Publications by authors named "Francesca Bisulli"

137 Publications

Postictal Psychosis in Epilepsy: A Clinicogenetic Study.

Ann Neurol 2021 Jul 20. Epub 2021 Jul 20.

Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK.

Objective: Psychoses affecting people with epilepsy increase disease burden and diminish quality of life. We characterized postictal psychosis, which comprises about one quarter of epilepsy-related psychoses, and has unknown causation.

Methods: We conducted a case-control cohort study including patients diagnosed with postictal psychosis, confirmed by psychiatric assessment, with available data regarding epilepsy, treatment, psychiatric history, psychosis profile, and outcomes. After screening 3,288 epilepsy patients, we identified 83 with psychosis; 49 had postictal psychosis. Controls were 98 adults, matched by age and epilepsy type, with no history of psychosis. Logistic regression was used to investigate clinical factors associated with postictal psychosis; univariate associations with a p value < 0.20 were used to build a multivariate model. Polygenic risk scores for schizophrenia were calculated.

Results: Cases were more likely to have seizure clustering (odds ratio [OR] = 7.59, p < 0.001), seizures with a recollected aura (OR = 2.49, p = 0.013), and a family history of psychiatric disease (OR = 5.17, p = 0.022). Cases showed predominance of right temporal epileptiform discharges (OR = 4.87, p = 0.007). There was no difference in epilepsy duration, neuroimaging findings, or antiseizure treatment between cases and controls. Polygenic risk scores for schizophrenia in an extended cohort of postictal psychosis cases (n = 58) were significantly higher than in 1,366 epilepsy controls (R  = 3%, p = 6 × 10 ), but not significantly different from 945 independent patients with schizophrenia (R  = 0.1%, p = 0.775).

Interpretation: Postictal psychosis occurs under particular circumstances in people with epilepsy with a heightened genetic predisposition to schizophrenia, illustrating how disease biology (seizures) and trait susceptibility (schizophrenia) may interact to produce particular outcomes (postictal psychosis) in a common disease. ANN NEUROL 2021.
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http://dx.doi.org/10.1002/ana.26174DOI Listing
July 2021

Seizure worsening in pregnancy in women with sleep-related hypermotor epilepsy (SHE): A historical cohort study.

Seizure 2021 Jul 5;91:258-262. Epub 2021 Jul 5.

IRCCS Istituto delle Scienze Neurologiche di Bologna, Full Member of the ERN EpiCARE, Bologna, Italy; Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.

Introduction: Data on seizure course during pregnancy in women with epilepsy are limited. In particular, little is known about the causes underlying possible seizure worsening in this population. We therefore set out to explore worsening, in pregnancy, of sleep-related hypermotor epilepsy (SHE), a syndrome in which seizures are known to be triggered by sleep fragmentation, a condition common in pregnancy.

Methods: From a cohort of consecutive patients with epilepsy who had one or more deliveries between January 2008 and March 2018, we retrospectively compared the rates of seizure worsening during pregnancy in SHE versus other epilepsies (NSHE). Worsening was defined as an increase in seizure frequency compared with the rate for the year prior to conception, including seizure recurrence after a year of seizure freedom, and/or new occurrence of tonic-clonic seizures.

Results: We considered data on 11 pregnancies in women with SHE and 104 pregnancies in women with NSHE. Seizures worsened in six SHE pregnancies (54.5%) versus 18 NSHE ones (17.3%) (OR adjusted for preconception seizure frequency and polytherapy = 5.7, 95% CI = 1.6-20.8, p = 0.019).

Conclusions: Women with SHE have a higher risk of seizure worsening in pregnancy. This finding should be considered from the perspective of patient counseling.
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http://dx.doi.org/10.1016/j.seizure.2021.06.034DOI Listing
July 2021

Results From an Italian Expanded Access Program on Cannabidiol Treatment in Highly Refractory Dravet Syndrome and Lennox-Gastaut Syndrome.

Front Neurol 2021 20;12:673135. Epub 2021 May 20.

Pediatric Neurology and Epileptology Unit, Brotzu Hospital Trust, Cagliari, Italy.

Purified cannabidiol (CBD) was administered to highly refractory patients with Dravet (DS) or Lennox-Gastaut (LGS) syndromes in an ongoing expanded access program (EAP). Herein, we report interim results on CBD safety and seizure outcomes in patients treated for a 12-month period. Thirty centers were enrolled from December 2018 to December 2019 within the open-label prospective EAP up to a maximum of 25 mg/kg per day. Adverse effects and liver function tests were assessed after 2 weeks; 1, 3, and 6 months of treatment; and periodically thereafter. Seizure endpoints were the percentage of patients with ≥50 and 100% reduction in seizures compared to baseline. A total of 93 patients were enrolled and included in the safety analysis. Eighty-two patients [27 (32.9%) DS, 55 (67.1%) LGS] with at least 3 months of treatment have been included in the effectiveness analysis; median previously failed antiseizure medications was eight. Pediatric and adult patients were uniformly represented in the cohort. At 3-month follow-up, compared to the 28-day baseline period, the percentage of patients with at least a 50% reduction in seizure frequency was 40.2% (plus 1.2% seizure-free). Retention rate was similar according to diagnosis, while we found an increased number of patients remaining under treatment in the adult group. CBD was mostly coadministered with valproic acid (62.2%) and clobazam (41.5%). In the safety dataset, 29 (31.2%) dropped out: reasons were lack of efficacy [16 (17.2%)] and adverse events (AEs) [12 (12.9%)], and one met withdrawal criteria (1.1%). Most reported AEs were somnolence (22.6%) and diarrhea (11.9%), followed by transaminase elevation and loss of appetite. CBD is associated with improved seizure control also in a considerable proportion of highly refractory patients with DS and LGS independently from clobazam use. Overall, CBD safety and effectiveness are not dose-related in this cohort.
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http://dx.doi.org/10.3389/fneur.2021.673135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173151PMC
May 2021

Akinetic mutism in COVID-19-related encephalopathy: A cytokine-mediated maladaptive sickness behavioral response?

