Publications by authors named "Laura Licchetta"

72 Publications

Natural history of Lafora disease: a prognostic systematic review and individual participant data meta-analysis.

Orphanet J Rare Dis 2021 08 16;16(1):362. Epub 2021 Aug 16.

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

Background: Lafora disease (LD) is a rare fatal autosomal recessive form of progressive myoclonus epilepsy. It affects previously healthy children or adolescents, causing pharmacoresistant epilepsy, myoclonus and severe psychomotor deterioration. This work aims to describe the clinical course of LD and identify predictors of outcome by means of a prognostic systematic review with individual participant data meta-analysis.

Methods: A search was conducted on MEDLINE and Embase with no restrictions on publication date. Only studies reporting genetically confirmed LD cases were included. Kaplan-Meier estimate was used to assess probability of death and loss of autonomy. Univariable and multivariable Cox regression models with mixed effects (clustered survival data) were performed to evaluate prognostic factors.

Results: Seventy-three papers describing 298 genetically confirmed LD cases were selected. Mean age at disease onset was 13.4 years (SD 3.7), with 9.1% aged ≥ 18 years. Overall survival rates in 272 cases were 93% [95% CI 89-96] at 5 years, 62% [95% CI 54-69] at 10 years and 57% [95% CI 49-65] at 15 years. Median survival time was 11 years. The probability of loss of autonomy in 110 cases was 45% [95% CI 36-55] at 5 years, 75% [95% CI 66-84] at 10 years, and 83% [95% CI 74-90] at 15 years. Median loss of autonomy time was 6 years. Asian origin and age at onset < 18 years emerged as negative prognostic factors, while type of mutated gene and symptoms at onset were not related to survival or disability.

Conclusions: This study documented that half of patients survived at least 11 years. The notion of actual survival rate and prognostic factors is crucial to design studies on the effectiveness of upcoming new disease-modifying therapies.
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http://dx.doi.org/10.1186/s13023-021-01989-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8365996PMC
August 2021

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

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

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

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

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

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

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

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

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

IRCCS Mondino Foundation Pavia Italy.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Conclusion: The proposed protocol, made of simple and easy to memorize tests, is an effective tool that evaluates multiple domains beyond language. Its use could help to recognize ictal aphasia effectively and differentiate it from impaired awareness, minimizing inter-examiner variability.
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http://dx.doi.org/10.1007/s10072-020-04872-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342325PMC
August 2021

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Women's issues.

Epileptic Disord 2020 Aug;22(4):355-363

Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Palo Alto, CA, USA.

Special considerations are required for women with epilepsy. These include issues such as catamenial exacerbation, concerns for contraception, teratogenesis (including both anatomical and neurodevelopmental effects), and other concerns for pregnancy complications such as increased seizures or adverse obstetric outcomes. In this manuscript, several cases are presented and discussed addressing some of the important issues in the management of women with epilepsy.
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http://dx.doi.org/10.1684/epd.2020.1173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755427PMC
August 2020

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

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

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

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

Clinical Reasoning: Young woman with orbital pain and diplopia.

Neurology 2020 02 3;94(7):e752-e757. Epub 2020 Feb 3.

From the Department of Biomedical and Neuromotor Sciences (R.I., R.L., L.L.), Alma Mater Studiorum, University of Bologna; IRCCS Istituto delle Scienze Neurologiche di Bologna (V.D., B.N., R.L., L.L.); and Neuroradiology Department (F.T., F.M.), IRCCS Institute of Neurological Sciences, Bellaria Hospital, Bologna, Italy.

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http://dx.doi.org/10.1212/WNL.0000000000008975DOI Listing
February 2020

Therapy in Sleep-Related Hypermotor Epilepsy (SHE).

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

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

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

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

FDG-PET assessment and metabolic patterns in Lafora disease.

Eur J Nucl Med Mol Imaging 2020 06 19;47(6):1576-1584. Epub 2019 Dec 19.

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

Purpose: To describe cerebral glucose metabolism pattern as assessed by F-fluorodeoxyglucose positron emission tomography (FDG-PET) in Lafora disease (LD), a rare, lethal form of progressive myoclonus epilepsy caused by biallelic mutations in EPM2A or NHLRC1.

