Publications by authors named "Edoardo Ferlazzo"

138 Publications

Sample selection and gold standard testing for a proper group comparison.

Eur J Neurol 2021 Nov 2;28(11):e86. Epub 2021 Sep 2.

Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy.

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http://dx.doi.org/10.1111/ene.15076DOI Listing
November 2021

Adjunctive Brivaracetam in Focal Epilepsy: Real-World Evidence from the BRIVAracetam add-on First Italian netwoRk STudy (BRIVAFIRST).

CNS Drugs 2021 Sep 2. Epub 2021 Sep 2.

Department of Human Neurosciences, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.

Background: In randomized controlled trials, add-on brivaracetam (BRV) reduced seizure frequency in patients with drug-resistant focal epilepsy. Studies performed in a naturalistic setting are a useful complement to characterize the drug profile.

Objective: This multicentre study assessed the effectiveness and tolerability of adjunctive BRV in a large population of patients with focal epilepsy in the context of real-world clinical practice.

Methods: The BRIVAFIRST (BRIVAracetam add-on First Italian netwoRk STudy) was a retrospective, multicentre study including adult patients prescribed adjunctive BRV. Patients with focal epilepsy and 12-month follow-up were considered. Main outcomes included the rates of seizure-freedom, seizure response (≥ 50% reduction in baseline seizure frequency), and treatment discontinuation. The incidence of adverse events (AEs) was also considered. Analyses by levetiracetam (LEV) status and concomitant use of strong enzyme-inducing antiseizure medications (EiASMs) and sodium channel blockers (SCBs) were performed.

Results: A total of 1029 patients with a median age of 45 years (33-56) was included. At 12 months, 169 (16.4%) patients were seizure-free and 383 (37.2%) were seizure responders. The rate of seizure freedom was 22.3% in LEV-naive patients, 7.1% in patients with prior LEV use and discontinuation due to insufficient efficacy, and 31.2% in patients with prior LEV use and discontinuation due to AEs (p < 0.001); the corresponding values for ≥ 50% seizure frequency reduction were 47.9%, 29.7%, and 42.8% (p < 0.001). There were no statistically significant differences in seizure freedom and seizure response rates by use of strong EiASMs. The rates of seizure freedom (20.0% vs. 16.6%; p = 0.341) and seizure response (39.7% vs. 26.9%; p = 0.006) were higher in patients receiving SCBs than those not receiving SCBs; 265 (25.8%) patients discontinued BRV. AEs were reported by 30.1% of patients, and were less common in patients treated with BRV and concomitant SCBs than those not treated with SCBs (28.9% vs. 39.8%; p = 0.017).

Conclusion: The BRIVAFIRST provided real-world evidence on the effectiveness of BRV in patients with focal epilepsy irrespective of LEV history and concomitant ASMs, and suggested favourable therapeutic combinations.
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http://dx.doi.org/10.1007/s40263-021-00856-3DOI Listing
September 2021

Predictive factors of Status Epilepticus and its recurrence in patients with adult-onset seizures: A multicenter, long follow-up cohort study.

Seizure 2021 Oct 18;91:397-401. Epub 2021 Jul 18.

Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension of Reggio Calabria, National Council of Research, Institute of Clinical Physiology, Reggio Calabria, Italy.

Purpose: Status epilepticus (SE) is associated with high morbidity and mortality. This multicenter retrospective cohort study aims to identify the factors associated with the occurrence of SE and the predictors of its recurrence in patients with adult-onset seizures.

Methods: We retrospectively analyzed data of 1115 patients with seizure onset>18 years, observed from 1983 to 2020 in 7 Italian Centers (median follow-up 2.1 years). Data were collected from the databases of the Centers. Patients with SE were consecutively recruited, and patients without SE history were randomly selected in a 2:1 ratio. To assess determinants of SE, different clinical-demographic variables were evaluated and included in univariate and multivariate logistic regression model.

Results: Three hundred forty-seven patients had a SE history, whereas the remaining 768 patients had either isolated seizures or epilepsy without SE history. The occurrence of SE was independently associated with increasing age at onset of disease (OR 1.02, 95% CI 1.01--1.03, p<0.001), female sex (OR 1.39, 95% CI 1.05--1.83, p=0.02) and known etiology (OR 3.58, 95% CI 2.61--4.93, p<0.001). SE recurred in 21% of patients with adult-onset SE and recurrence was associated with increasing number of anti-seizure medications taken at last follow-up (OR 1.88, 95% CI 1.31--2.71, p<0.001).

Conclusions: In patients with adult-onset seizures, SE occurrence is associated with known etiologies, advanced age and female sex. Patients with recurrent SE are likely to have a refractory epilepsy, deserving careful treatment to prevent potentially fatal events.
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http://dx.doi.org/10.1016/j.seizure.2021.07.009DOI Listing
October 2021

Therapeutic approach to difficult-to-treat typical absences and related epilepsy syndromes.

Expert Rev Clin Pharmacol 2021 Jul 26:1-7. Epub 2021 Jul 26.

Regional Epilepsy Centre, Great Metropolitan "BMM" Hospital, Reggio, Calabria, Italy.