Brain Behav Immun Health 2021 Aug 13;15:100272. Epub 2021 May 13.

Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy.

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http://dx.doi.org/10.1016/j.bbih.2021.100272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117477PMC
August 2021

Brain dysfunction in COVID-19 and CAR-T therapy: cytokine storm-associated encephalopathy.

Ann Clin Transl Neurol 2021 04 29;8(4):968-979. Epub 2021 Mar 29.

Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy.

Objective: Many neurological manifestations are associated with COVID-19, including a distinct form of encephalopathy related to cytokine storm, the acute systemic inflammatory syndrome present in a subgroup of COVID-19 patients. Cytokine storm is also associated with immune effector cell-associated neurotoxicity syndrome (ICANS), a complication of chimeric antigen receptor T-cell (CAR-T) therapy, a highly effective treatment for refractory hematological malignancies. We investigated whether COVID-19-related encephalopathy, ICANS, and other encephalopathies associated with cytokine storm, share clinical and investigative findings.

Methods: Narrative literature review.

Results: Comparisons between COVID-19-related encephalopathy and ICANS revealed several overlapping features. Clinically, these included dysexecutive syndrome, language disturbances, akinetic mutism and delirium. EEG showed a prevalence of frontal abnormalities. Brain MRI was often unrevealing. CSF elevated cytokine levels have been reported. A direct correlation between cytokine storm intensity and severity of neurological manifestations has been shown for both conditions. Clinical recovery occurred spontaneously or following immunotherapies in most of the patients. Similar clinical and investigative features were also reported in other encephalopathies associated with cytokine storm, such as hemophagocytic lymphohistiocytosis, sepsis, and febrile infection-associated encephalopathies.

Interpretation: COVID-19-related encephalopathy and ICANS are characterized by a predominant electro-clinical frontal lobe dysfunction and share several features with other encephalopathies associated with cytokine storm, which may represent the common denominator of a clinical spectrum of neurological disorders. Therefore, we propose a unifying definition of cytokine storm-associated encephalopathy (CySE), and its diagnostic criteria.
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http://dx.doi.org/10.1002/acn3.51348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045903PMC
April 2021

Italian cohort of Lafora disease: Clinical features, disease evolution, and genotype-phenotype correlations.

J Neurol Sci 2021 May 20;424:117409. Epub 2021 Mar 20.

Unit of Medical Genetics, IRCCS Istituto Giannina Gaslini, Genova, Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università degli Studi di Genova, Genova, Italy.

Background: Lafora disease (LD) is characterized by progressive myoclonus, refractory epilepsy, and cognitive deterioration. This complex neurodegenerative condition is caused by pathogenic variants in EPM2A/EPM2B genes, encoding two essential glycogen metabolism enzymes known as laforin and malin. Long-term follow-up data are lacking. We describe the clinical features and genetic findings of a cohort of 26 Italian patients with a long clinical follow-up.

Methods: Patients with EPM2A/EPM2B pathogenic variants were identified by direct gene sequencing or gene panels with targeted re-sequencing. Disease progression, motor functions, and mental performance were assessed by a simplified disability scale. Spontaneous/action myoclonus severity was scored by the Magaudda Scale.

Results: Age range was 12.2-46.2 years (mean:25.53 ± 9.14). Age at disease onset ranged from 10 to 22 years (mean:14.04 ± 2.62). The mean follow-up period was 11.48 ± 7.8 years. Twelve out of the 26 (46%) patients preserved walking ability and 13 (50%) maintained speech. A slower disease progression with preserved ambulation and speech after ≥4 years of follow-up was observed in 1 (11%) out of the 9 (35%) EPM2A patients and in 6 (35%) out of the 17 (65%) EPM2B patients. Follow-up was >10 years in 7 (41.2%) EPM2B individuals, including two harbouring the homozygous p.(D146N) pathogenic variant.

Conclusions: This study supports an overall worse disease outcome with severe deterioration of ambulation and speech in patients carrying EPM2A mutations. However, the delayed onset of disabling symptoms observed in the EPM2B subjects harbouring the p.(D146N) pathogenic variant suggests that the underlying causative variant may still influence LD severity.
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http://dx.doi.org/10.1016/j.jns.2021.117409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166462PMC
May 2021

Risk of SUDEP during infancy.

Epilepsy Behav 2021 Mar 16:107896. Epub 2021 Mar 16.

Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.

