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OBJECTIVE Non-traumatic headache is a frequent reason for visits to the emergency department (ED). We evaluated the performance of the Manchester Triage System (MTS) in prioritising patients presenting to the ED with non-traumatic headache. METHODS In this single-centre observational retrospective study, we compared the association of MTS priority classification codes with a final diagnosis of a severe neurological condition requiring timely management (ischaemic or haemorrhagic stroke, subarachnoid haemorrhage, cerebral sinus venous thrombosis, central nervous system infection or brain tumour). The study was conducted and reported according to the STROBE statement. The overall prioritisation accuracy of MTS was estimated by the area under the receiver operating characteristic (ROC) curve. The correctness of triage prediction was estimated based on the "very urgent" MTS grouping. An undertriage was defined as a patient with an urgent and severe neurological who received a low priority/urgency MTS code (green/yellow). RESULTS Over 30 months, 3002 triage evaluations of non-traumatic headache occurred (1.7% of ED visits). Of these, 2.3% (68/3002) were eventually diagnosed with an urgent and severe neurological condition. The MTS had an acceptable prioritisation accuracy, with an area under the ROC curve of 0.734 (95% CI 0.668-0.799). The sensitivity of the MTS for urgent codes (yellow, orange and red) was 79.4% (95% CI 74.5-84.3), with a specificity of 54.1% (95% CI 52.9-55.3). The triage prediction was incorrect in only 6.3% (190/3002) of patients with headache. CONCLUSION The MTS is a safe and accurate tool for prioritising patients with non-traumatic headache in the ED. However, MTS may need further specific tools for evaluating the more complicated symptoms and for correctly identifying patients with urgent and severe underlying pathologies. RELEVANCE TO CLINICAL PRACTICE The triage nurse using MTS may need additional tools to improve the assessment of patients with headache, although MTS provides a good safety profile.

Background The effectiveness of adjunctive perampanel has not been systematically assessed in seizure types other than its approved indications of focal seizures and primary generalised tonic–clonic seizures (PGTCS) in idiopathic generalised epilepsies (IGEs). Objective We aimed to identify and review available evidence on outcomes with perampanel in generalised seizures and epilepsies to examine its potential as a broad-spectrum anti-seizure medication. Methods Bibliographic databases of publications, clinical trials, and conference abstracts were searched up to August 2020 to identify studies reporting seizure or safety outcomes in patients of any age, with any type of epilepsy-associated generalised seizures treated with perampanel. Data extracted from selected records were tabulated by seizure type and syndrome, and analysed qualitatively (PROSPERO protocol CRD42020201564). Results Ninety-one reports met inclusion criteria and were selected: 15 reports of 1 randomised controlled trial (RCT), 8 reports of 4 non-randomised interventional studies, 37 reports of observational studies, 21 case reports and 10 systematic reviews and meta-analyses. Extracted data included 359 patients with PGTCS of any aetiology, 251 with myoclonic seizures, 112 with absence seizures, 50 with tonic seizures and 32 children with epileptic spasms. The most commonly reported epilepsy type was IGE (N = 378) and the most common syndromes were juvenile myoclonic epilepsy (N = 92), progressive myoclonic epilepsies (N = 59) and absence epilepsies (N = 43). The RCT provided Class I evidence of the efficacy and tolerability of adjunctive perampanel for PGTCS in patients aged ≥ 12 years with IGE. Data from other studies provides weaker (observational) evidence of its effectiveness in multiple generalised seizure types, including myoclonic, absence and tonic seizures. There were no patterns suggesting seizure worsening or aggravation in any seizure or epilepsy type. Conclusions The identified studies suggest the potential of perampanel as a broad-spectrum antiseizure medication. Much of the available data, however, come from non-randomised, non-controlled studies and are open to high risk of bias. Further studies are warranted to provide more robust evidence. Supplementary Information The online version contains supplementary material available at 10.1007/s40263-021-00831-y.