Methods: We retrospectively included patients with genetically confirmed LD who underwent FDG-PET scan referred to three Italian epilepsy centers. FDG-PET images were evaluated both visually and using SPM12 software. Subgroup analysis was performed on the basis of genetic and clinical features employing SPM. Moreover, we performed a systematic literature review of LD cases that underwent FDG-PET assessment.

Results: Eight Italian patients (3M/5F, 3 EPM2A/5 NHLRC1) underwent FDG-PET examination after a mean of 6 years from disease onset (range 1-12 years). All patients showed bilateral hypometabolic areas, more diffuse and pronounced in advanced disease stages. Most frequently, the hypometabolic regions were the temporal (8/8), parietal (7/8), and frontal lobes (7/8), as well as the thalamus (6/8). In three cases, the FDG-PET repeated after a mean of 17 months (range 7-36 months) showed a metabolic worsening compared with the baseline examination. The SPM subgroup analysis found no significant differences based on genetics, whereas it showed a more significant temporoparietal hypometabolism in patients with visual symptoms compared with those without. In nine additional cases identified from eight publications, FDG-PET showed heterogeneous findings, ranging from diffusely decreased cerebral glucose metabolism to unremarkable examinations in two cases.

Conclusions: FDG-PET seems highly sensitive to evaluate LD at any stage and may correlate with disease progression. Areas of decreased glucose metabolism in LD are extensive, often involving multiple cortical and subcortical regions, with thalamus, temporal, frontal, and parietal lobes being the most severely affected. Prospective longitudinal collaborative studies are needed to validate our findings.
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http://dx.doi.org/10.1007/s00259-019-04647-3DOI Listing
June 2020

Sleep-related hypermotor epilepsy (SHE): Contribution of known genes in 103 patients.

Seizure 2020 Jan 23;74:60-64. Epub 2019 Nov 23.

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

Purpose: Genetics of Sleep-related Hypermotor Epilepsy (SHE) includes mutations in several genes that cumulatively account for 30 % of families. This approximate estimate comes from different case-series, each focused on the screening of a single gene. We systematically investigated a large cohort of SHE patients to estimate the frequency of pathogenic variants in the main genes thus far implicated in this epilepsy syndrome.

Methods: We selected familial and isolated cases diagnosed with clinical/confirmed SHE who underwent genetic analysis by comparable next generation sequencing (NGS) techniques (WES/ multigene epilepsy panel). The identified heterozygous variants were classified according to the American College of Medical Genetics and Genomics guidelines.

Results: We included 103 SHE patients (M/F:61/42) who underwent NGS. Sixteen (15.5 %) were familial cases, 16.5 % had focal cortical dysplasia (FCD). We identified three pathogenic variants in CHRNA4 (2.9 %, CI: 0.6-8.3 %), two of whom novel; one pathogenic variant in KCNT1 (1 %, CI: 0.02-5.29 %); four loss-of-function variants in DEPDC5 (3.9 %, CI: 1.1-9.7 %), one of whom never reported; finally, one missense change in NPRL2 (1 %, CI: 0.02-5.29 %), already reported as pathogenic. Three out of the four patients with DEPDC5 variants had FCD.

Conclusions: The overall frequency of pathogenic variants in our SHE cohort was 8.7 %, 19 % and 7 % considering familial and sporadic cases, respectively. Pathogenic variants in the GATOR1-complex genes account for 5 % of the cases. DEPDC5 shows the highest variants frequency, especially in patients with genetic-structural etiology. From a practical perspective, analysis of this gene is recommended even in isolated cases, because of possible implications for patient management.
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http://dx.doi.org/10.1016/j.seizure.2019.11.009DOI Listing
January 2020

Ictal vasodepressive syncope in temporal lobe epilepsy.

Clin Neurophysiol 2020 01 4;131(1):155-157. Epub 2019 Nov 4.

Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.

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http://dx.doi.org/10.1016/j.clinph.2019.10.009DOI Listing
January 2020

Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2.

Nat Commun 2019 10 29;10(1):4920. Epub 2019 Oct 29.

Department of Human Neurosciences, Sapienza University of Rome, Viale dell'Università, 30, 00185, Rome, Italy.

