Publications by authors named "Umberto Aguglia"

141 Publications

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

Eur J Neurol 2021 Sep 2. 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
September 2021

Identifying and managing CAR T-cell-mediated toxicities: on behalf of an Italian CAR-T multidisciplinary team.

Expert Opin Biol Ther 2021 Sep 15:1-15. Epub 2021 Sep 15.

Stem Cell Transplant Program CIC 587, Great Metropolitan Hospital "Bianchi-Melacrino-Morelli", Reggio, Calabria, Italy.

Introduction: Chimeric antigen receptor (CAR)-T-cell therapy is a new treatment for patients with hematologic malignancies in which other therapies have failed.

Areas Covered: The review provides an overview for recognizing and managing the most acute toxicities related to CAR-T cells.

Expert Opinion: The development of immune-mediated toxicities is a common challenge of CAR-T therapy. The mechanism that determines this toxicity is still unclear, although an unfavorable tumor microenvironment and a pro-inflammatory state put patients at risk. The monitoring, diagnosis, and treatment of post-CAR-T toxicities must be determined and based on international guidelines and internal clinical practice. It is urgent to identify biomarkers that can identify patients at greater risk of developing complications. The adoption of consistent grading criteria is necessary to improve toxicity management strategies continually. The first-line therapy consists of supportive care and treatment with tocilizumab or corticosteroids. An early start of cytokine blockade therapies could mitigate toxicity. The plan will include cytokine release prophylaxis, a risk-adapted treatment, prevention of on-target/off-tumor effect, and a switch on/off CAR-T approach.
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http://dx.doi.org/10.1080/14712598.2021.1974394DOI 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

Myositis/Myasthenia after Pembrolizumab in a Bladder Cancer Patient with an Autoimmunity-Associated HLA: Immune-Biological Evaluation and Case Report.

Int J Mol Sci 2021 Jun 10;22(12). Epub 2021 Jun 10.

Unit of Oncology, Unit. Grand Metropolitan Hospital "Bianchi Melacrino Morelli", 89124 Reggio Calabria, Italy.

Pembrolizumab (mAb to PD-1) has been recently approved for the therapy of pretreated urothelial cancer. Despite the efficacy, it is often accompanied by unpredictable and sometime severe immune-related (ir) adverse events (AEs). Here, we report the clinical and immune-biological characterization of a patient with a metastatic bladder cancer who developed myositis signs (M) and a myasthenia-like syndrome (MLS) during treatment with pembrolizumab. The patient presented an autoimmunity-associated HLA haplotype (HLA-A*02/HLA-B*08/HLA-C*07/HLA-DRB1*03) and experienced an increase in activated CD8 T-cells along the treatment. The symptomatology regressed after pembrolizumab discontinuation and a pyridostigmine and steroids-based therapy. This is the first report of concurrent M and MLS appearance in cancer patients receiving pembrolizumab. More efforts are needed to define early the risk and the clinical meaning of irAEs in this setting.
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http://dx.doi.org/10.3390/ijms22126246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230397PMC
June 2021

PML risk is the main factor driving the choice of discontinuing natalizumab in a large multiple sclerosis population: results from an Italian multicenter retrospective study.

J Neurol 2021 Jun 28. Epub 2021 Jun 28.

Neurosciences Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy.

Background: Natalizumab (NTZ) is an effective treatment for relapsing-remitting multiple sclerosis (RRMS). However, patients and physicians may consider discontinuing NTZ therapy due to safety or efficacy issues. The aim of our study was to evaluate the NTZ discontinuation rate and reasons of discontinuation in a large Italian population of RRMS patients.

Materials And Methods: The data were extracted from the Italian MS registry in May 2018 and were collected from 51,845 patients in 69 Italian multiple sclerosis centers. MS patients with at least one NTZ infusion in the period between June 1st 2012 to May 15th 2018 were included. Discontinuation rates at each time point were calculated. Reasons for NTZ discontinuation were classified as "lack of efficacy", "progressive multifocal leukoencephalopathy (PML) risk" or "other".

Results: Out of 51,845, 5151 patients, 3019 (58.6%) females, with a mean age of 43.6 ± 10.1 years (median 40), were analyzed. Out of 2037 (39.5%) who discontinued NTZ, a significantly higher percentage suspended NTZ because of PML risk compared to lack of efficacy [1682 (32.7% of 5151) vs 221 (4.3%), p < 0.001]; other reasons were identified for 99 (1.9%) patients. Patients discontinuing treatment were older, had longer disease duration and worse EDSS at the time of NTZ initiation and at last follow-up on NTZ treatment. The JCV index and EDSS at baseline were predictors for stopping therapy (HR 2.94, 95% CI 1.22-4.75; p = 0.02; HR 1.36, 95% CI 1.18-5.41; p = 0.04).