: typical absences (TAs), are brief, generalized epileptic seizures of abrupt onset and termination clinically manifesting with impairment of awareness and associated with 3 Hz spike-wave discharges on EEG. TAs may occur in different idiopathic generalized epilepsies (IGE). Despite treatment with adequate anti-seizure medications (ASMs), TAs may persist in ~25% of subjects. This narrative review focuses on the therapeutic approach to difficult-to-treat TAs occurring in the setting of IGE.: a literature search was conducted on the topic of treatment of TAs.: ethosuximide (ESX), valproic acid (VPA) and lamotrigine (LTG), alone or in combination, are considered the first-choice drugs. In women of childbearing potential, VPA should be avoided. Alternative therapies (benzodiazepines, levetiracetam, topiramate, or zonisamide) should be considered in subjects unresponsive to monotherapy after the exclusion of pseudo-drug resistance. Newer ASMs such as brivaracetam and perampanel seem to be promising options. Well-conducted clinical trials aimed to evaluate the efficacy of alternative monotherapy (beyond ESX, VPA or LTG) or combination of ASMs on difficult-to-treat TAs, are warranted.
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http://dx.doi.org/10.1080/17512433.2021.1959317DOI Listing
July 2021

Epidemiology and Outcomes of Status Epilepticus.

Int J Gen Med 2021 28;14:2965-2973. Epub 2021 Jun 28.

Science of Health Department, Magna Græcia University, Catanzaro, Italy.

Status epilepticus (SE) is a neurological and medical emergency, defined as a condition resulting either from the failure of the mechanisms responsible of seizure self-limitation or from the initiation of mechanisms which lead to atypically prolonged seizures. Further than death, SE can have long-term consequences, including neuronal injury, depending on the type, cause and duration of seizures with severe associated disabilities. In Europe, SE shows an incidence rate ranging about 9 to 40/100,000/y. In adults, mortality of patients with SE is ~30%, and even higher (up to 40%) in refractory status epilepticus. To date, etiology, duration, presence of comorbidity, level of consciousness, semiology and age are the main clinical predictors of SE outcome.
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http://dx.doi.org/10.2147/IJGM.S295855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254099PMC
June 2021

Diagnostic and therapeutic approach to drug-resistant juvenile myoclonic epilepsy.

Expert Rev Neurother 2021 May 25:1-9. Epub 2021 May 25.

Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy.

Introduction: Juvenile myoclonic epilepsy (JME), also known as Janz syndrome, is a common form of generalized epilepsy of presumed genetic origin representing up to 10% of all epilepsy cases. Despite adequate anti-seizure medication (ASM) treatment, seizures persist in one-third of JME patients.

Areas Covered: A literature search was conducted using Pubmed search on the topics of drug-resistant JME.

Expert Opinion: About 30% of JME patients are drug-resistant. Valproate (VPA) is considered the first-choice drug. In women of childbearing potential, levetiracetam (LEV) should represent the first-choice treatment. Alternative monotherapy or add-on therapy should be considered in subjects with resistant seizures after the exclusion of pseudo-drug resistance. The choice of the add-on ASM depends on the predominant seizure type. In subjects with persistent bilateral tonic-clonic seizures, LEV or lamotrigine should be firstly considered. In patients with difficult-to-treat myoclonic seizures, clonazepam or LEV are recommended. In case of persistent absences, ethosuximide should be considered. With appropriate selection and safeguards in place, VPA should remain available as an option in women of childbearing potential whose seizures are resistant to other treatments.
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http://dx.doi.org/10.1080/14737175.2021.1931126DOI Listing
May 2021

SMART: stroke-like migraine attacks after radiation therapy or seizures with migraine-like attacks after radiation therapy? Terms do matter in clinical practice.

Neurol Sci 2021 Aug 22;42(8):3447-3448. Epub 2021 Apr 22.

Department of Medical and Surgical Sciences, Magna Græcia University of Catanzaro, Catanzaro, Italy.

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http://dx.doi.org/10.1007/s10072-021-05228-9DOI Listing
August 2021

Generation of human induced pluripotent stem cell lines (UNIMGi003-A and UNIMGi004-A) from two Italian siblings affected by Unverricht-Lundborg disease.

Stem Cell Res 2021 05 9;53:102329. Epub 2021 Apr 9.

Department of Clinical and Experimental Medicine, Magna Græcia University, 88100 Catanzaro, Italy. Electronic address:

Unverricht-Lundborg disease (ULD) is an inherited form of progressive myoclonus epilepsy caused by mutations in the gene encoding Cystatin B (CSTB), an inhibitor of lysosomal proteases. The most common mutation described in ULD patients is an unstable expansion of a dodecamer sequence located in the CSTB gene promoter. This expansion is causative of the downregulation of CSTB gene expression and, consequently, of its inhibitory activity. Here we report the generation of induced pluripotent stem cell (iPSC) lines from two Italian siblings having a family history of ULD and affected by different clinical and pathological phenotypes of the disease.
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http://dx.doi.org/10.1016/j.scr.2021.102329DOI Listing
May 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

Dystonia in Angelman syndrome: a common, unrecognized clinical finding.

J Neurol 2021 Jun 23;268(6):2208-2212. Epub 2021 Jan 23.

Department of Medical and Surgical Sciences, Magna Graecia University, Germaneto, Catanzaro, Italy.