Psychogenic non-epileptic seizures (PNES) resemble epileptic seizures but are not due to underlying epileptic activity and in some cases coexist alongside epilepsy. We described the clinical characteristics of patients with PNES as reported in the literature from the outbreak of the COVID-19 pandemic. We evaluated differences between patients with a diagnosis made immediately before the pandemic (pPNES) and those newly diagnosed during it (nPNES).A systematic search with individual patient analysis of PNES cases published since the COVID-19 pandemic outbreak was performed. Differences between pPNES and nPNES were analyzed using Chi-square or Fisher exact test.Eleven articles were included, with 133 patients (106 pPNES and 27 nPNES). In the pPNES group, PNES frequency increased during the pandemic in 20/106 patients, whereas in 78/106, the frequency remained stable or decreased. nPNES was associated with higher risks of SARS-CoV-2 infection and epilepsy diagnosis, whereas psychiatric comorbidities were less frequent.During the pandemic, most patients with pPNES remained stable or improved, whereas nPNES was associated with a lower burden of psychiatric comorbidities. These intriguing findings suggest that, at least in some patients, the COVID-19 pandemic may not necessarily lead to worsening in the frequency of PNES and quality of life.

Resumen Introduccion y objetivos Tras el flujo migratorio procedente del Africa Subsahariana (ASS) en Europa, el numero de diagnosticos de esquistosomiasis urogenital (EUG) es cada vez mayor. Este fenomeno representa un desafio para los urologos que trabajan en zonas no endemicas. El objetivo de este estudio es describir el tratamiento urologico y los procedimientos quirurgicos de los pacientes con EUG en un centro de referencia terciario Pacientes Todos los sujetos del ASS diagnosticados con EUG entre enero del 2011 y noviembre del 2018 fueron inscritos retrospectivamente. Se recogio y analizo la informacion detallada de los pacientes con EUG tratados mediante procedimientos urologicos. Resultados Treinta pacientes fueron diagnosticados con EUG, 12 (42,8%) fueron tratados mediante cirugia. El procedimiento quirurgico mas comun fue la reseccion transuretral de vejiga (RTUV) para las lesiones sospechosas persistentes despues del tratamiento con praziquantel administrado en 7 casos (58%). Otros procedimientos quirurgicos (realizados una vez) fueron RTUV combinada con ureteroscopia laser por sospecha de neoplasia de vejiga con calculos renales, litotricia endoscopica y nefrolitotomia percutanea para calculos vesicales y renales, nefrectomia laparoscopica para enfermedad renal terminal, colocacion de nefrostomia bilateral para hidroureteronefrosis, cirugia testicular exploratoria por sospecha de torsion testicular. Cuatro pacientes (33%) se perdieron en el seguimiento. Conclusion Se ha observado un numero cada vez mayor de migrantes del ASS diagnosticados con EUG. Algunos pacientes requirieron intervencion quirurgica por sospecha de lesiones neoplasicas o danos en organos en fase terminal. En varios pacientes fue particularmente dificil realizar un seguimiento regular. Se necesitan mas estudios multicentricos para lograr un manejo estandar en terminos de diagnostico, tratamiento y seguimiento de los sujetos con EUG.

The use of e-cigarettes is gaining popularity despite knowing about cardiovascular health risks. Cases of intentional or accidental intoxication following ingestion of the refill solution are also a growing concern. Most of these cases were fatal and related to cardiac arrest and hypoxic brain injury. We report the case of a 54-year-old woman who developed bilateral acute ischemic stroke in the anterior and posterior cerebral circulation following intentional oral intake of e-liquid nicotine refill solution. The diagnostic work-up concluded an etiology of embolic stroke of undetermined source, most likely of cardiac origin. We assume that sympathetic overactivation lead to temporary cardiac arrhythmia and subsequent thrombi formation. Moreover, we discuss several additional pathogenic aspects of oral intake of e-liquid refill solution for the development of central nervous system pathology. This case expands the clinical spectrum of health hazards associated with the introduction of e-cigarettes and raises awareness of the need for preventive measures.

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins. ispartof: NEUROBIOLOGY OF AGING vol:92 ispartof: location:United States status: published

Introduction Cerebrovascular disease is the most common cause of seizures in adults and the elderly. So far, no drug is recommended as primary prevention of acute symptomatic poststroke seizures (ASPSS) or poststroke epilepsy (PSE). This systematic review aimed to evaluate the association between the use of statins after stroke and the risk of developing ASPSS or PSE following cerebral infarct or hemorrhage (primary prevention). Methods We included studies evaluating the poststroke use of statins as primary prevention of ASPSS or PSE, irrespective of stroke type. We excluded uncontrolled studies and studies with prestroke statin use. The main outcome included the occurrence of ASPSS or PSE and the effect of statins by type and dose. The odds ratios (ORs) or hazard ratios (HR) with 95% confidence intervals (CIs) were used as the measures of association between treatment and outcome. Results Four studies were included. One study showed a reduced risk of ASPSS after ischemic stroke (OR: 0.25; 95% CI: 0.10–0.59; p = 0.0016). Three studies consistently reported a reduced risk of PSE after ischemic stroke, and one study a reduced risk of PSE after hemorrhagic stroke (HR: 0.62; 95% CI: 0.42–0.90; p = 0.01). Conclusions Data from the literature suggest an association between statin use and a reduced risk of ASPSS after ischemic stroke and a reduced risk of PSE after ischemic and hemorrhagic stroke. Although the certainty of the evidence is low, these findings appear promising and worthy of further investigation.