Familial Adult Myoclonic Epilepsy (FAME) is characterised by cortical myoclonic tremor usually from the second decade of life and overt myoclonic or generalised tonic-clonic seizures. Four independent loci have been implicated in FAME on chromosomes (chr) 2, 3, 5 and 8. Using whole genome sequencing and repeat primed PCR, we provide evidence that chr2-linked FAME (FAME2) is caused by an expansion of an ATTTC pentamer within the first intron of STARD7. The ATTTC expansions segregate in 158/158 individuals typically affected by FAME from 22 pedigrees including 16 previously reported families recruited worldwide. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and STARD7 gene expression is not affected. These data, in combination with other genes bearing similar mutations that have been implicated in FAME, suggest ATTTC expansions may cause this disorder, irrespective of the genomic locus involved.
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http://dx.doi.org/10.1038/s41467-019-12671-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820779PMC
October 2019

Sleep-related hypermotor epilepsy: A prediction cohort study on sleep/awake patterns of seizures.

Epilepsia 2019 11 15;60(11):e115-e120. Epub 2019 Oct 15.

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

Sleep-related hypermotor epilepsy (SHE) is characterized by hyperkinetic seizures arising from sleep. Awake seizures occasionally occur and are associated with a worse prognosis, with important implications for driving and quality of life. We evaluated the clinical features and sleep/wakefulness distribution of seizures at onset and lifelong in a large cohort of clinical/confirmed SHE. Chi-square test and a multivariate logistic regression model were used to identify predictors of awake seizures lifelong (primary endpoint). Positive and negative likelihood ratio (LR+, LR-) were calculated. We included 165 patients (male/female: 105/60) with a 27.6-year median follow-up. Most (67.9%) presented with seizures exclusively from sleep; 32.1% presented with seizures both while asleep and while awake, or exclusively during wakefulness. Presentation with seizures in wakefulness shows a sensitivity of 62.5% and a specificity of 96.5% to predict the occurrence of awake seizures lifelong, with an LR + of 18 (95% confidence interval [CI] = 5.75-55) and LR- of 0.39 (95% CI = 0.29-0.52). On multivariate analysis, distribution of sleep/awake seizures at onset was confirmed as an independent risk factor of awake seizures lifelong (odds ratio = 56.7). Patients presenting with awake seizures have a 94% probability of awake seizures lifelong, whereas in those presenting with asleep seizures only, the percentage lowers to 27%. This aspect should be mentioned during physician-to-patient communication about prognosis.
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http://dx.doi.org/10.1111/epi.16369DOI Listing
November 2019

Polysomnographic features differentiating disorder of arousals from sleep-related hypermotor epilepsy.

Sleep 2019 12;42(12)

Department of Neuroscience, Niguarda Hospital, Milan, Italy.

Objective: The differential diagnosis between sleep-related hypermotor epilepsy (SHE) and disorders of arousal (DOA) may be challenging. We analyzed the stage and the relative time of occurrence of parasomnic and epileptic events to test their potential diagnostic accuracy as criteria to discriminate SHE from DOA.

Methods: Video-polysomnography recordings of 89 patients with a definite diagnosis of DOA (59) or SHE (30) were reviewed to define major or minor events and to analyze their stage and relative time of occurrence. The "event distribution index" was defined on the basis of the occurrence of events during the first versus the second part of sleep period time. A group analysis was performed between DOA and SHE patients to identify candidate predictors and to quantify their discriminative performance.

Results: The total number of motor events (i.e. major and minor) was significantly lower in DOA (3.2 ± 2.4) than in SHE patients (6.9 ± 8.3; p = 0.03). Episodes occurred mostly during N3 and N2 in DOA and SHE patients, respectively. The occurrence of at least one major event outside N3 was highly suggestive for SHE (p = 2*e-13; accuracy = 0.898, sensitivity = 0.793, specificity = 0.949). The occurrence of at least one minor event during N3 was highly suggestive for DOA (p = 4*e-5; accuracy = 0.73, sensitivity = 0.733, specificity = 0.723). The "event distribution index" was statistically higher in DOA for total (p = 0.012) and major events (p = 0.0026).

Conclusion: The stage and the relative time of occurrence of minor and major motor manifestations represent useful criteria to discriminate DOA from SHE episodes.
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http://dx.doi.org/10.1093/sleep/zsz166DOI Listing
December 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

Treatment with metformin in twelve patients with Lafora disease.

Orphanet J Rare Dis 2019 06 21;14(1):149. Epub 2019 Jun 21.

IRCCS Istituto delle Scienze Neurologiche di Bologna, Ospedale Bellaria, Bologna, Italy.