Risk of sudden unexpected death in epilepsy (SUDEP) in children is influenced by different factors such as etiology, seizure type and frequency, treatment, and environment. A greater severity of epilepsy, in terms of seizure frequency, seizures type, especially with nocturnal generalized tonic-clonic seizures (GTCS), and resistance to anti-seizure medication are predisposing factors to SUDEP. Potential mechanisms of SUDEP might involve respiratory, cardiovascular, and central autonomic dysfunctions, either combined or in isolation. Patients with epilepsy carrying mutations in cardiac channelopathy genes might be disposed to seizure-induced arrhythmias. Other than in channelopathies, SUDEP has been reported in further patients with genetic epilepsies due to mutations of genes such as DEPDC5, TBC1D24, FHF1, or 5q14.3 deletion. Age-related electro-clinical differences in GTCS may therefore be relevant in explaining differences in SUDEP between adults and children. Typical GTCS represent a rare seizure type in infants and toddlers, they are characterized by a shorter tonic phase and, in direct proportion, by shorter postictal generalized EEG suppression (PGES). The presence of night-time supervision has been found to reduce SUDEP risk, likely reducing SUDEP incidence in children. Reconsideration of safety protocols in epilepsy monitoring units with the aim of reducing the risk of SUDEP, and the use of devices for seizure detection, might contribute to reduce the risk of death in patients affected by epilepsy. This article is part of the Special Issue "Severe Infantile Epilepsies".
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http://dx.doi.org/10.1016/j.yebeh.2021.107896DOI Listing
March 2021

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

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

IRCCS Mondino Foundation Pavia Italy.

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

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

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

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

The Arousal Disorders Questionnaire: a new and effective screening tool for confusional arousals, Sleepwalking and Sleep Terrors in epilepsy and sleep disorders units.

Sleep Med 2021 04 29;80:279-285. Epub 2021 Jan 29.

Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy. Electronic address:

Background: Arousal Disorders (DoA) include Confusional Arousals, Sleepwalking and Sleep Terrors. DoA diagnosis is mainly clinical but no validated questionnaires exist for DoA screening according to the criteria of the International Classification of Sleep Disorders, Third Edition. Recently our group proposed the Arousal Disorders Questionnaire (ADQ) as a new diagnostic tool for DoA diagnosis. The objective of this study was to evaluate the diagnostic accuracy of the ADQ in a sleep and epilepsy center.

Methods: One interviewer blinded to clinical and video-polysomnographic (VPSG) data administered the ADQ to 150 patients consecutively admitted to our Sleep and Epilepsy Centers for a follow-up visit. The final diagnosis, according to VPSG recordings of at least one major episode, classified patients either with DoA (DoA group) or with other sleep-related motor behaviors confounding for DoA (nDoA group).

Results: 47 patients (31%) composed the DoA group; 56 patients with REM sleep behavior disorder, 39 with sleep-hypermotor epilepsy, six with night eating syndrome, and two with drug-induced DoA composed the nDoA group. The ADQ had a sensitivity of 72% (95% CI: 60-82) and a specificity of 96% (95% CI: 89-98) for DoA diagnosis; excluding the items regarding consciousness and episode recall, sensitivity was 83% (95% CI: 71-90) and specificity 93% (95% CI: 86-97).

Conclusions: The ADQ showed good accuracy in screening patients with DoA in a sleep and epilepsy center setting. Diagnostic criteria related to cognition and episode recall reduced ADQ sensitivity, therefore a better definition of these criteria is required, especially in adults.
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http://dx.doi.org/10.1016/j.sleep.2021.01.037DOI Listing
April 2021

Is Focal Cortical Dysplasia/Epilepsy Caused by Somatic Mutations Always a Unilateral Disorder?

Neurol Genet 2021 Feb 8;7(1):e540. Epub 2020 Dec 8.

Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories (R. Guerrini, M.C., A.R, C.B., V.C.), Children's Hospital A. Meyer, University of Florence; Medical Genetics Unit (T.P.), Sant'Orsola-Malpighi University Hospital, Bologna; IRCCS Bologna Institute for Neurological Sciences (F.B.), Bologna. Member of ERN EpiCARE; Department of Medical and Surgical Sciences (P.D.), University of Bologna; Clinical Epileptology and Experimental Neurophysiology Unit (R. Garbelli), IRCCS Istituto Neurologico C. Besta, Milan; Pathology Unit (A.M.B.), Children's Hospital A. Meyer-University of Florence; and "C. Munari" Epilepsy Surgery Center (L.T.), Niguarda Hospital, Milan, Italy.

Objective: To alert about the wide margin of unpredictability that distribution of somatic mosaicism may have in the brain and the risk for independent epileptogenesis arising from the seemingly healthy contralateral hemisphere after complete removal of epileptogenic focal cortical dysplasia (FCD).

Methods: Clinical, EEG, MRI, histopathology, and molecular genetics in 2 patients (1 and 2) treated with focal resections and subsequent complete hemispherectomy for epileptogenic FCD due to somatic mutations. Autoptic brain study of bilateral asymmetric hemispheric dysplasia and identification of alternative allele fraction (AAF) rates for (patient 3).

Results: The strongly hyperactivating p.Ser2215Phe (patient 1) and p.Leu1460Pro (patient 2) mutations were at low-level AAF in the dysplastic tissue. After repeated resections and eventual complete hemispherectomy, both patients manifested intractable seizures arising from the contralateral, seemingly healthy hemisphere. In patient 3, the p.Glu17Lys mutation exhibited random distribution and AAF rates in different tissues with double levels in the more severely dysplastic cerebral hemisphere.