Background The main purpose of this study is to assess efficacy and tolerability of perampanel (PER), a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonist, as an add-on treatment in adult patients with refractory focal-onset seizures. Patients and Methods A prospective, open label, observational study was conducted in patients with refractory focal-onset seizures treated with PER at our Epilepsy Unit, from May 2015 to February 2016. Patients were followed up for 1 year. Frequency of seizure and tolerability was assessed every 3 months. Patients were under a polytherapy, and the mean number of concomitant antiepileptic drugs (AEDs) at PER initiation was 2.9. Results We consecutively enrolled 52 patients (M/F = 18/34). Three were lost on follow-up. Mean age was 38.7 years, with a mean duration of disease of 28.1 years. After 1 year of treatment, 57.14% reported a 50% or greater reduction in seizure frequency; five (10.21%) were seizure free. Six (12.25%) patients reported a reduction lower than 50%. Mean dosage of PER was 7.57 mg. Thirty-one patients were taking enzyme-inducing AEDs (carbamazepine, oxcarbazepine, phenytoin). In this subgroup, the responder rate was 45.2%. Twenty-one patients reported side-effects, most frequently somnolence (11), vertigo/ataxia (6), and aggressiveness (5). Eleven (22.4%) patients reduced or discontinued at least one concomitant AED, while the electroencephalography improved in four (8.16%). Sixteen (32.65%) patients withdrew PER, after a mean duration of 163 days, the mean dosage being 6.4 mg (range 4–12). Conclusions Adjunctive PER can achieve clinically meaningful improvement, or even seizure freedom, in almost two-thirds of patients suffering from refractory focal-onset epilepsies. It seems similarly safe and well-tolerated. Enzyme-inducing AEDs may limit the efficacy of PER.

Summary Pluripotent stem (PS)-cell-derived cell types hold promise for treating degenerative diseases. However, PS cell differentiation is intrinsically heterogeneous; therefore, clinical translation requires the development of practical methods for isolating progenitors from unwanted and potentially teratogenic cells. Muscle-regenerating progenitors can be derived through transient PAX7 expression. To better understand the biology, and to discover potential markers for these cells, here we investigate PAX7 genomic targets and transcriptional changes in human cells undergoing PAX7-mediated myogenic commitment. We identify CD54, integrin α9β1, and Syndecan2 (SDC2) as surface markers on PAX7-induced myogenic progenitors. We show that these markers allow for the isolation of myogenic progenitors using both fluorescent- and CGMP-compatible magnetic-based sorting technologies and that CD54+α9β1+SDC2+ cells contribute to long-term muscle regeneration in vivo. These findings represent a critical step toward enabling the translation of PS-cell-based therapies for muscle diseases.

Targeted differentiation of pluripotent stem (PS) cells into myotubes enables in vitro disease modeling of skeletal muscle diseases. Although various protocols achieve myogenic differentiation in vitro, resulting myotubes typically display an embryonic identity. This is a major hurdle for accurately recapitulating disease phenotypes in vitro, as disease commonly manifests at later stages of development. To address this problem, we identified four factors from a small molecule screen whose combinatorial treatment resulted in myotubes with enhanced maturation, as shown by the expression profile of myosin heavy chain isoforms, as well as the upregulation of genes related with muscle contractile function. These molecular changes were confirmed by global chromatin accessibility and transcriptome studies. Importantly, we also observed this maturation in three-dimensional muscle constructs, which displayed improved in vitro contractile force generation in response to electrical stimulus. Thus, we established a model for in vitro muscle maturation from PS cells.