Introduction: Angelman syndrome (AS) is a neurodevelopmental disorder characterized by cognitive disability, speech impairment, hyperactivity and seizures. Movement disorders have been reported in almost all AS subjects and they are described as "tremulous movements of limbs, unsteadiness, clumsiness or quick, jerky motions". The presence of dystonia has barely been mentioned in subjects with AS and has never been studied in detail. The purpose of this study is to evaluate the prevalence, clinical features and severity of dystonia in a series of adolescents and adults with AS.

Methods: Whole body video recordings of patients with genetically confirmed AS were evaluated. Dystonia was evaluated by mean of the movement subscale of Burke-Fahn-Marsden Dystonia Rating Scale (BFM).

Results: Forty-four subjects with AS were evaluated. Fourteen recordings were excluded due to poor cooperation. We finally analyzed data of 30 subjects (15 F) with a median age of 28 years (range 15-51). Dystonia was present in 28/30 (93.3%) subjects. Among these, dystonia involved the upper limbs in 28/28 (100%), lower limbs in 8/28 (28.5%), mouth in 7/28 (25%), neck in 3/28 (10.7%), trunk in 1/28 (3.6%). Severity of dystonia ranged from slight to moderate. There was a linear correlation between severity of dystonia and increasing age. There was no difference in terms of severity of dystonia among genetic subgroups.

Conclusions: Dystonia is a common and previously underrecognized clinical feature of adults and adolescents with AS.
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http://dx.doi.org/10.1007/s00415-020-10395-4DOI Listing
June 2021

Management of status epilepticus in patients with liver or kidney disease: a narrative review.

Expert Rev Neurother 2020 Dec 28:1-14. Epub 2020 Dec 28.

Regional Epilepsy Centre, Great Metropolitan "Bianchi-Melacrino-Morelli" Hospital, Reggio, Italy.

: Status epilepticus (SE) is a neurologic and medical emergency with significant related morbidity and mortality. Hepatic or renal dysfunction can considerably affect the pharmacokinetics of drugs used for SE through a variety of direct or indirect mechanisms.: This review aims to focus on the therapeutic management of SE in patients with hepatic or renal impairment, highlighting drugs' selection and dose changes that may be necessary due to altered drug metabolism and excretion. The references for this review were identified by searches of PubMed and Google Scholar until May 2020.: According to literature evidence and clinical experience, in patients with renal disease, the authors suggest considering lorazepam as the drug of choice in pre-hospital and intra-hospital early-stage SE, phenytoin in definite SE, propofol in refractory or super-refractory SE. In patients with liver disease, the authors suggest the use of lorazepam as drug of choice in pre-hospital and intra-hospital early-stage SE, lacosamide in definite SE, propofol in refractory or super-refractory SE. A list of preferred drugs for all SE stages is provided.
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http://dx.doi.org/10.1080/14737175.2021.1862649DOI Listing
December 2020

Proprioceptive-induced seizures in non-ketotic hyperglycemia. A video-EEG documentation.

Seizure 2020 Oct 18;81:178-179. Epub 2020 Aug 18.

Regional Epilepsy Centre, Great Metropolitan "Bianchi-Melacrino-Morelli Hospital", Reggio Calabria, Italy; Department of Medical and Surgical Sciences, Magna Græcia University of Catanzaro, Italy; Institute of Molecular Bioimaging and Physiology, National Research Council, Catanzaro, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.seizure.2020.08.013DOI Listing
October 2020

Perampanel Confirms to Be Effective and Well-Tolerated as an Add-On Treatment in Patients With Brain Tumor-Related Epilepsy (PERADET Study).

Front Neurol 2020 25;11:592. Epub 2020 Jun 25.

Center for Tumor-Related Epilepsy, UOSD Neuroncology, IRCCS IFO Regina Elena National Cancer Institute, Rome, Italy.

Epilepsy is one of the most common symptoms of brain tumors. It is often drug resistant and generally worsen patients' quality of life (QoL). Brain tumors release glutamate among other mediators, contributing to seizures onset, and this is accompanied by an increased AMPA receptors' expression on neuronal cells' membrane. Perampanel (PER) is a relatively new antiseizure medication (ASM) that acts as a selective non-competitive AMPA receptors' antagonist. Given its mechanism of action, we aimed to evaluate through a prospective, observational study, the efficacy and safety of PER as an add-on treatment in patients with brain tumor-related epilepsy (BTRE). The study was called PERADET. Thirty-six adult patients (intention to treat population-ITT) affected by BTRE, with uncontrolled focal-onset seizures treated with 1-3 ASMs were recruited from four Italian epilepsy centers. Perampanel was added-on, titrated from 2 mg/day up to a maximum of 12 mg/day. Tumor history and therapy, type, and seizures frequency, previous ASMs were collected at 6 and 12 months. A battery of QoL tests were administered at baseline, 6 and 12 months. The primary endpoint was to assess the efficacy of PER by calculating the percent change in seizure frequency and the responder rate. The secondary endpoints were tolerability, retention rate at 12 months, and improvement in quality of life. At the end of 12 months, 21 patients (per protocol population-PP) were available for evaluation. In this population the responder rate (percentage of patients who experienced a 50% or greater reduction in seizure frequency) was 90.4 with 33.3% of patients being seizure-free. In the ITT group the responder rate at the end of 12 months was 66.6 with 25% of patients being seizure free. PER was well tolerated (30.6% of patients experienced an adverse event, none was severe; three needed a treatment interruptions). Our study indicate that PER may be efficacious against BTRE as suggested by its mechanism of action and our current knowledge on mechanisms of brain tumor epileptogenicity. (Prot. n° 0008872.25-06-2019); RS 919/17.
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http://dx.doi.org/10.3389/fneur.2020.00592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336340PMC
June 2020

A Family With a Complex Phenotype Caused by Two Different Rare Metabolic Disorders: GLUT1 and Very-Long-Chain Fatty Acid Dehydrogenase (VLCAD) Deficiencies.

