with < 24 months of postsurgical follow-up were excluded from the analysis. RESULTS The patients who underwent surgery before 18 years of age showed better seizure outcomes than those after 18 years of age (80% vs 53.3% Engel Class Ia outcome, respectively; p < 0.001). Multivariate analysis showed that the only variables significantly associated with seizure freedom were complete resection of the lesion, a shorter duration of epilepsy, and temporal lobe resection. CONCLUSIONS The findings of this study indicate that pediatric patients are more responsive to epilepsy surgery and that a shorter duration of epilepsy, complete resection, and a temporal lobe localization are determinant factors for a positive seizure outcome.
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http://dx.doi.org/10.3171/2016.9.JNS161176DOI Listing
November 2017

PARADISE 24 instrument: An observational study on psychosocial difficulties, quality of life, and disability levels in patients with epilepsy.

Epilepsy Behav 2016 11 12;64(Pt A):160-165. Epub 2016 Oct 12.

Neurology, Public Health, Disability Unit, Neurological Institute C. Besta IRCCS Foundation, Milan, Italy.

Aim: The aim of this observational study was to test the effectiveness of the PARADISE 24 instrument in describing the psychosocial difficulties (PSDs) reported by people with epilepsy, their relation with disability, and quality-of-life (QoL) levels and, overall, to explore a horizontal epidemiology methodology applied to a sample of patients with epilepsy.

Methods: A convenience sample of 80 adult patients with epilepsy was included in this cross-sectional study. Patients were interviewed using a structured protocol composed of demographic, clinical, and patient-reported outcome measures to collect PSDs associated with epilepsy.

Results: There were 80 patients, 40 females; mean age was 41.2years; mean disease duration was 18.7years; and mean number of AED was 2.09. Moderate severity rating according to clinicians' rating scale, low impact of comorbidities (mean: 2.36, SD: 2.97), high levels of QoL (mean: 30.00, SD: 4.4), medium levels of resilience (mean: 13.56, SD: 2.66), high levels of perceived empathy (mean: 15.05, SD: 4.74), poor or moderate perceived social support, and low levels of disability (mean: 10.85, SD: 10.05) were observed. The most frequently reported PSDs were related to tiredness (80%), emotional problems (73.75%), anxiety (68.75%), depressive mood (66.25%), and driving problems (61.25%). The EUROHIS-QOL (p=.003) had a negative significant relationship with PARADISE 24 while WHODAS-12 (p=.000) and CRS (p=.027) had a positive significant relationship with PARADISE 24.

Conclusions: The PARADISE 24 permits data comparison and the creation of a complete description of a person's functioning and of all of his/her PSDs and allows better and more tailored interventions.
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http://dx.doi.org/10.1016/j.yebeh.2016.08.019DOI Listing
November 2016

Different parvalbumin and GABA expression in human epileptogenic focal cortical dysplasia.

Epilepsia 2016 07 13;57(7):1109-19. Epub 2016 May 13.

Clinical Epileptology and Experimental Neurophysiology Unit, Istituto Neurologico "C. Besta", Milan, Italy.

Objective: Several studies have reported that inhibitory networks are altered in dysplastic tissue obtained from epilepsy surgery specimens. A consistent decrease in the number of inhibitory interneuronal subpopulation that expresses parvalbumin (PV) was reported in postsurgical tissue from patients with focal cortical dysplasia (FCD). We tested if the decrease in PV protein expression observed in epileptic tissue corresponds to a parallel impairment in the γ-aminobutyric acid (GABA)ergic compartment.

Methods: We analyzed postsurgical tissue from 30 surgically treated patients who underwent surgery for intractable epilepsy including 26 patients with FCD (types I, II, and III) and 4 patients without any microscopic visible lesion (cryptogenic) as controls. Serial sections were processed using in situ hybridization with GAD-65 and GAD-67 probes and immunocytochemistry with antibody against PV. The density of inhibitory PV-immunoreactive interneurons in relation to GABAergic cells was estimated in controls and in all different pathologic groups by using a two- and three-dimensional (2D and 3D) cell-counting technique. Field fraction and line profile analyses were added to estimate immunostaining proportion and distribution of PV signal generated in gray matter.

Results: A reduction of PV-positive cells and PV-immunoreactivity was observed exclusively in FCD type I/III specimens compared with cryptogenic tissue from control patients with a poor postsurgical outcome. In FCD type II, a profound rearrangement in the cortical distribution of PV immunoreactivity was observed, without a quantitative reduction of the number of neurons and terminals. In situ hybridization did not reveal significant variations of GAD expression in any FCD subtype.