To test the factorial structure of the Italian version of the Insomnia Severity Index (ISI) using a confirmatory approach and to assess its psychometric properties. ISI questionnaire was completed by 272 patients (average age 41.28, range 18-73) with insomnia diagnosis performed by a sleep medicine physician and retrospectively enrolled in the study. All patients underwent Cognitive Behavioral Treatment for Insomnia (CBT-I) and completed sleep diaries before starting the treatment. Data from sleep diaries were analyzed for assessing concurrent validity of the ISI. Confirmatory factor analysis (CFA) for ordinal Likert-type items was applied to compare four competing models proposed in the literature. 244 patients, out of the 272, completed the ISI at the end of CBT-I. A comparison of ISI score before and after treatment was performed. The CFA analysis confirmed the presence of three main factors conceptualized as severity and impact of the disease along with sleep satisfaction. Significant correlations of the first three items of the questionnaire, investigating three different subtypes of insomnia, and the subjective measures from the sleep diaries were found, thus supporting the concurrent validity of the test. Sleep efficiency (SE) had a significant inverse correlation with the severity and satisfaction factors and with ISI's total score. After CBT-I treatment, a significant reduction of ISI's scores was observed, thus confirming the effectiveness of the CBT-I treatment. The internal reliability coefficient was 0.75. The ISI questionnaire maintains good psychometric properties in the Italian version, thus confirming that this instrument is reliable for detecting insomnia severity and identifying patients' symptoms.

Sleepwalking, sleep terrors, and confusional arousals are non-REM sleep parasomnias grouped under the specific category of disorders of arousal (DOA). These conditions are characterized by incomplete arousals from deep sleep that lead to a broad variety of emotional and motor behaviors. The advent of electroencephalography (EEG) and the discovery of rapid eye movement (REM) sleep as opposed to non-REM sleep allowed researchers to consider these phenomena from a neurophysiological rather than a purely psychopathological perspective. The utilization of new neurophysiologic techniques such as high-density scalp EEG, stereo-EEG, and advanced signal analysis methods shed further light on the mechanisms underpinning DOA and supported the notion that they should be viewed within the frame of the so-called dissociate state of being as intermediate state between wake and NREM sleep. Furthermore, other important issues like the boundaries between motor-behavioral manifestations in DOA and NFLE, neurocognitive functions, the occurrence of mentation/dream imagery during episodes in DOA and DOA daytime consequences, and treatment are still matters of debate.

Migrants may constitute a risk group and should have specific targets for health policy. To identify their health needs, it is important to investigate their epidemiological profile and their access to health services. The aim of this study was to identify the pattern of hospital and neurological services use among immigrants living in Brescia (Italy). The analysis took into account the records of 45,645 immigrants admitted to the ER (Emergency Room) as well as the discharge data of 6419 patients hospitalized in the Department of Neurology of the Azienda Ospedaliera Spedali Civili di Brescia, over a 3.5 years period. To take confounding factors into account, immigrant patients admitted to the department of Neurology were compared to a selection of Italian patients matched by age and sex. The main objectives were to explore causes of admission of the immigrant population-along with socio-demographic characteristics-to the Emergency Room and to the Neurology Units. Immigrants showed a similar pattern of hospital use to the Italian patients, although with a higher frequency of infective diseases and traumatic injuries. They also showed a higher mean Diagnosis-Related Group (DRG) weight than the Italians. Average length of hospitalization was longer in immigrant population. However, the use of neurological services by migrants is less than their demographic share. Poorer economic and social conditions, as well as a worse labor market experienced by immigrants may expose them to risk factors for injuries and infective diseases. Reducing the language and bureaucratic barriers, as well as enhancing cross-cultural skills of physicians, might be crucial in decreasing the length and the cost of hospitalization.

Introduction: Restless Legs Syndrome/Willis-Ekbom Disease (RLS/WED) is a sleep disorder characterized by an urge to move the legs, frequently associated or triggered by unpleasant sensations in the lower limbs that affects approximately 2.5% of adults. Therapy and management of RLS/WED require long-term interventions, since the typical manifestation of this disorder is chronic. Areas covered: In this review, we provide an update regarding the treatment of RLS/WED with particular attention to future challenges for its management. We reviewed a large variety of treatments studied in clinical trials and supported by the most updated guidelines. Alongside with first-line interventions other pharmacological options including opioids, benzodiazepines, iron therapy, and newly studied drugs are discussed. Furthermore, due to the occurrence of augmentation and worsening of symptoms we also reviewed the development of non-pharmacologic alternatives. Expert commentary: The management of RLS/WED is a challenge because of different long-term issues. Several complications, such as loss of the therapeutic effect of dopaminergic or non-dopaminergic agents and augmentation, are still unsolved concerns. However, the development of new drugs acting on adenosinergic and glutamatergic neurotransmission seems promising. Randomized controlled trials are needed in order to recognize effectiveness of new drugs or non-pharmacological treatment strategies.