Conclusions: Our understanding of the distribution of somatic mutations in the brain in relation to the type of malformation and its hypothesized time of origin may be faulty. Large studies may reveal that the risk of a first surgery being disappointing might be related more to the specific somatic mammalian target of rapamycin mutation identified than to completeness of resection and that the advantages of repeated resections after a first unsuccessful operation should be weighed against the risk of the contralateral hemisphere becoming in turn epileptogenic.
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http://dx.doi.org/10.1212/NXG.0000000000000540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735020PMC
February 2021

Epilepsy in MT-ATP6 - related mils/NARP: correlation of elettroclinical features with heteroplasmy.

Ann Clin Transl Neurol 2021 03 21;8(3):704-710. Epub 2021 Jan 21.

IRCCS Istituto delle Scienze Neurologiche di Bologna, Full Member of the ERN EpiCARE, Bologna, Italia.

The study aims to characterize the epilepsy phenotype of maternally inherited Leigh's syndrome (MILS) and neuropathy, ataxia, retinitis pigmentosa (NARP) due to mutations in the mitochondrial ATP6 gene and to correlate electroclinical features with mutant heteroplasmy load (HL). We investigated 17 individuals with different phenotype, from asymptomatic carriers to MILS: 11 carried the m.8993T> G mutation, 5 the m.8993T> C and one the novel, de novo m.8858G> A mutation. Seizures occurred in 37.5% of patients, EEG abnormalities in 73%. We ranked clinical and EEG abnormalities severity and performed quantitative EEG to estimate Abnormality Ratio (AR) and Spectral Relative Power (SRP). Spearman's rho and Kruskal-Wallis test were used for correlation with heteroplasmy load (HL). HL correlated with disease severity (Rho = 0.63, P = 0.012) and was significantly higher in patients with seizures or EEG abnormalities (P = 0.014). HL correlated with EEG severity score only for the m.8993T> G (Rho = 0.73, P = 0.040), showing a trend toward a positive correlation with AR and delta SPR, irrespective of the mutation.
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http://dx.doi.org/10.1002/acn3.51259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951109PMC
March 2021

The Impact of the COVID-19 Pandemic on People With Epilepsy. An Italian Survey and a Global Perspective.

Front Neurol 2020 18;11:613719. Epub 2020 Dec 18.

IRCCS Istituto delle Scienze Neurologiche di Bologna, Full Member of the ERN EpiCare, Bologna, Italy.

We explored the impact of the coronavirus disease-19 (COVID-19) emergency on the health of people with epilepsy (PwE). We also investigated their attitude toward telemedicine. The PubMed database up to September 10, 2020 was searched for questionnaire-based studies conducted in PwE during the COVID-19 emergency, and the literature retrieved was reviewed. In addition, all patients who had a telephone consultation with our center between May 7 and July 31, 2020 were invited to fill in a 57-item online questionnaire focusing on epilepsy and comorbidities, any changes in lifestyle or clinical conditions and any emergency-related problems arising during the COVID-19 emergency, and their views on telemedicine. Associations between variables were detected through test and Fisher's exact test. Univariate and multivariate logistic regression models were used to evaluate the effects of different factors on clinical conditions. Twelve studies met the literature search criteria. They showed that the rate of seizure worsening during the emergency ranged from 4 to 35% and was mainly correlated with epilepsy severity, sleep disturbances and COVID-19-related issues. Our questionnaire was filled in by 222 PwE or caregivers. One hundred (76.6%) reported unchanged clinical conditions, 25 (11.3%) an improvement, and 27 (12%) a deterioration. Reported clinical worsening was associated with a psychiatric condition and/or medication (OR = 12.59, < 0.001), sleep disorders (OR = 8.41, = 0.001), limited access to healthcare (OR = 4.71, = 0.016), and experiencing seizures during the emergency (OR = 4.51, = 0.007). Telemedicine was considered acceptable by 116 subjects (52.3%). Most PwE did not experience a significant change in their clinical conditions during the COVID-19 emergency. However, severity of epilepsy, concomitant disability, comorbid psychiatric conditions, sleep disorders and limited access to healthcare may affect their health.
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http://dx.doi.org/10.3389/fneur.2020.613719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775598PMC
December 2020

If seizures left speechless: CA-P-S C-A-R-E, a proposal of a new ictal language evaluation protocol.

Neurol Sci 2021 Aug 27;42(8):3249-3255. Epub 2020 Nov 27.

Department of Biomedical and NeuroMotor Sciences (DiBiNeM), University of Bologna, Bologna, Italy.

Introduction: We aimed to create standardized protocol for language examination in patients who underwent video-EEG recording and assessed its efficacy in the characterization of ictal language impairment, its ability to differentiate this from impaired awareness, and interobserver reliability in clinical practice.

Methods: From our database of video-EEG recordings, we selected a representative sample of 63 focal seizures with presumed language impairment. A multidisciplinary team of epileptologists, EEG technicians, and speech therapists analyzed the selected videos to highlight the critical issues of ordinary ictal language evaluation. We subsequently followed a multi-step process to develop the protocol and assess its interobserver reliability.

Results: A protocol based on seven tests in hierarchical succession was created, summed up in the acronym CA-P-S C-A-R-E (Closed Answers, Pro-speak question, Simple orders, Common object denomination, Audio repetition, Reading, Evoke). Following its preliminary administration for 5 months, we assessed the inter-observer reliability of 16 healthcare professionals in distinguishing between language impairment and impaired awareness among a sample of 10 seizures, finding a substantial agreement (kappa 0.61).