Conclusions: Roughly 60% of MS patients stayed on NTZ treatment during the observation period. For those patients in whom NTZ discontinuation was required, it was mainly due to PML concerns.
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http://dx.doi.org/10.1007/s00415-021-10676-6DOI Listing
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

Long-term prognosis of juvenile myoclonic epilepsy: A systematic review searching for sex differences.

Seizure 2021 Mar 23;86:41-48. Epub 2021 Jan 23.

IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy(2).

Purpose: Juvenile myoclonic epilepsy (JME), like other forms of idiopathic generalized epilepsy, shows a marked female predominance. However, few studies have specifically addressed the role of sex in its long-term prognosis. We performed a systematic review of the literature relevant to JME prognosis, focusing on sex-based differences in prognostic factors and outcome.

Methods: A comprehensive literature search of the PubMed and Scopus databases was performed, considering all articles up to April 2020 in which long-term prognosis in JME had been explored and sex differences in outcome or prognostic factors were specified.

Results: We included 25 articles published between 1984 and 2020. Sex differences in epilepsy outcome were explored by 21 of the 25 studies, but only three reported different outcomes in male vs female patients. All three found female sex to be associated with a later response to antiseizure medications, worse seizure control, and a higher risk of relapse in their entire study samples, which included JME patients. Eight studies found sex-based differences in possible predictors of long-term outcome: prolonged epileptiform EEG runs and the presence of eye closure sensitivity, both more frequent in women, were factors possibly linked to a poorer prognosis, as were praxis induction and generalized EEG asymmetric changes, which instead were more common in men. Valproate use, more frequent in men, was associated with a better outcome.

Conclusion: Most studies do not highlight sex differences in JME prognosis. However, some sex specificities do emerge, especially with regard to particular reflex traits and EEG abnormalities. Finally, sex may condition therapeutic choices, and thus have a possible impact on long-term outcome.
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http://dx.doi.org/10.1016/j.seizure.2021.01.005DOI Listing
March 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

Alternatives to valproate in girls and women of childbearing potential with Idiopathic Generalized Epilepsies: state of the art and guidance for the clinician proposed by the Epilepsy and Gender Commission of the Italian League Against Epilepsy (LICE).

Seizure 2021 Feb 21;85:26-38. Epub 2020 Dec 21.

Epilepsy Center, IRCCS Mondino Foundation, Pavia, Italy(2).

Following recent European Medication Agency restrictions on valproate (VPA) use in girls and women of childbearing potential (WOCP), the Commission on Epilepsy and Gender of the Italian League against Epilepsy integrated current literature and legislative data in order to provide clinicians with guidance on antiseizure medication (ASM) prescription for Idiopathic Generalized Epilepsies (IGEs) in this population, avoiding VPA. We reviewed the updated literature on ASMs and examined the teratogenicity of those showing efficacy in IGEs. For all relevant ASMs, we considered the indications for use and the pregnancy and contraception-related recommendations given in the Italian Summary of Product Characteristics (SmPC) and on the websites of the European Medicines Agency (EMA) and other European Union (EU) countries' regulatory agencies. With the exception of absence seizures, the literature lacks high quality studies on ASMs in IGEs. In girls and WOCP, levetiracetam and lamotrigine should be considered the first-choice drugs in Generalized Tonic-Clonic Seizures Alone and in Juvenile Myoclonic Epilepsy, lamotrigine in Juvenile Absence Epilepsy, and ethosuximide in Childhood Absence Epilepsy. Although supported by the literature, several ASMs are off label, contraindicated or burdened by special warnings in pregnancy. Some discrepancies emerged between the various SmPC warnings for different brands of the same active principle. We provided a therapeutic algorithm for each IGE syndrome and highlighted the need for revised prescription rules, consistent with the latest literature data, uniformity of SmPC warnings for the same active principle, and more data on the efficacy of new ASMs in IGEs and their safety in pregnancy.
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http://dx.doi.org/10.1016/j.seizure.2020.12.005DOI Listing
February 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

Teriflunomide as precipitating factor of renal failure in a patient with relapsing-remitting multiple sclerosis and focal segmental glomerulosclerosis.

Mult Scler Relat Disord 2020 Nov 20;46:102506. Epub 2020 Sep 20.

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

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http://dx.doi.org/10.1016/j.msard.2020.102506DOI Listing
November 2020

Disease-modifying drugs can reduce disability progression in relapsing multiple sclerosis.

Brain 2020 10;143(10):3013-3024

Ospedale Generale Regionale 'F. Miulli', Neurology Unit, Acquaviva delle Fonti (BA), Italy.