SPG10 is an autosomal dominant hereditary spastic paraplegia (HSP) caused by mutations in the gene KIF5A encoding the heavy chain of kinesin, a motor protein implied in motility functions within cells. Most of the KIF5A mutations are clustered in 2 areas of motor domain of the protein, the switch regions I and II, that are necessary for microtubules interaction. The set of mutations in KIF5A described so far account for a spectrum of clinical heterogeneity ranging from pure HSP to isolated peripheral nerve involvement (Charcot-Marie-Tooth phenotype) or complicated HSP phenotypes. We here describe a patient presenting with progressive walking difficulties and burning dysesthesias, numbness, and pain at distal segments of the 4 limbs. Neurological examination revealed severe spastic gait and vibratory and proprioception sensory reduction in the lower limbs. Motor and sensory nerve conduction studies disclosed axonal damage of peripheral nerves at lower limbs. We identified the novel variant c.967C>T in the KIF5A gene resulting in the R323W change, which is located at the C-terminus of the motor domain of the KIF5A protein, just upstream the linker region but out of the switch regions. Our findings confirm that the "mixed" central-peripheral involvement is the most frequent clinical picture related to KIF5A motor domain mutations and that motor domain "in toto," even outside of the switch regions, is a hot spot for pathogenic mutations. We stress the concept that detection of a peripheral axonal neuropathy in an autosomal dominant HSP patient should be regarded as an important diagnostic tool and should guide clinicians to seek, first of all, KIF5A mutations.

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder characterized by progressive gait and limb ataxia, cerebellar, pyramidal and dorsal column involvement, visual defects, scoliosis, pes cavus and cardiomyopathy. It is caused by a homozygous guanine-adenine-adenine (GAA) trinucleotide repeat expansion in intron 1 of the frataxin gene (FXN) on chromosome 9q13-q21.1. Onset is usually in the first or second decade of life; however, late-onset cases of Freidreich ataxia (LOFA), after the age of 25 years, and very late-onset cases of Freidreich ataxia (VLOFA), after the age of 40 years, have been reported. VLOFA is quite rare and usually presents a milder progression of the disease. We report the case of a 64-year-old woman affected with VLOFA whose first symptoms (balance and gait disturbances) occurred at the age of 44 years. At the age of 62 years, she started complaining of a slowly progressive dysphonia showing the clinical aspects of laryngeal dystonia. Molecular analysis showed a 210- and 230-trinucleotide GAA repeat expansion in the two alleles of the FXN gene. Laryngeal dystonia has been reported only in very few cases of ataxia syndrome and never before in FRDA patients. It may represent a rare clinical manifestation of VLOFA thus confirming the high variability of the clinical spectrum of FRDA.

Mitochondrial diseases are a heterogeneous group of disorders resulting from primary dysfunction of the respiratory chain due to both nuclear and mitochondrial DNA mutations. The wide heterogeneity of biochemical dysfunctions and pathogenic mechanisms typical of this group of diseases has hindered therapy trials; therefore, available treatment options remain limited. Therapeutic strategies aimed at increasing mitochondrial functions (by enhancing biogenesis and electron transport chain function), improving the removal of reactive oxygen species and noxious metabolites, modulating aberrant calcium homeostasis and repopulating mitochondrial DNA could potentially restore the respiratory chain dysfunction. The challenge that lies ahead is the translation of some promising laboratory results into safe and effective therapies for patients. In this review we briefly update and discuss the most feasible therapeutic approaches for mitochondrial diseases.

Aims: To prospectively assess the incidence and etiology (ie, primary vs symptomatic) of headache in women during the first month postdelivery, with particular emphasis on the type of presentation as a clue for identifying potentially harmful etiologies. A secondary aim was to evaluate the relative frequency of migraine- vs tension-type headache in cases of primary headache. Methods: A total of 900 consecutive women were enrolled in the study and examined within 3 days of delivery, both clinically and with transcranial color-coded sonography (TCCS). During the course of follow-up, all subjects presenting with headache suspected of being secondary to intracranial pathology underwent a complete clinical and instrumental assessment with TCCS and magnetic resonance imaging (MRI) and angiography. A telephone interview was administered to all subjects 1 month after delivery. Two-tailed t test, Mann-Whitney test, Pearson chi-square test, and multiple logistic regression were used to analyze the data. Results: At the end of the follow-up period, 241 women (26.8% of the sample) reported at least one headache attack. In 88 of these 241 cases (9.8%), the headache attack occurred soon after delivery and was already recorded at the first visit. Thunderclap headache occurred in 34 (3.8%) of the subjects. In all but one of these subjects, the course was spontaneously benign. None of the recorded variables allowed discrimination of the subjects with thunderclap headache from those without headache. Three subjects had thunderclap headache following dural anesthesia, and one subject was found to have reversible cerebral vasoconstriction syndrome. Headache with gradual onset was recorded in 207 subjects (23%). Three of these subjects fulfilled the criteria for pre-eclampsia, and 13 had postural headache after dural anesthesia. Migraine history and urinary protein were independent predictors of gradual onset headache, and migraine history and parity were significant independent predictors of pulsating pain with gradual onset headache. Conclusion: Headache appeared early in the first days postdelivery, and its incidence increased in the first month thereafter. Predictors were different according to whether the headache had a gradual onset or a thunderclap presentation. Primary headache accounted for the overwhelming majority of the recorded cases.