Front Neurol 2020 23;11:514. Epub 2020 Jun 23.

Unit of Neurology and Neuromuscular Disorders, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.

GLUT1 Deficiency Syndrome (GLUT1-DS) is a rare and potentially treatable neurometabolic condition, caused by a reduced glucose transport into the brain and clinically characterized by an epileptic encephalopathy with movement disorders. A wide inter-intrafamilial phenotypic variability has been reported. Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is an inherited metabolic disorder of mitochondrial long-chain fatty acid oxidation (FAO) with also a variable age of onset and clinical presentation including cardiomyopathy, hypoketotic hypoglycemia, and liver disease. Sometimes, VLCAD manifests later with a prevalent muscle involvement characterized by exercise intolerance and recurrent rhabdomyolysis. We report a 40-year-old man with mild mental retardation and sporadic choreo-athetoid movements, who complained of recurrent episodes of rhabdomyolysis triggered by exercise or fasting since his twenties. His 15-year-old son had a psychomotor developmental delay with episodes of drowsiness mainly at fasting and exercise-induced choreo-athetoid movements but no history of pigmenturia. Clinical and laboratory findings in the son suggested a diagnosis of GLUT1-DS confirmed by genetic analysis that revealed a heterozygous mutation c.997C>T (p.R333W) that was also found in the proband. However, the presence in the latter of recurrent exercise-induced rhabdomyolysis, never reported in GLUT1-DS, implied a second metabolic disorder. Increased plasma C14:1-carnitine levels and the identification of two known heterozygous mutations c. 553G>A (p.G185S) and c.1153C>T (p.R385W) in confirmed the additional diagnosis of VLCAD deficiency in the proband. Nowadays, there is an increasing evidence of "double trouble" cases of genetic origin. Consequently, when atypical features accompany a known phenotype, associated comorbidities should be considered.
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http://dx.doi.org/10.3389/fneur.2020.00514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324651PMC
June 2020

Self-induced psychogenic non-epileptic seizure. A case report.

Seizure 2020 08 17;80:159-160. Epub 2020 Jun 17.

Department of Medical and Surgical Sciences, Magna Græcia University of Catanzaro, Italy; Regional Epilepsy Centre, Great Metropolitan "Bianchi-Melacrino-Morelli" Hospital, Reggio Calabria, Italy; Institute of Molecular Bioimaging and Physiology, National Research Council, Catanzaro, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.seizure.2020.06.026DOI Listing
August 2020

Testing rimegepant for migraine-time to revise the trial design?

Lancet 2020 06;395(10241):1901

Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Italy; Regional Epilepsy Centre, Great Metropolitan Hospital, Reggio Calabria 89100, Italy.

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http://dx.doi.org/10.1016/S0140-6736(20)30241-5DOI Listing
June 2020

Cryptogenic cerebral venous thrombosis in a multiple-sclerosis-patient treated with Alemtuzumab.

Mult Scler Relat Disord 2020 Sep 30;44:102246. Epub 2020 May 30.

Regional Epilepsy Centre, Great Metropolitan Hospital, Reggio Calabria, Italy; Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Italy.

Alemtuzumab is a highly effective treatment for relapsing-remitting multiple sclerosis (MS). Its molecular target is CD 52, a GPI-anchored protein. Herein, we describe the case of a 40-year-old man with MS treated with alemtuzumab, who developed cerebral sinus thrombosis. In the literature, alemtuzumab was associated with venous thrombosis, attributed to a paroxysmal nocturnal hemoglobinuria (PNH)-like mechanism. In our case, no PNH clones were detected. Other common causes of cerebral venous thrombosis, like infections and thrombophilia, were excluded, thus the pathogenic mechanism remains obscure.
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http://dx.doi.org/10.1016/j.msard.2020.102246DOI Listing
September 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

The efficacy of perampanel as adjunctive therapy in drug-resistant focal epilepsy in a "real world" context: focus on temporal lobe epilepsy.

J Neurol Sci 2020 Aug 15;415:116903. Epub 2020 May 15.

Institute of Neurology, University "Magna Graecia", Catanzaro, Italy. Electronic address:

Background: Perampanel (PER) is a novel antiepileptic drug approved as an add-on therapy for focal onset seizures with or without generalization and primary generalized tonic-clonic seizures. Aim of this study was to evaluate PER efficacy and tolerability as add-on therapy in patients with drug-resistant focal onset seizures and especially temporal lobe epilepsy (TLE).

Methods: An observational, prospective, multicentre study on adult with drug-resistant focal epilepsy consecutively recruited from six Italian tertiary epilepsy centres. All patients received add-on PER according to indication and clinical judgement. Seizure frequency and adverse events (AEs) were recorded at 6 and 12 months after PER introduction.