Significance: Our study suggests a preservation of inhibitory networks in FCD postsurgical tissue, demonstrated by a substantial normal count of GABAergic neurons. A selective PV expression impairment is demonstrated in FCD type I and III and an abnormal, but not reduced, distribution of PV cells and terminals is confirmed in type II FCD. Possible functional consequences are discussed.
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http://dx.doi.org/10.1111/epi.13405DOI Listing
July 2016

Expanding the spectrum of cognitive outcomes after temporal lobe epilepsy surgery: A prospective study of theory of mind.

Epilepsia 2016 06 18;57(6):920-30. Epub 2016 Apr 18.

Unit of Epilepsy and Experimental Neurophysiology, Department of Diagnostics and Applied Technology, Neurological Institute "C. Besta", Milan, Italy.

Objective: Because temporal lobe epilepsy (TLE) can impair theory of mind (ToM), we examined the effects of anterior temporal lobectomy (ATL) by comparing the preoperative to postoperative ToM course with that of other cognitive functions characteristically impaired in TLE.

Methods: Eighty-five patients with left (n = 39) or right (n = 46) drug-resistant TLE and an age at epilepsy onset of >12 (n = 54) or ≤12 years (n = 31) were evaluated before and 1 year after surgery; 40 healthy controls were assessed at baseline. The participants' recognition and comprehension of faux pas (FPs) or correct rejection of nonexistent FPs was assessed using the Faux Pas task; and their language, memory, and planning were, respectively, assessed using the Boston Naming, Short Story, and Tower of London tests.

Results: Baseline ToM was impaired in the patients with left or right TLE in comparison with the controls, and significantly influenced by education and age at seizure onset, with more severe deficits being observed in those with less education and an age at onset of ≤12 years. After ATL, their recognition and comprehension of FPs was unchanged, whereas the rejection of nonexistent FPs improved in the patients with early seizure onset. Education, preoperative ToM, postoperative executive function, and fluid intelligence and the number of antiepileptic drugs predicted postoperative ToM. Postoperative naming and episodic memory were associated with ATL laterality and education, and planning was associated with age at seizure onset and chronological age.

Significance: After ATL, the components of ToM may be unchanged or slightly improved depending on cognitive reserve and age at seizure onset, thus suggesting that ATL does not further aggravate the deficits caused by TLE. Moreover, the course of ToM is distinct from that of other cognitive functions. These findings expand the spectrum of the cognitive phenotypes associated with TLE and ATL, and offer potential elements for individual prognoses.
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http://dx.doi.org/10.1111/epi.13384DOI Listing
June 2016

Neuropsychological profiles and outcomes in children with new onset frontal lobe epilepsy.

Epilepsy Behav 2016 Feb 13;55:79-83. Epub 2016 Jan 13.

Department of Pediatrics, University of L'Aquila, L'Aquila, Italy. Electronic address:

Frontal lobe epilepsy (FLE) is the second most frequent type of localization-related epilepsy, and it may impact neurocognitive functioning with high variability. The prevalence of neurocognitive impairment in affected children remains poorly defined. This report outlines the neuropsychological profiles and outcomes in children with new onset FLE, and the impact of epilepsy-related factors, such as seizure frequency and antiepileptic drug (AED) load, on the neurocognitive development. Twenty-three consecutive children (15 males and 8 females) with newly diagnosed cryptogenic FLE were enrolled; median age at epilepsy onset was 7 years (6-9.6 years). They underwent clinical and laboratory evaluation and neuropsychological assessment before starting AED treatment (time 0) and after one year of treatment (time 1). Twenty age-matched patients affected by idiopathic generalized epilepsy (10 male and 10 females) and eighteen age-matched healthy subjects (9 males and 9 females) were enrolled as controls and underwent the same assessment. All patients with FLE showed a significant difference in almost all assessed cognitive domains compared with controls, mainly in frontal functions and memory. At time 1, patients were divided into two groups according to epilepsy-related factors: group 1 (9 patients) with persisting seizures despite AED polytherapy, and group 2 (14 patients) with good seizure control in monotherapy. A significant difference was highlighted in almost all subtests in group 1 compared with group 2, both at time 0 and at time 1. In children with FLE showing a broad range of neurocognitive impairments, the epilepsy-related factors mostly related to a worse neurocognitive outcome are poor seizure control and the use of AED polytherapy, suggesting that epileptic discharges may have a negative impact on the functioning of the involved cerebral regions.
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http://dx.doi.org/10.1016/j.yebeh.2015.12.006DOI Listing
February 2016

Short- and long-term surgical outcomes of temporal lobe epilepsy associated with hippocampal sclerosis: Relationships with neuropathology.