An ever-expanding number of disease-modifying drugs for multiple sclerosis have become available in recent years, after demonstrating efficacy in clinical trials. In the real-world setting, however, disease-modifying drugs are prescribed in patient populations that differ from those included in pivotal studies, where extreme age patients are usually excluded or under-represented. In this multicentre, observational, retrospective Italian cohort study, we evaluated treatment exposure in three cohorts of patients with relapsing-remitting multiple sclerosis defined by age at onset: paediatric-onset (≤18 years), adult-onset (18-49 years) and late-onset multiple sclerosis (≥50 years). We included patients with a relapsing-remitting phenotype, ≥5 years follow-up, ≥3 Expanded Disability Status Scale (EDSS) evaluations and a first neurological evaluation within 3 years from the first demyelinating event. Multivariate Cox regression models (adjusted hazard ratio with 95% confidence intervals) were used to assess the risk of reaching a first 12-month confirmed disability worsening and the risk of reaching a sustained EDSS of 4.0. The effect of disease-modifying drugs was assessed as quartiles of time exposure. We found that disease-modifying drugs reduced the risk of 12-month confirmed disability worsening, with a progressive risk reduction in different quartiles of exposure in paediatric-onset and adult-onset patients [adjusted hazard ratios in non-exposed versus exposed >62% of the follow-up time: 8.0 (3.5-17.9) for paediatric-onset and 6.3 (4.9-8.0) for adult-onset, P < 0.0001] showing a trend in late-onset patients [adjusted hazard ratio = 1.9 (0.9-4.1), P = 0.07]. These results were confirmed for a sustained EDSS score of 4.0. We also found that relapses were a risk factor for 12-month confirmed disability worsening in all three cohorts, and female sex exerted a protective role in the late-onset cohort. This study provides evidence that sustained exposure to disease-modifying drugs decreases the risk of disability accumulation, seemingly in a dose-dependent manner. It confirms that the effectiveness of disease-modifying drugs is lower in late-onset patients, although still detectable.
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http://dx.doi.org/10.1093/brain/awaa251DOI Listing
October 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

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

Reply to Dr. Capovilla on "Reply to the article "Management of status epilepticus in adults. Position paper of the Italian League Against Epilepsy"".

Epilepsy Behav 2020 06 6;107:107048. Epub 2020 Apr 6.

IRCCS Istituto delle Scienze Neurologiche, Bellaria Hospital, Bologna, Italy; Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy.

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http://dx.doi.org/10.1016/j.yebeh.2020.107048DOI Listing
June 2020

Administration of subcutaneous interferon beta 1a in the evening: data from RELIEF study.

J Neurol 2020 Jun 5;267(6):1812-1823. Epub 2020 Mar 5.

Department G. F. Ingrassia, Neuroscience Section, University of Catania, Via Santa Sofia, 78, 95123, Catania, Italy.

Background: Subcutaneous recombinant interferon-beta 1a (IFN-β1a SC) is indicated for treatment of relapsing multiple sclerosis (RMS); however, it is associated with development of flu-like syndrome (FLS) in 75% of patients. No recommendations are available on whether evening or morning administration could induce better or worse FLS.

Objective: Primary objective was to investigate whether morning administration of IFN-β1a 44 µg (Rebif) would affect the severity of FLS versus evening administration, in patients with RMS. Secondary objectives were to investigate whether timing of administration could lead to a better quality of life.

Methods: Multicenter, open-label, 12-week, randomized, controlled, parallel-group, phase 4 study.

Results: Of 217 patients screened at 29 Italian sites, 200 were included in the study. Among these, 104 patients were randomized to IFN-β1a SC administration in the morning and 96 in the evening. Morning administration resulted in higher FLS scores, as measured by the Multiple Sclerosis Treatment Concern Questionnaire, at week 4 (p = 0.0083) and week 8 (p = 0.0079); however, the difference was no longer significant at the end of 12 weeks.

Conclusion: IFN-β1a evening injections in the first 8 weeks of treatment led to an improvement in FLS; when continuing therapy, time of administration could be decided according to patient's lifestyle and preference.
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http://dx.doi.org/10.1007/s00415-020-09771-xDOI Listing
June 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

Management of status epilepticus in adults. Position paper of the Italian League against Epilepsy.

Epilepsy Behav 2020 01 22;102:106675. Epub 2019 Nov 22.

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

Since the publication of the Italian League Against Epilepsy guidelines for the treatment of status epilepticus in 2006, advances in the field have ushered in improvements in the therapeutic arsenal. The present position paper provides neurologists, epileptologists, neurointensive care specialists, and emergency physicians with updated recommendations for the treatment of adult patients with status epilepticus. The aim is to standardize treatment recommendations in the care of this patient population.
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January 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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March 2020
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