Results: Study sample comprised 246 patients, 77 of which with TLE. Seventy-five (35.9%) out of 209 and 66 (38.8%) out of 170 patients still taking PER resulted to be responders (i.e. ≥50% of seizure frequency or seizure free) after six and 12 months, respectively. In the TLE group, 39 (57.3%) out of 68 subjects on PER after 6 months and 32 (60.4%) out of 53 subjects taking PER after 12 months were responders. Overall reported incidence of AEs was 26.1%. In 28 cases (11.3%) AEs lead/contributed to PER discontinuation. The most frequently reported AE were dizziness (14/84) and somnolence (14/84). Regarding TLE patients, 25.9% of them experienced at least one AE and discontinuation for AEs occurred in eight (10.4%).

Conclusions: This study confirmed the good efficacy and safety of PER for drug-resistant focal epilepsy in real-life conditions and, above all, for the first time provide its effectiveness in patients with TLE.
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http://dx.doi.org/10.1016/j.jns.2020.116903DOI Listing
August 2020

Late drug-resistance in mild MTLE: Can it be influenced by preexisting white matter alterations?

Epilepsia 2020 05 20;61(5):924-934. Epub 2020 Apr 20.

Institute of Neurology, University Magna Graecia, Catanzaro, Italy.

Objective: To identify early structural alterations preceding the development of drug-resistance in mild mesial temporal lobe epilepsy (mMTLE), a drug-responsive syndrome ideal for investigating epilepsy pathophysiology and potential prognostic markers of long-term clinical outcome, using magnetic resonance imaging (MRI) at baseline and after 12-year follow-up.

Methods: Since 2002, a total of 55 participants with a baseline diagnosis of mMTLE underwent three-dimensional (3D) T1 1.5T MRI. Based on long-term outcome (follow-up 12 ± 3 years), we identified 39 patients with stable mMTLE (smMTLE) and 16 patients who had developed drug-resistance overtime (refractory MTLE [rMTLE]). At follow-up, 21 smMTLE and 13 rMTLE patients underwent 3T-MRI including diffusion-weighted scans. Structural images were processed using longitudinal voxel-based morphometry and standard Freesurfer analysis. Statistical analyses were carried out accounting for age, age at onset, gender, hippocampal volume, and hippocampal sclerosis (Hs).

Results: Patients presented similar demographic, clinical, and Hs features. White matter volume of the arcuate fasciculi, corticospinal tracts, left retrosplenial cingulum, and left inferior longitudinal fasciculus was reduced only in rMTLE patients before the development of drug-resistance. At follow-up, rMTLE showed decreased fractional anisotropy in the corpus callosum, superior longitudinal fasciculi, and major bundles of the right hemisphere.

Significance: White matter temporal and extratemporal abnormalities are preexisting in patients with mild MTLE who will develop drug-resistance, independently from the presence of Hs. Thus, these changes might be due to an inherited genetic alteration rather than a subordinate worsening after repeated seizures, multiple antiepileptic drugs, or initial precipitating factors.
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http://dx.doi.org/10.1111/epi.16503DOI Listing
May 2020

A Comprehensive Machine-Learning-Based Software Pipeline to Classify EEG Signals: A Case Study on PNES vs. Control Subjects.

Sensors (Basel) 2020 Feb 24;20(4). Epub 2020 Feb 24.

Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy.

The diagnosis of psychogenic nonepileptic seizures (PNES) by means of electroencephalography (EEG) is not a trivial task during clinical practice for neurologists. No clear PNES electrophysiological biomarker has yet been found, and the only tool available for diagnosis is video EEG monitoring with recording of a typical episode and clinical history of the subject. In this paper, a data-driven machine learning (ML) pipeline for classifying EEG segments (i.e., epochs) of PNES and healthy controls (CNT) is introduced. This software pipeline consists of a semiautomatic signal processing technique and a supervised ML classifier to aid clinical discriminative diagnosis of PNES by means of an EEG time series. In our ML pipeline, statistical features like the mean, standard deviation, kurtosis, and skewness are extracted in a power spectral density (PSD) map split up in five conventional EEG rhythms (delta, theta, alpha, beta, and the whole band, i.e., 1-32 Hz). Then, the feature vector is fed into three different supervised ML algorithms, namely, the support vector machine (SVM), linear discriminant analysis (LDA), and Bayesian network (BN), to perform EEG segment classification tasks for CNT vs. PNES. The performance of the pipeline algorithm was evaluated on a dataset of 20 EEG signals (10 PNES and 10 CNT) that was recorded in eyes-closed resting condition at the Regional Epilepsy Centre, Great Metropolitan Hospital of Reggio Calabria, University of Catanzaro, Italy. The experimental results showed that PNES vs. CNT discrimination tasks performed via the ML algorithm and validated with random split (RS) achieved an average accuracy of 0.97 ± 0.013 (RS-SVM), 0.99 ± 0.02 (RS-LDA), and 0.82 ± 0.109 (RS-BN). Meanwhile, with leave-one-out (LOO) validation, an average accuracy of 0.98 ± 0.0233 (LOO-SVM), 0.98 ± 0.124 (LOO-LDA), and 0.81 ± 0.109 (LOO-BN) was achieved. Our findings showed that BN was outperformed by SVM and LDA. The promising results of the proposed software pipeline suggest that it may be a valuable tool to support existing clinical diagnosis.
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http://dx.doi.org/10.3390/s20041235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071461PMC
February 2020

Connectivity measures suggest a sub-cortical generator of myoclonus in Angelman syndrome.