Epilepsia 2016 Feb 17;57(2):306-15. Epub 2015 Dec 17.

Epilepsy Surgery Centre C. Munari, Niguarda Hospital, Milan, Italy.

Objective: Hippocampal sclerosis (HS) is the most frequent neuropathologic finding in patients undergoing surgery for intractable temporal lobe epilepsy (TLE). The International League Against Epilepsy (ILAE) has recently proposed a new classification of HS based on specific patterns of cell loss. The aim of this study was to investigate the relationships between HS types, their etiologic factors, and the short- and long-term postsurgical outcomes of patients undergoing surgery because of drug-resistant TLE with HS.

Methods: Two hundred thirteen patients with a neuropathologic diagnosis of HS and a minimum follow-up of 2 years were divided on the basis of their ILAE HS type and further classified into: (1) isolated HS, (2) HS associated with focal cortical dysplasia (FCD IIIa), or (3) HS associated with other lesions. Their clinical and neuropathologic data were correlated with their Engel class postsurgical outcomes.

Results: The main findings were the following: (1) HS type 1 was associated with a longer duration of epilepsy; (2) >80% of the patients had an Engel class I short- and long-term outcomes, regardless of HS type and associated pathology; (3) short- and long-term postsurgical outcomes were less satisfactory in the patients who were completely seizure-free (Engel class Ia), and patients with HS type 2 had better long-term seizure outcomes than those with type 1; (4) the concomitant presence of FCD contributed to a worse outcome, regardless of HS type; and (5) a shorter duration of epilepsy significantly correlated with an Engel class Ia outcome.

Significance: These data suggest that HS type and associated pathologies may predict the risk of recurrence, but other variables such as the duration of epilepsy need to be considered. A common neuropathologic classification system may help to identify preoperative predictive factors and improve the selection of patients who may benefit from epilepsy surgery.
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http://dx.doi.org/10.1111/epi.13277DOI Listing
February 2016

Bitemporal epilepsy: A specific anatomo-electro-clinical phenotype in the temporal lobe epilepsy spectrum.

Seizure 2015 Sep 26;31:112-9. Epub 2015 Jul 26.

Claudio Munari Epilepsy Surgery Centre, Niguarda Hospital, Piazza dell'Ospedale Maggiore 3, 20162 Milano, Italy. Electronic address:

Purpose: Temporal lobe epilepsy (TLE) with bilateral ictal involvement (bitemporal epilepsy, BTLE) is an intriguing form of TLE whose characteristics need to be carefully identified as BTLE patients are not good surgical candidates. The purpose of this study was to define the anatomo-electro-clinical features differentiating BTLE from unilateral TLE (UTLE).

Methods: Forty-eight BTLE patients underwent long-term video-EEG monitoring (VEEG) and experienced seizures with bilateral temporal lobe involvement. Their main electro-clinical (demographics, interictal and ictal EEG, ictal signs) and neuro-imaging [brain magnetic resonance imaging (MRI)] data were compared with those of a group of 38 UTLE patients.

Results: In comparison with the UTLE patients, the BTLE cohort was significantly older at the time of epilepsy onset (p = 0.023), more frequently experienced bilateral asynchronous interictal epileptiform discharges during wakefulness (p = 0.001) and sleep (p < 0.001), bilateral upper limb dystonia (p = 0.005), and auditory auras (p = 0.027), and less frequently showed a recognisable initial ictal EEG pattern of focal flattening or low-voltage fast activity (p < 0.001), post-ictal memory of seizures (p = 0.001), staring (p < 0.001), head deviation (p = 0.004), oro-alimentary automatisms (p = 0.006), and positive brain MRI (p < 0.001). MRI revealed neoplastic lesions (p = 0.007) or alterations other than hippocampal sclerosis (p = 0.028) only in the UTLE patients.

Conclusion: The possibility of recognising BTLE patients during pre-surgical evaluation or being able to suspect bitemporal seizures before VEEG by identifying particular anatomo-electro-clinical patterns is diagnostically important for epileptologists and can help to prevent possible surgical failures.
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http://dx.doi.org/10.1016/j.seizure.2015.07.013DOI Listing
September 2015

The dilemma of adult-onset Rasmussen encephalitis clinical assessment: Proposal for a new bedside tool to evaluate disease progression.

Epilepsy Behav 2015 May 8;46:249-51. Epub 2015 May 8.