Conclusion: The proposed protocol, made of simple and easy to memorize tests, is an effective tool that evaluates multiple domains beyond language. Its use could help to recognize ictal aphasia effectively and differentiate it from impaired awareness, minimizing inter-examiner variability.
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http://dx.doi.org/10.1007/s10072-020-04872-xDOI Listing
August 2021

Encephalopathy in COVID-19 Presenting With Acute Aphasia Mimicking Stroke.

Front Neurol 2020 19;11:587226. Epub 2020 Oct 19.

Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy.

Neurological manifestations are emerging as relatively frequent complications of corona virus disease 2019 (COVID-19), including stroke and encephalopathy. Clinical characteristics of the latter are heterogeneous and not yet fully elucidated, while the pathogenesis appears related to neuroinflammation in a subset of patients. A middle-aged man presented with acute language disturbance at the emergency department. Examination revealed expressive aphasia, mild ideomotor slowing, and severe hypocapnic hypoxemia. Multimodal CT assessment and electroencephalogram (EEG) did not reveal any abnormalities. COVID-19 was diagnosed based on chest CT findings and positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription PCR (RT-PCR) on nasopharyngeal swab. The following day, neurological symptoms progressed to agitated delirium and respiratory status worsened, requiring admission to the ICU and mechanical ventilation. Brain MRI and cerebrospinal fluid (CSF) studies were unremarkable. RT-PCR for SARS-CoV-2 on CSF was negative. He received supportive treatment and intravenous low-dose steroids. His neurological and respiratory status resolved completely within 2 weeks. We report a patient with reversible COVID-19-related encephalopathy presenting as acute aphasia, mimicking stroke or status epilepticus, eventually evolving into delirium. Although large-vessel stroke is frequently encountered in COVID-19, our case suggests that focal neurological deficits may occur as the earliest feature of encephalopathy. Neurological status reversibility and the absence of abnormalities on brain MRI are consistent with a functional rather than a structural neuronal network impairment.
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http://dx.doi.org/10.3389/fneur.2020.587226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604480PMC
October 2020

COVID-19-related encephalopathy presenting with aphasia resolving following tocilizumab treatment.

J Neuroimmunol 2020 12 24;349:577400. Epub 2020 Sep 24.

Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche di Bologna, Full Member of the ERN EpiCARE, Bologna, Italy. Electronic address:

Encephalopathy is emerging as a recurrent complication of COVID-19 yet remains poorly characterized. We report the case of a middle-aged woman with COVID-19-related encephalopathy presenting as expressive aphasia and inattentiveness, subsequently progressing to agitation and marked confusion. Brain MRI and CSF analysis were unremarkable, while EEG showed slowing with frontal sharp waves. Neuropsychiatric symptoms resolved following treatment with tocilizumab. CNS involvement in COVID-19 may present as a subacute encephalopathy characterized by prominent frontal lobe dysfunction, with language disturbances as first neurological manifestation. Future studies should further investigate the role of tocilizumab in treating COVID-19-related encephalopathy.
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http://dx.doi.org/10.1016/j.jneuroim.2020.577400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513756PMC
December 2020

Intravenous immunoglobulin therapy in COVID-19-related encephalopathy.

J Neurol 2021 Aug 8;268(8):2671-2675. Epub 2020 Oct 8.

Department of Biomedical and Neuromotor Sciences, University of Bologna, Bellaria Hospital, Via Altura 3 40139, Bologna, Italy.

Objective: To report on efficacy and safety of intravenous immunoglobulin (IVIg) therapy in a case series of patients with COVID-19-related encephalopathy.

Methods: We retrospectively collected data on all patients with COVID-19 hospitalized at two Italian hospitals who developed encephalopathy during disease course and were treated with IVIg.

Results: Five patients (two females, mean age 66.8 years) developed encephalopathy after a mean of 12.6 days, since the onset of respiratory/constitutional symptoms related to COVID-19. Four patients suffered severe respiratory distress, three of which required invasive mechanical ventilation. Neurological manifestations included impaired consciousness, agitation, delirium, pyramidal and extrapyramidal signs. EEG demonstrated diffuse slowing in all patients. Brain MRI showed non-specific findings. CSF analysis revealed normal cell count and protein levels. In all subjects, RT-PCR for SARS-CoV-2 in CSF tested negative. IVIg at 0.4 g/kg/die was commenced 29.8 days (mean, range: 19-55 days) after encephalopathy onset, leading to complete electroclinical recovery in all patients, with an initial improvement of neuropsychiatric symptoms observed in 3.4 days (mean, range: 1-10 days). No adverse events related to IVIg were observed.

Conclusions: Our preliminary findings suggest that IVIg may represent a safe and effective treatment for COVID-19-associated encephalopathy. Clinical efficacy may be driven by the anti-inflammatory action of IVIg, associated with its anti-cytokine qualities.
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http://dx.doi.org/10.1007/s00415-020-10248-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543032PMC
August 2021

Interrater agreement of classification of photoparoxysmal electroencephalographic response.

Epilepsia 2020 09 19;61(9):e124-e128. Epub 2020 Sep 19.

Department of Pediatric Clinical Epileptology, Sleep Disorders, and Functional Neurology, University Hospitals of Lyon, Lyon, France.