Background: Lafora disease (LD) is a rare, lethal, progressive myoclonus epilepsy for which no targeted therapy is currently available. Studies on a mouse model of LD showed a good response to metformin, a drug with a well known neuroprotective effect. For this reason, in 2016, the European Medicines Agency granted orphan designation to metformin for the treatment of LD. However, no clinical data is available thus far.

Methods: We retrospectively collected data on LD patients treated with metformin referred to three Italian epilepsy centres.

Results: Twelve patients with genetically confirmed LD (6 EPM2A, 6 NHLRC1) at middle/late stages of disease were treated with add-on metformin for a mean period of 18 months (range: 6-36). Metformin was titrated to a mean maintenance dose of 1167 mg/day (range: 500-2000 mg). In four patients dosing was limited by gastrointestinal side-effects. No serious adverse events occurred. Three patients had a clinical response, which was temporary in two, characterized by a reduction of seizure frequency and global clinical improvement.

Conclusions: Metformin was overall safe in our small cohort of LD patients. Even though the clinical outcome was poor, this may be related to the advanced stage of disease in our cases and we cannot exclude a role of metformin in slowing down LD progression. Therefore, on the grounds of the preclinical data, we believe that treatment with metformin may be attempted as early as possible in the course of LD.
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http://dx.doi.org/10.1186/s13023-019-1132-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588886PMC
June 2019

Clinical Features and Pathophysiology of Disorders of Arousal in Adults: A Window Into the Sleeping Brain.

Front Neurol 2019 17;10:526. Epub 2019 May 17.

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

Disorders of Arousal (DoA) are NREM parasomnias that have been typically regarded as self-limited childhood manifestations. It is now clear that DoA can persist in adults, often presenting with distinctive characteristics. So far, few studies have described the clinical course and characteristics of DoA in adulthood, therefore a large part of their semiology is ignored. The aim of this study is to describe the clinical manifestations of DoA in an adult population and to provide a pathophysiological interpretation of their features. We screened our database for all 1,600 adult (≥15 years) patients with sleep-related motor behaviors between 1995 and 2016. We identified 45 patients with typical DoA episodes, of whom a complete history, neurological examination and diagnostic video-polysomnography (VPSG) were available. All patients provided a detailed description of their episodes (with particular regards to semiology, frequency, and association with stressful life events) in different life periods. VPSG recordings were reviewed and DoA episodes were identified and assigned to three different categories according to their complexity. Our population was composed of 45 adult patients ranging between 15 and 76 years. Sleepwalking was reported by 86% of patients, possibly associated with complex interactions with the environment and violent behaviors in 53% of cases; distressing mental contents were reported by 64%. Recall of the episodes was reported in 77% of patients. Non-restorative sleep was reported in 46% of patients. Stress was a potential episode trigger in 80% of patients. VPSG recordings documented 334 DoA episodes. According to our classification of motor patterns, 282 episodes (84%) were Simple Arousal Movements (SAMs), 34 (10%) Rapid Arousal Movements (RAMs) and 18 (5%) Complex Arousal Movements (CAMs). Our study confirms that DoA in adulthood present with distinctive characteristics, such as non-restorative sleep, violence and complex, or bizarre behaviors. Alternative classifications of DoA based on motor patterns could be useful to characterize DoA episodes in adults, as different motor patterns often coexist in the same individual and minor episodes are more common but generally underreported by patients. Prospective studies are needed for a definitive characterization of DoA in adulthood throughout the life course.
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http://dx.doi.org/10.3389/fneur.2019.00526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534078PMC
May 2019

SCN1A mutations in focal epilepsy with auditory features: widening the spectrum of GEFS plus.

Epileptic Disord 2019 Apr;21(2):185-191

Medical Genetics Unit, Sant'Orsola-Malpighi University Hospital, Bologna.