Clin Neurophysiol 2019 12 24;130(12):2231-2237. Epub 2019 Oct 24.

Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy; Regional Epilepsy Centre, Great Metropolitan Hospital "Bianchi-Melacrino-Morelli", Reggio Calabria, Italy.

Objective: The clinical and neurophysiological characteristics of myoclonus in Angelman syndrome (AS) have been evaluated in single case or small cohorts, with contrasting results. We evaluated the features of myoclonus in a wide cohort of AS patients.

Methods: We performed polygraphic EEG-EMG recording in 24 patients with genetically confirmed AS and myoclonus. Neurophysiological investigations included jerk-locked back-averaging (JLBA), cortico-muscular coherence (CMC) and generalised partial directed coherence (GPDC). CMC and GPDC analyses were compared to those obtained from 10 healthy controls (HC).

Results: Twenty-four patients (aged 3-35 years, median 20) were evaluated. Sequences of quasi-continuous rhythmic jerks mostly occurred at alpha frequency or just below (mean 8.4 ± 1.4 Hz), without EEG correlate. JLBA did not show any clear transient preceding the jerks. CMC showed bilateral over-threshold CMC in alpha band that was prominent on the contralateral hemisphere in the patient group as compared to HC group. GPDC showed a significantly higher alpha outflow from both hemispheres toward activated muscles in the patient group, and a significantly higher beta outflow from contralateral hemisphere in the HC group.

Conclusions: These neurophysiological findings suggest a subcortical generator of myoclonus in AS.

Significance: Myoclonus in AS has not a cortical origin as previously hypothesised.
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http://dx.doi.org/10.1016/j.clinph.2019.08.031DOI Listing
December 2019

Epilepsy, cerebral calcifications, and gluten-related disorders: Are anti-transglutaminase 6 antibodies the missing link?

Seizure 2019 Dec 16;73:17-20. Epub 2019 Oct 16.

Regional Epilepsy Centre, Great Metropolitan Hospital "Bianchi-Melacrino-Morelli", Reggio Calabria, Italy; Department of Medicine, Surgery and Health Sciences, Magna Græcia University, Catanzaro, Italy. Electronic address:

Purpose: Gluten-related disorders (GRDs) are a group of immune-mediated diseases often associated to neurologic manifestations. Epilepsies with cerebral calcifications, with or without coeliac disease (CD), are rare neurological disorders characterized by childhood-onset focal seizures, often refractory to antiepileptic drugs. Transglutaminase 6 antibodies (anti-TG6) have been considered a biomarker for gluten-related ataxia and neuropathy, but their prevalence in epilepsies with cerebral calcifications is unknown. The aim of this study is to evaluate anti-TG6 prevalence in patients with epilepsies and cerebral calcifications.

Method: this was a cross-sectional study conducted at five Italian epilepsy centres. The following groups were included. Group 1: nine patients with CD, posterior cerebral calcifications and epilepsy (CEC); group 2: nine patients with epilepsy and posterior cerebral calcifications, without CD; group 3: twenty patients with focal epilepsy of unknown etiology; group 4: twenty-two healthy controls (HC). All subjects were tested for serological evidence of anti-TG6 IgA and IgG. Differences among groups were analysed using χ ² test.

Results: anti-TG6 were present in 1/9 subjects (11%) of group 1, 2/9 subjects (22%) of group 2, 0/20 subjects in group 3, 3/22 (13.6%) of HC. No significant difference was found among the 4 groups.

Conclusions: Anti-TG6 do not seem to be associated to epilepsies with cerebral calcifications.
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http://dx.doi.org/10.1016/j.seizure.2019.10.012DOI Listing
December 2019

Younger age at stroke onset but not thrombolytic treatment predicts poststroke epilepsy: An updated meta-analysis.

Epilepsy Behav 2020 03 31;104(Pt B):106540. Epub 2019 Oct 31.

Regional Epilepsy Centre, Great Metropolitan Hospital, Reggio Calabria, Italy; Department of Medical and Surgical Sciences, Magna Græcia University, Catanzaro, Italy.

Aims: Stroke is the most commonly identified cause of late-onset epilepsy. Risk factors for poststroke epilepsy (PSE) are partially elucidated, and many studies have been performed in recent years. We aimed to update our previous systematic review and meta-analysis on risk factors for PSE.

Methods: PubMed, Google Scholar, and Scopus databases were searched. Articles published in English (1987-2019) were included. Odds ratios (OR) and mean values were calculated for examined variables.

Results: Thirty studies with different designs were included, enrolling 26,045 patients who experienced stroke, of whom 1800 had PSE, corresponding to a prevalence of 7%. Cortical lesions (OR: 3.58, 95% confidence interval (CI): 2.35-5.46, p < 0.001), hemorrhagic component (OR: 2.47, 95% CI: 1.68-3.64, p < 0.001), early seizures (ES) (OR: 4.88, 95% CI: 3.08-7.72, p < 0.001), and younger age at stroke onset (difference in means: 2.97 years, 95% CI: 0.78 to 5.16, p = 0.008) favor PSE. Sex and acute treatment with recombinant tissue plasminogen activator (rtPA) do not predict the occurrence of PSE.