Our goal was to assess the interrater agreement (IRA) of photoparoxysmal response (PPR) using the classification proposed by a task force of the International League Against Epilepsy (ILAE), and a simplified classification system proposed by our group. In addition, we evaluated IRA of epileptiform discharges (EDs) and the diagnostic significance of the electroencephalographic (EEG) abnormalities. We used EEG recordings from the European Reference Network (EpiCARE) and Standardized Computer-based Organized Reporting of EEG (SCORE). Six raters independently scored EEG recordings from 30 patients. We calculated the agreement coefficient (AC) for each feature. IRA of PPR using the classification proposed by the ILAE task force was only fair (AC = 0.38). This improved to a moderate agreement by using the simplified classification (AC = 0.56; P = .004). IRA of EDs was almost perfect (AC = 0.98), and IRA of scoring the diagnostic significance was moderate (AC = 0.51). Our results suggest that the simplified classification of the PPR is suitable for implementation in clinical practice.
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http://dx.doi.org/10.1111/epi.16655DOI Listing
September 2020

Seizures with paroxysmal arousals in sleep-related hypermotor epilepsy (SHE): Dissecting epilepsy from NREM parasomnias.

Epilepsia 2020 10 19;61(10):2194-2202. Epub 2020 Sep 19.

Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.

Objective: Sleep-related hypermotor epilepsy (SHE) is a focal epilepsy characterized by seizures occurring mostly during sleep, ranging from brief seizures with paroxysmal arousals (SPAs) to hyperkinetic seizures and ambulatory behaviors. SPAs are brief and stereotypic seizures representing the beginning of a major seizure. Distinguishing SPAs from disorders of arousal (DOAs) and their briefest episodes called simple arousal movements (SAMs) is difficult. We performed a characterization of SPAs and SAMs to identify video-polysomnographic (VPSG) features that can contribute to the diagnosis of SHE or DOA.

Methods: Fifteen SHE, 30 DOA adult patients, and 15 healthy subjects underwent full-night VPSG. Two neurologist experts in sleep disorders and epilepsy classified all the sleep-related movements and episodes recorded. For each SPAs and SAMs, sleep stage at onset, duration, limb involvement, progression, and semiology have been identified.

Results: A total of 121 SPAs were recorded, emerging mostly during stage 1-2 non-rapid eye movement (NREM) sleep (median duration: 5 seconds). At the beginning, the SPAs motor pattern was hyperkinetic in 78 cases (64%), involving more than three non-contiguous or all body parts. The standard was a constant progression of movements during SPAs without any motor arrests. In DOA patients a total of 140 SAMs were recorded (median duration: 12 seconds) mostly emerging during stage 3 NREM sleep. In SAMs, we did not observe any tonic/dystonic or hypermotor patterns or stereotypy; motor arrest was present over the course of about half of the episodes. In comparison with both DOA and healthy subjects, SHE patients showed a higher number of sleep-related movements per night and a reduction of sleep efficiency.

Significance: SPAs and SAMs present different semiological and clinical features. Their recognition could be useful to drive the diagnosis when major episodes are not recorded during VPSG in patients with a clear clinical history of SHE or DOA.
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http://dx.doi.org/10.1111/epi.16659DOI Listing
October 2020

Relationship between plasma concentrations and clinical effects of perampanel: A prospective observational study.

Epilepsy Behav 2020 11 25;112:107385. Epub 2020 Aug 25.

Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche di Bologna, Epilepsy Center, (Reference Center for Rare and Complex Epilepsies - EpiCARE), Bologna, Italy.

Purpose: The purpose of the study was to investigate the potential correlation between plasma concentration of the newer antiseizure medication (ASM) perampanel (PMP) and both tolerability and seizure control in patients with epilepsy.

Methods: The study design was multicenter, open, and prospective. Plasma samples were collected in the morning 12 h apart from once-a-day bedtime PMP dose. Perampanel tolerability was assessed on the day of drug monitoring by clinical examination and patients' interview. Response to PMP was defined as ≥50% reduction from baseline seizure frequency (pretreatment). The main outcomes were the comparisons of PMP plasma concentration-to-weight-adjusted dose ratio (C/D) [(μg/mL)/(mg/kg/day)] between patients with and without PMP-related adverse effects (AEs) and between responders and nonresponders.

Results: Ninety-seven patients (54% men), mean ± SD age 36 ± 14 years were enrolled in the study. The mean PMP dose was 6.7 ± 2.3 mg, drug treatment averaged 46 ± 34 weeks. The mean plasma concentration was 360 ± 268 ng/mL (range: 37-1213 ng/mL). Forty patients (41%) reported at least one AE, mainly dizziness and behavioral changes. No significant difference was found in median PMP C/Ds between patients with (2.94) and without (2.76) AEs, otherwise comparable for clinical variables. Forty-four patients (45%) were responders, at a median PMP C/D of 3.10, similar to the value of 2.76 found in nonresponders. These two groups also overlapped for clinical characteristics.

Conclusion: This is the first prospective real-life study to evaluate the relationship between PMP plasma concentrations, seizure control, and AEs. In line with the few real-world available data, we did not find any significant correlation between PMP plasma concentrations and both tolerability and seizure control.
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http://dx.doi.org/10.1016/j.yebeh.2020.107385DOI Listing
November 2020

Accurate Detection of Hot-Spot MTOR Somatic Mutations in Archival Surgical Specimens of Focal Cortical Dysplasia by Molecular Inversion Probes.

Mol Diagn Ther 2020 10;24(5):571-577

IRCCS Istituto delle Scienze Neurologiche di Bologna, Epilepsy Center (Reference Center for Rare and Complex Epilepsies - EpiCARE), Bologna, Italy.