Clinical Epileptology and Experimental Neurophysiology Unit, Foundation IRCCS "Carlo Besta" Neurological Institute, Milan, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.yebeh.2015.04.029DOI Listing
May 2015

An unusual behavioural and motor paroxysmal disorder caused by insulinoma-related hypoglycemia: a possible cause of epilepsy misdiagnosis.

Seizure 2014 Nov 9;23(10):909-11. Epub 2014 Jul 9.

Clinical Epileptology and Experimental Neurophysiology Unit, Fondazione IRCCS, Istituto Neurologico 'C. Besta', Milan, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.seizure.2014.06.018DOI Listing
November 2014

Hemispherotomy in Rasmussen encephalitis: long-term outcome in an Italian series of 16 patients.

Epilepsy Res 2014 Aug 8;108(6):1106-19. Epub 2014 Apr 8.

Department of Neuroscience, Bambino Gesù Children's Hospital, Rome, Italy.

Surgical disconnection of the affected hemisphere is considered the treatment of choice for Rasmussen encephalitis (RE), however few data on long-term outcomes after disconnective surgery are available. We report on long-term seizure, cognitive and motor outcomes after disconnective surgery in 16 (8 M, 8 F) RE patients. Pre- and post-operative evaluations included long-term video-EEG monitoring, MRI, assessment of motor function, and cognitive evaluation. Hemispherotomy, by various techniques was used to obtain functional disconnection of the affected hemisphere. The patients, of median current age 23.5 years, range 12-33, were operated on between 1993 and 2009. Median age at disease onset was 5.8 years (range 3-11.4). Median time from seizure onset to surgery was 3.8 years, range 8 months to 21 years. Post-surgical follow-up was a median of 9.5 years, range 3-20. At surgery all patients were receiving two or more antiepileptic drugs (AEDs). All but three patients were seizure-free at latest follow-up. AEDs had been stopped in ten patients; in the remaining six AEDs were markedly reduced. Postural control improved in all patients. Gain in cognitive functioning was significantly (p=0.002) related to disease duration. The long-term outcomes, in terms of seizure control, motor improvement, and cognitive improvement provide important support for disconnective surgery as first choice treatment for RE.
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http://dx.doi.org/10.1016/j.eplepsyres.2014.03.018DOI Listing
August 2014

Refractory epilepsy and encephalocele: lesionectomy or tailored surgery?

Seizure 2014 Aug 6;23(7):583-4. Epub 2014 Apr 6.

Magna Graecia University, Catanzaro, Italy; Regional Epilepsy Center, Bianchi-Melacrino-Morelli Hospital, Reggio Calabria, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.seizure.2014.03.019DOI Listing
August 2014

Long-term outcome after limited cortical resections in two cases of adult-onset Rasmussen encephalitis.

Epilepsia 2014 May 4;55(5):e38-43. Epub 2014 Apr 4.

Division of Clinical Epileptology & Experimental Neurophysiology, Foundation IRCCS Neurological Institute "Carlo Besta", Milan, Italy.

Rasmussen encephalitis (RE) is a progressive inflammatory disorder characterized by brain hemiatrophy, unilateral focal deficits, and drug-refractory focal epilepsy. Epilepsia partialis continua (EPC) is a hallmark of the disease. Several immunomodulatory treatments may slow but not halt the disease progression. The treatment of choice still relies on surgical hemispheric disconnection, which is burdened by heavy neurologic morbidity. More limited cortical resections, although more tolerable, are usually considered to be, at best, only transiently effective in RE. Hemispheric disconnections may be not feasible when neurologic functions are preserved and the dominant hemisphere is affected. Adult patients with a milder RE course that preserves neurologic function for a long period are particularly at risk of developing severe deficits after surgery. In this study we present the histories of two patients with adult-onset RE who have undergone selective cortical resections to control EPC, avoiding, at the same time, the severe postsurgical deficits that may be induced by hemispheric disconnective surgery. The good result obtained on EPC has been stable over a prolonged period; however, this result was not paralleled by the stop of neurologic progression in one of the two cases. A PowerPoint slide summarizing this article is available for download in the Supporting Information section http://dx.doi.org/10.1111/epi.12596/supinfo.
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http://dx.doi.org/10.1111/epi.12596DOI Listing
May 2014

Early post-operative convulsive status epilepticus in a patient with drug-refractory temporal lobe epilepsy and type I focal cortical dysplasia.

Seizure 2014 May 16;23(5):399-401. Epub 2014 Jan 16.

Division of Clinical Epileptology and Experimental Neurophysiology, "Carlo Besta" Neurological Institute Foundation, Milan, Italy.