Conclusion: Despite limitations due to the uneven quality and design of the studies, the present meta-analysis confirms that cortical involvement, hemorrhagic component, and ES are associated with a higher risk of PSE. In this update, younger age at stroke onset but not thrombolytic treatment seems to increase the risk for PSE. This article is part of the Special Issue "Seizures & Stroke".
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http://dx.doi.org/10.1016/j.yebeh.2019.106540DOI Listing
March 2020

Establishment and characterization of induced pluripotent stem cells (iPSCs) from central nervous system lupus erythematosus.

J Cell Mol Med 2019 11 19;23(11):7382-7394. Epub 2019 Sep 19.

Department of Experimental and Clinical Medicine, Stem Cell Laboratory, Research Center for Advanced Biochemistry and Molecular Biology, "Magna Graecia" University, Catanzaro, Italy.

Involvement of the central nervous system (CNS) is an uncommon feature in systemic lupus erythematosus (SLE), making diagnosis rather difficult and challenging due to the poor specificity of neuropathic symptoms and neurological symptoms. In this work, we used human-induced pluripotent stem cells (hiPSCs) derived from CNS-SLE patient, with the aim to dissect the molecular insights underlying the disease by gene expression analysis and modulation of implicated pathways. CNS-SLE-derived hiPSCs allowed us to provide evidence of Erk and Akt pathways involvement and to identify a novel cohort of potential biomarkers, namely CHCHD2, IDO1, S100A10, EPHA4 and LEFTY1, never reported so far. We further extended the study analysing a panel of oxidative stress-related miRNAs and demonstrated, under normal or stress conditions, a strong dysregulation of several miRNAs in CNS-SLE-derived compared to control hiPSCs. In conclusion, we provide evidence that iPSCs reprogrammed from CNS-SLE patient are a powerful useful tool to investigate the molecular mechanisms underlying the disease and to eventually develop innovative therapeutic approaches.
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http://dx.doi.org/10.1111/jcmm.14598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815917PMC
November 2019

An Italian multicentre study of perampanel in progressive myoclonus epilepsies.

Epilepsy Res 2019 10 16;156:106191. Epub 2019 Aug 16.

Neurophysiopathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. Electronic address:

Perampanel (PER) is a novel anti-seizure medication useful in different types of epilepsy. We intended to assess the effectiveness of PER on cortical myoclonus and seizure frequency in patients with progressive myoclonus epilepsy (PME), using quantitative validated scales. Forty-nine patients aged 36.6 ± 15.6 years with PME of various aetiology (18 EPM1, 12 EPM2, five with sialidosis, one with Kufs disease, one with EPM7, and 12 undetermined) were enrolled between January 2017 and June 2018. PER at the dose of 2-12 mg (5.3 ± 2.5) was added to existing therapy. Myoclonus severity was assessed using a minimal myoclonus scale (MMS) in all the patients before and after 4-6 months of steady PER dose, and by means of the Unified Myoclonus Rating Scale (UMRS) in 20 patients. Logistic regression analysis was used to identify the factors potentially predicting treatment efficacy. Four patients dropped out in the first two months due to psychiatric side effects. In the remaining patients, PER reduced myoclonus severity as assessed using MMS (Wilcoxon test: p < 0.001) and UMRS (p < 0.001), with the 'Action myoclonus' section of the UMRS showing the greatest improvement. The patients with EPM1 or EPM1-like phenotype were more likely to improve with PER (p = 0.011). Convulsive seizures which have recurred at least monthly in 17 patients were reduced by >50%. Side effects occurred in 22/49 (44.8%) patients, the most common being irritability followed by drowsiness. PER is effective in treating myoclonus and seizures in PME patients. The frequency of psychiatric side effects suggests the need for careful patient monitoring.
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http://dx.doi.org/10.1016/j.eplepsyres.2019.106191DOI Listing
October 2019

Incidence of early poststroke seizures during reperfusion therapies in patients with acute ischemic stroke: An observational prospective study: (TESI study: "Trombolisi/Trombectomia e crisi Epilettiche precoci nello Stroke Ischemico").

Epilepsy Behav 2020 03 17;104(Pt B):106476. Epub 2019 Aug 17.

Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Italy; Regional Epilepsy Centre and Neurology Unit, Great Metropolitan Hospital "Bianchi-Melacrino-Morelli" of Reggio Calabria, Italy.

Introduction: The aim of this study was to prospectively investigate the occurrence of early poststroke seizures (within 7 days of stroke) in patients undergoing reperfusion therapies (intravenous rtPA [recombinant tissue plasminogen activator] and/or endovascular thrombectomy) in comparison to those not undergoing these procedures.

Methods: Patients aged ≥18 years with acute ischemic stroke admitted in five Italian centers were prospectively recruited. Clinical data, details on stroke type and etiology, stroke treatment, and radiological data were collected. The frequency of early poststroke seizures was assessed, and predictive factors for their occurrence were evaluated.

Results: Five hundred and sixteen patients (262 in the reperfusion therapies group) were included. Stroke severity on admission and at discharge was higher among patients undergoing reperfusion therapies. Ten patients (3.8%) undergoing reperfusion therapies and 6 (2.3%) of those not receiving these treatments experienced early poststroke seizures (p = 0.45). There were no differences in any of the baseline characteristics between patients experiencing and those not experiencing early seizures.

Conclusion: The incidence of early poststroke seizures was overall rare, and no significant differences emerged between patients receiving and those not receiving reperfusion therapies. This article is part of the Special Issue "Seizures and Stroke".
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http://dx.doi.org/10.1016/j.yebeh.2019.106476DOI Listing
March 2020

Eyelid myoclonia with absences: Electroclinical features and prognostic factors.