Background: Formalin-fixed, paraffin-embedded brain specimens are a potentially rich resource to identify somatic variants, but their DNA is characterised by low yield and extensive degradation, and matched peripheral samples are usually unavailable for analysis.

Methods: We designed single-molecule molecular inversion probes to target 18 MTOR somatic mutational hot-spots in unmatched, histologically proven focal cortical dysplasias from formalin-fixed, paraffin-embedded tissues of 50 patients.

Results: We achieved adequate DNA and sequencing quality in 28 focal cortical dysplasias, mostly extracted within 2 years from fixation, showing a statistically significant effect of time from fixation as a major determinant for successful genetic analysis. We identified and validated seven encompassing hot-spot residues (found in 14% of all patients and in 25% of those sequenced and analysed). The allele fraction had a range of 2-5% and variants were absent in available neighbouring non-focal cortical dysplasia specimens. We computed an alternate allele threshold for calling true variants, based on an experiment-wise mismatch count distribution, well predicting call reliability.

Conclusions: Single-molecule molecular inversion probes are experimentally simple, cost effective and scalable, accurately detecting clinically relevant somatic variants in challenging brain formalin-fixed, paraffin-embedded tissues.
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http://dx.doi.org/10.1007/s40291-020-00488-1DOI Listing
October 2020

Did the COVID-19 pandemic silence the needs of people with epilepsy?

Epileptic Disord 2020 Aug;22(4):439-442

Epilepsy Monitoring Unit, Department of Neurology, Hospital del Mar, Barcelona, Spain. Member of ERN EpiCARE, Hospital del Mar Medical Research Institute (IMIM) Barcelona, Spain.

The COVID-19 pandemic shook European healthcare systems, with unavoidable gaps in the management of patients with chronic diseases. We describe the impact of the pandemic on epilepsy care in three tertiary epilepsy centres from Spain and Italy, the most affected European countries. The three epilepsy centres, members of the European EpiCARE network, manage more than 5,700 people with epilepsy. In Bologna and Barcelona, the hospitals housing the epilepsy centres were fully converted into COVID-19 units. We describe the reorganization of the clinics and report on the frequency of SARS-CoV-2 in people with epilepsy as well as the frequency of seizures in patients admitted to the COVID units. Finally, we elaborate on critical issues regarding the second phase of the pandemic. The activities related to epilepsy care were reduced to less than 10% and were deprioritized. Discharges were expedited and elective epilepsy surgeries, including vagal nerve stimulator implantations, cancelled. Hospitalizations and EEG examinations were limited to emergencies. The outpatient visits for new patients were postponed, and follow-up visits mostly managed by telehealth. Antiseizure medication weaning plans and changes in vagal nerve stimulator settings were halted. Among the 5,700 people with epilepsy managed in our centres, only 14 tested positive for SARS-CoV-2, without obvious impact on their epilepsy. None of the 2,122 patients admitted to COVID units experienced seizures among the early symptoms. Epilepsy care was negatively impacted by the pandemic, irrespective of COVID-19 epidemiology or conversion of the hospital into a COVID-19 centre. The pandemic did not silence the needs of people with epilepsy, and this must be considered in the planning of the second phase.
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http://dx.doi.org/10.1684/epd.2020.1175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537265PMC
August 2020

EEG findings in COVID-19 related encephalopathy.

Clin Neurophysiol 2020 09 18;131(9):2265-2267. Epub 2020 Jul 18.

IRCCS - Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.

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http://dx.doi.org/10.1016/j.clinph.2020.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367805PMC
September 2020

Whole-exome sequencing in adult patients with developmental and epileptic encephalopathy: It is never too late.

Clin Genet 2020 11 1;98(5):477-485. Epub 2020 Sep 1.

IRCCS, Istituto delle Scienze Neurologiche di Bologna (Reference Center for Rare and Complex Epilepsies-EpiCARE), Bologna, Italy.

Developmental and epileptic encephalopathies (DEE) encompass rare, sporadic neurodevelopmental disorders and usually with pediatric onset. As these conditions are characterized by marked clinical and genetic heterogeneity, whole-exome sequencing (WES) represents the strategy of choice for the molecular diagnosis. While its usefulness is well established in pediatric DEE cohorts, our study is aimed at assessing the WES feasibility in adult DEE patients who experienced a diagnostic odyssey prior to the advent of this technique. We analyzed exomes from 71 unrelated adult DEE patients, consecutively recruited from an Italian cohort for the EPI25 Project. All patients underwent accurate clinical and electrophysiological characterization. An overwhelming percentage (90.1%) had already undergone negative genetic testing. Variants were classified according to the American College of Medical Genetics and Genomics guidelines. WES disclosed 24 (likely) pathogenic variants among 18 patients in epilepsy-related genes with either autosomal dominant, recessive or X-linked inheritance. Ten of these were novel. We obtained a diagnostic yield of 25.3%, higher among patients with brain malformations, early-onset epilepsy and dysmorphisms. Despite a median diagnostic delay of 38.7 years, WES analysis provided the long-awaited diagnosis for 18 adult patients, which also had an impact on the clinical management of 50% of them.
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http://dx.doi.org/10.1111/cge.13823DOI Listing
November 2020

Autosomal dominant lateral temporal lobe epilepsy associated with a novel reelin mutation.

Epileptic Disord 2020 Aug;22(4):443-448

CNR-Neuroscience Institute, Section of Padua, Padova, Italy, Department of Biomedical Sciences, University of Padua, Padova, Italy.