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http://dx.doi.org/10.1016/j.seizure.2014.01.006DOI Listing
May 2014

Electroclinical, MRI and surgical outcomes in 100 epileptic patients with type II FCD.

Epileptic Disord 2012 Sep;14(3):257-66

C. Munari Epilepsy Surgery Centre.

Focal cortical dysplasias (FCDs) are highly epileptogenic malformations associated with drug-resistant epilepsy, susceptible to surgical treatment. Among the different types of FCD, the type II includes two subgroups based on the absence (IIa) or presence (IIb) of balloon cells. The aim of this retrospective study was to investigate possible differences in electroclinical presentations and surgical outcomes between the two subgroups in 100 consecutive surgically treated patients with type II FCDs. All patients underwent a comprehensive presurgical assessment including stereo-EEG (SEEG) when necessary. No significant differences in gender, age at epilepsy onset, duration of epilepsy, age at surgery or seizure frequency were found between the two subgroups. Patients with type IIb FCD frequently showed sleep-related epilepsy. Their peculiar electrographic pattern was characterised by localised rhythmic or pseudo-rhythmic spikes or polyspikes ("brushes") enhanced during non-REM sleep and also associated with well-localised, brief, low-voltage fast activity. The incidence and frequency of short bursts of fast discharges, interrupted by activity suppression, increased during slow-wave sleep and often recurred pseudo-periodically. The occurrence of "brushes", present in 76% of the patients with type IIb FCD, was significantly associated (p<0.001) with the presence of balloon cells. We discuss the possible pathogenetic mechanisms underlying this activity. MRI diagnosis of type II FCD was made in 93% of the patients with balloon cells (BCs), suggesting that the presence of balloon cells might be, at least partially, responsible for the MRI features. Patients had very good postsurgical outcomes (83% in Engel class I) even after a long period of follow-up.
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http://dx.doi.org/10.1684/epd.2012.0525DOI Listing
September 2012

Blurring in patients with temporal lobe epilepsy: clinical, high-field imaging and ultrastructural study.

Brain 2012 Aug 22;135(Pt 8):2337-49. Epub 2012 Jun 22.

Clinical Epileptology and Experimental Neurophysiology Unit, Fondazione IRCCS, Istituto Neurologico ‘C. Besta’, 20133 Milan, Italy.

Magnetic resonance imaging-positive temporal lobe atrophy with temporo-polar grey/white matter abnormalities (usually called 'blurring') has been frequently reported in patients with temporal lobe epilepsy associated with hippocampal sclerosis. The poor distinction of grey and white matter has been attributed to various causes, including developmental cortical abnormalities, gliosis, myelin alterations, a non-specific increase in temporal lobe water content and metabolic/perfusion alterations. However, there is still no consensus regarding the genesis of these abnormalities and no histopathological proof for a structural nature of magnetic resonance imaging changes. The aim of this study was to investigate the pathological substrate of temporo-polar blurring using different methodological approaches and evaluate the possible clinical significance of the abnormalities. The study involved 32 consecutive patients with medically intractable temporal lobe epilepsy and hippocampal sclerosis who underwent surgery after a comprehensive electroclinical and imaging evaluation. They were divided into two groups on the basis of the presence/absence of temporo-polar blurring. Surgical specimens were examined neuropathologically, and selected samples from both groups underwent high-field 7 T magnetic resonance imaging and ultrastructural studies. At the clinical level, the two groups were significantly different in terms of age at epilepsy onset (earlier in the patients with blurring) and epilepsy duration (longer in the patients with blurring). Blurring was also associated with lower neuropsychological test scores, with a significant relationship to abstract reasoning. On 7 T magnetic resonance image examination, the borders between the grey and white matter were clear in all of the samples, but only those with blurring showed a dishomogeneous signal in the white matter, with patchy areas of hyperintensity mainly in the depth of the white matter. Sections from the patients with blurring that were processed for myelin staining revealed dishomogeneous staining of the white matter, which was confirmed by analyses of the corresponding semi-thin sections. Ultrastructural examinations revealed the presence of axonal degeneration and a significant reduction in the number of axons in the patients with blurring; there were no vascular alterations in either group. These data obtained using different methodological approaches provide robust evidence that temporo-polar blurring is caused by the degeneration of fibre bundles and suggest slowly evolving chronic degeneration with the redistribution of the remaining fibres. The article also discusses the correlations between the morphological findings and clinical data.
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http://dx.doi.org/10.1093/brain/aws149DOI Listing
August 2012