Epilepsia 2019 06 14;60(6):1104-1113. Epub 2019 May 14.

Department G.F. Ingrassia, Section of Neurosciences, University of Catania, Catania, Italy.

Objective: Eyelid myoclonia with absences (EMA) is a syndrome characterized by eyelid myoclonia with or without absences, eye closure-induced generalized electroencephalographic (EEG) paroxysms and photosensitivity. Few data are available about the prognostic factors of this syndrome. The main objectives of our study were to describe the clinical and EEG features of a group of patients with EMA and to evaluate the presence of prognostic factors.

Methods: We retrospectively selected a cohort of patients with diagnosis of EMA evaluated in the epilepsy service of the Neurological Clinic of Catania, in the Neurology and Clinical Neurophysiopathology Unit of Oasi Research Institute, Troina and in the Regional Epilepsy Centre of Bianchi-Melacrino-Morelli Hospital of Reggio Calabria. We considered the features of the patients during the first year of disease, and at the last follow-up visit. We stratified the patients into two groups: "seizure-free", defined as the absence of seizures for at least 2 years, and "not seizure-free" and we evaluated the evolution of their characteristics and the presence of factors associated with outcome.

Results: We enrolled 51 patients (40 women (78%); mean age: 30.8 years ± 15.5 [range 10-79]). The mean follow-up time was 8.7 ± 5.8 years. Eleven patients (21.6%) achieved the condition of seizure-free. Family history of epilepsy was associated with the condition of seizure-free (P = 0.05). At the last follow-up visit, EEG photosensitivity and eye closure sensitivity were significantly associated with the condition of "not seizure-free".

Significance: The results of our study revealed that a positive family history of epilepsy might be associated with a better outcome in EMA. Furthermore, the persistence of photosensitivity and eye closure sensitivity might indicate persistence of seizures, offering an aid in therapeutic management.
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http://dx.doi.org/10.1111/epi.15157DOI Listing
June 2019

Hypertension, seizures, and epilepsy: a review on pathophysiology and management.

Neurol Sci 2019 Sep 4;40(9):1775-1783. Epub 2019 May 4.

Medical and Surgical Sciences Department, School of Medicine, Magna Græcia University of Catanzaro, Viale Europa, Catanzaro, Italy.

Background: Epilepsy and hypertension are common chronic conditions, both showing high prevalence in older age groups. This review outlines current experimental and clinical evidence on both direct and indirect role of hypertension in epileptogenesis and discusses the principles of drug treatment in patients with hypertension and epilepsy.

Methods: We selected English-written articles on epilepsy, hypertension, stroke, and cerebrovascular disease until December, 2018.

Results: Renin-angiotensin system might play a central role in the direct interaction between hypertension and epilepsy, but other mechanisms may be contemplated. Large-artery stroke, small vessel disease and posterior reversible leukoencephalopathy syndrome are hypertension-related brain lesions able to determine epilepsy by indirect mechanisms. The role of hypertension as an independent risk factor for post-stroke epilepsy has not been demonstrated. The role of hypertension-related small vessel disease in adult-onset epilepsy has been demonstrated. Posterior reversible encephalopathy syndrome is an acute condition, often caused by a hypertensive crisis, associated with the occurrence of acute symptomatic seizures. Chronic antiepileptic treatment should consider the risk of drug-drug interactions with antihypertensives.

Conclusions: Current evidence from preclinical and clinical studies supports the vision that hypertension may be a cause of seizures and epilepsy through direct or indirect mechanisms. In both post-stroke epilepsy and small vessel disease-associated epilepsy, chronic antiepileptic treatment is recommended. In posterior reversible encephalopathy syndrome blood pressure must be rapidly lowered and prompt antiepileptic treatment should be initiated.
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http://dx.doi.org/10.1007/s10072-019-03913-4DOI Listing
September 2019

A network analysis based approach to characterizing periodic sharp wave complexes in electroencephalograms of patients with sporadic CJD.

Int J Med Inform 2019 01 14;121:19-29. Epub 2018 Nov 14.

Dipartimento di Scienze Mediche e Chirurgiche, University "Magna Graecia" of Catanzaro, Italy.

Creutzfeldt-Jacob disease (CJD) is a rapidly progressive, uniformly fatal transmissible spongiform encephalopathy. Sporadic CJD (sCJD) is the most common form of CJD. Electroencephalography (EEG) is one of the main methods to perform clinical diagnosis of CJD, mainly because of periodic sharp wave complexes (PSWCs). In this paper, we propose a network analysis based approach to characterizing PSWCs in EEGs of patients with sCJD. Our approach associates a network with each EEG at disposal and defines a new numerical coefficient and some network motifs, which characterize the presence of PSWCs in an EEG tracing. The new coefficient, called connection coefficient, and the detected network motifs are capable of characterizing the EEG tracing segments with PSWCs. Furthermore, network motifs are able to detect what are the most active and/or connected brain areas in the tracing segments with PSWCs. The results obtained show that, analogously to what happens for other neurological diseases, network analysis can be successfully exploited to investigate sCJD.
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http://dx.doi.org/10.1016/j.ijmedinf.2018.11.003DOI Listing
January 2019
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