Epilepsy with auditory features (EAF) is a focal epilepsy syndrome characterized by prominent auditory ictal manifestations. Two main genes, LGI1 and RELN, have been implicated in EAF, but the genetic aetiology remains unknown in half of families and most sporadic cases. We previously described a pathogenic SCN1A missense variant (p.Thr956Met) segregating in a large family in which the proband and her affected daughter had EAF, thus satisfying the minimum requirement for diagnosis of autosomal dominant EAF (ADEAF). However, the remaining eight affected family members had clinical manifestations typically found in families with genetic epilepsy with febrile seizures plus (GEFS+). We aimed to investigate the role/impact of SCN1A mutations in EAF. We detailed the phenotype of this family and report on SCN1A screening in a cohort of 29 familial and 52 sporadic LGI1 variant-negative EAF patients. We identified two possibly pathogenic missense variants (p.Tyr790Phe and p.Thr140Ile) in sporadic patients (3.8%) showing typical EAF and no antecedent febrile seizures. Both p.Thr956Met and p.Tyr790Phe were previously described in unrelated patients with epilepsies within the GEFS+ spectrum. SCN1A mutations may be involved in EAF within the GEFS+ spectrum, however, the role of SCN1A in EAF without features that lead to a suspicion of underlying GEFS+ remains unclear and should be elucidated in future studies.
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http://dx.doi.org/10.1684/epd.2019.1046DOI Listing
April 2019

Contribution of ultrarare variants in mTOR pathway genes to sporadic focal epilepsies.

Ann Clin Transl Neurol 2019 03 25;6(3):475-485. Epub 2019 Feb 25.

IRCCS Istituto delle Scienze Neurologiche di Bologna Bologna Italy.

Objective: We investigated the contribution to sporadic focal epilepsies (FE) of ultrarare variants in genes coding for the components of complexes regulating mechanistic Target Of Rapamycin (mTOR)complex 1 (mTORC1).

Methods: We collected genetic data of 121 Italian isolated FE cases and 512 controls by Whole Exome Sequencing (WES) and single-molecule Molecular Inversion Probes (smMIPs) targeting 10 genes of the GATOR1, GATOR2, and TSC complexes. We collapsed "qualifying" variants (ultrarare and predicted to be deleterious or loss of function) across the examined genes and sought to identify their enrichment in cases compared to controls.

Results: We found eight qualifying variants in cases and nine in controls, demonstrating enrichment in FE patients ( = 0.006; exact unconditional test, one-tailed). Pathogenic variants were identified in and both major genes for Mendelian FE syndromes.

Interpretation: Our findings support the contribution of ultrarare variants in genes in the mTOR pathway complexes GATOR and TSC to the risk of sporadic FE and a shared genetic basis between rare and common epilepsies. The identification of a monogenic etiology in isolated cases, most typically encountered in clinical practice, may offer to a broader community of patients the perspective of precision therapies directed by the underlying genetic cause.
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http://dx.doi.org/10.1002/acn3.722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414475PMC
March 2019

Juvenile absence epilepsy relapsing as recurrent absence status, mimicking transient global amnesia, in an elderly patient.

Epileptic Disord 2018 Dec;20(6):557-561

IRCCS Institute of Neurological Sciences, Bologna, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.

We describe a 68-year-old woman who had typical absence seizures since 14 years of age. The absences were refractory to treatment and persisted into adulthood, with no seizure-free periods until seizure control at 59 years of age. After six years of being seizure-free, she presented with an episode characterized by mental confusion, abnormal behaviour, and amnesia, lasting for several hours. An EEG performed the day after, when the patient had already recovered, was unremarkable. The episode was interpreted as transient global amnesia. After two and three years, respectively, she presented with two analogous episodes lasting >24 hours. An EEG disclosed, on both occasions, subcontinuous generalized spike-and-wave discharges, consistent with absence status epilepticus (AS). The last episode occurred at 68 years of age and was successfully treated with intravenous lorazepam. After one month of follow-up, no further episodes occurred. AS is common in juvenile absence epilepsy, however, our patient showed a rather atypical course, characterized by refractory and persistent absences during adolescence and adulthood, and a tendency for AS to recur with no more absences in later life. Despite the known epilepsy history, AS episodes were initially misdiagnosed. Moreover, EEG recording and subsequent treatment were not performed until the second day of status.
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http://dx.doi.org/10.1684/epd.2018.1016DOI Listing
December 2018

Cortical myoclonic tremor induced by fixation-off sensitivity: An unusual cause of insomnia.

Neurology 2018 12 9;91(23):1061-1063. Epub 2018 Nov 9.

From IRCCS (L.L., F.B. L.V., F.P., P.T.), Institute of Neurological Sciences of Bologna; Department of Biomedical and Neuromotor Sciences (L.L., F.B. L.F., L.A., G.L., F.P., P.T.), University of Bologna; and Child Neuropsychiatry Unit (G.C.), University Hospital Verona, Italy.

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http://dx.doi.org/10.1212/WNL.0000000000006620DOI Listing
December 2018
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