Reelin mutations are responsible for a minority of families with autosomal dominant lateral temporal lobe epilepsy. Here, we report a novel nuclear family with distinct clinical and neuroradiological findings. We studied the proband and her mother by means of EEG, video-EEG, 3T MRI, FDG-PET and genetic testing. Both patients had a focal drug-resistant epilepsy with onset at the age of 16 and focal seizures with typical auditory features combined with fear, followed by loss of contact or evolving to bilateral tonic-clonic seizures. The proband's ictal EEG showed clear left temporal seizure onset, and cerebral MRI revealed subtle left temporal changes (mild hypotrophy, slight blurring of the white and grey matter and hyperintensity) with corresponding left temporal mesial focal hypometabolism on FDG-PET. Genetic testing identified a missense variant, c.6631C>T (p.Arg2211Cys), in reelin repeat #5 in both patients, which markedly affected the secretion of the protein. The data from this family support previous findings indicating that reelin mutations are a cause of autosomal dominant lateral temporal lobe epilepsy which has a clinical spectrum that may also encompass drug-resistant epilepsy associated with mild MRI temporal changes.
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http://dx.doi.org/10.1684/epd.2020.1176DOI Listing
August 2020

COVID-19-Associated Encephalopathy and Cytokine-Mediated Neuroinflammation.

Ann Neurol 2020 10 14;88(4):860-861. Epub 2020 Aug 14.

Department of Biomedical and NeuroMotor Sciences, Alma Mater Studiorum-University of Bologna, Bologna, Italy.

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http://dx.doi.org/10.1002/ana.25855DOI Listing
October 2020

Antidepressant effect of vagal nerve stimulation in epilepsy patients: a systematic review.

Neurol Sci 2020 Nov 10;41(11):3075-3084. Epub 2020 Jun 10.

Institute of Neurology, University Magna Graecia, Germaneto (CZ), Italy.

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.
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http://dx.doi.org/10.1007/s10072-020-04479-2DOI Listing
November 2020

Low CSF hypocretin-1 levels in an adult patient with hypothalamic hamartoma.

Neurology 2020 04 10;94(15):670-672. Epub 2020 Mar 10.

From the Department of Biomedical and Neuromotor Sciences (L.M., F.B., L.L., F.P., G.P., P.T.), University of Bologna; and IRCCS Istituto delle Scienze Neurologiche di Bologna (F.B., L.L., F.P., M. Moresco, M. Martinoni, M.Z., G.P., P.T.), Italy.

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http://dx.doi.org/10.1212/WNL.0000000000009243DOI Listing
April 2020

Therapy in Sleep-Related Hypermotor Epilepsy (SHE).

Curr Treat Options Neurol 2020 Jan 30;22(1). Epub 2020 Jan 30.

Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.

Purpose Of Review: The purpose of this review is to summarize and discuss current options and new advances in the treatment of sleep-related hypermotor epilepsy (SHE), focusing on pharmacological and surgical treatments.

Recent Findings: Carbamazepine (CBZ) has traditionally been regarded as the first-line treatment option in SHE patients. In patients showing an unsatisfactory response to monotherapy, topiramate (TPM), lacosamide (LCM) and acetazolamide (ACZ) could be reasonable add-on strategies. The increasing understanding of the role of neuronal nicotinic acetylcholine receptor (nAChR) in SHE pathophysiology has led to the evaluation of compounds able to modulate this receptor system, including nicotine patches and fenofibrate. Despite polytherapy with two or more antiepileptic drugs (AEDs), about one-third of SHE patients suffer from drug-resistant seizures. In selected drug-resistant patients, epilepsy surgery is a therapeutic approach that offers high probability of recovery, with up to two-third of patients becoming seizure-free after resection of the epileptogenic zone. An evidence-based approach from randomized placebo-controlled trials in SHE patients is lacking, and current treatment recommendations are based only on case reports and small series. Furthermore, most of these case reports and case series involve patients with a known genetic defect, which only accounts for a small proportion of SHE patients. Therefore, a prospective study in a large cohort of sporadic SHE patients is necessary in order to provide clinicians with an evidence-based treatment for this rare form of epilepsy. An early and effective anti-epileptic treatment is mandatory for SHE patients, in order to prevent the risk of increasing seizure frequency throughout the disease course with relevant impact on patients' cognitive profile and daytime performances.
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http://dx.doi.org/10.1007/s11940-020-0610-1DOI Listing
January 2020

Advances in genetic testing and optimization of clinical management in children and adults with epilepsy.

Expert Rev Neurother 2020 03 27;20(3):251-269. Epub 2020 Jan 27.

Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

: Epileptic disorders are a heterogeneous group of medical conditions with epilepsy as the common denominator. Genetic causes, electro-clinical features, and management significantly vary according to the specific condition.: Relevant diagnostic advances have been achieved thanks to the advent of Next Generation Sequencing (NGS)-based molecular techniques. These revolutionary tools allow to sequence all coding (whole exome sequencing, WES) and non-coding (whole genome sequencing, WGS) regions of human genome, with a potentially huge impact on patient care and scientific research.: The application of these tests in children and adults with epilepsy has led to the identification of new causative genes, widening the knowledge on the pathophysiology of epilepsy and resulting in therapeutic implications. This review will explore the most recent advancements in genetic testing and provide up-to-date approaches for the choice of the correct test in patients with epilepsy.
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http://dx.doi.org/10.1080/14737175.2020.1713101DOI Listing
March 2020
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