Background and Aim of the Study Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by severe “thunderclap” headache, with or without associated neurological symptoms and neuroimaging findings of reversible vasoconstriction of cerebral arteries. Puerperium is a recognized precipitant, but the incidence of puerperal RCVS is unknown. We conducted a prospective study to assess incidence, risk factors and clinical features of RCVS. Material and Method Nine-hundred consecutive puerperae were prospectively enrolled within three days of delivery. Past medical history, basal demographic, anthropometric and biological variables were recorded. Transcranial Colour Coded Sonography (TCCS) was performed to assess early signs of vasospasm in brain vessels. A structured telephone interview was planned in all subjects one month post delivery. Results Thunderclap headache was recorded in 8 subjects (0.9%) on the first visit. At the one month follow-up interview 27 more patients reported having had at least one episode of thunderclap headache. In these 33 (3.8%) patients the course was spontaneously benign. One patient presented to the Emergency ward with throbbing thunderclap headache three weeks after delivery. Diagnostic work-up ended up in the diagnosis of RCVS, the outcome was favorable Conclusion In normally coursing pregnancies and after uncomplicated delivery the risk of puerperal RCVS is negligible (0.1%). On the other way thunderclap headache may occur in a measurable proportion of (3.4%), although in the vast majority of cases ( 33/34 = 97%) it is of benign course. Transcranial Doppler sonography may be helpful to pick up those cases in whom further neuroradiological investigation is warranted.

Conditions involving muscle wasting, such as muscular dystrophies, cachexia, and sarcopenia, would benefit from approaches that promote skeletal muscle regeneration. Stem cells are particularly attractive because they are able to differentiate into specialized cell types while retaining the ability to self-renew and, thus, provide a long-term response. This review will discuss recent advancements on different types of stem cells that have been attributed to be endowed with muscle regenerative potential. We will discuss the nature of these cells and their advantages and disadvantages in regards to therapy for muscular dystrophies.

Hashimoto's encephalopathy (HE) is a rare neuropsychiatric syndrome associated with antithyroid antibodies. It may have an acute onset (episodes of cerebral ischemia, seizure, and psychosis) or it may present as an indolent form (depression, cognitive decline, myoclonus, tremors, and fluctuations in level of consciousness). We here describe a case of encephalopathy presenting as non-convulsive status epilepticus associated with Hashimoto's thyroiditis (HT), unresponsive to corticosteroid therapy, with improvement after plasma exchange treatment. A previously healthy 19-year-old woman, presented generalized tonic-clonic seizures. About a month later, she manifested a speech disorder characterized by difficulties in the production and comprehension of language. Within a few days she also developed confusion and difficulties in recognizing familiar places, with gradual worsening over time. EEG revealed a non-convulsive status epilepticus (NCSE). CSF examination showed slightly elevated cell count and four oligoclonal bands. MRI was unremarkable, and (18)F-FDG brain PET showed widespread hypometabolism, mostly in posterior regions bilaterally. Laboratory and ultrasound findings showed signs of HT. Treatment with steroid was introduced without any improvement. After five sessions of plasma exchange there was a decrease of antithyroid antibodies, as well as EEG and clinical improvement. Three months after discharge (18)F-FDG brain PET showed a complete normalization of the picture, and the patient was asymptomatic. This report emphasizes the successful treatment of HE with plasma exchange in a patient who presented with NCSE. Based on the actual evidence, the term "Encephalopathy associated with Hashimoto's thyroiditis" may be the most proper. Furthermore, to our knowledge, this is the first case of an adult patient studied twice with an (18)F-FDG brain PET: prior to treatment with plasma exchange, and at 3 months follow-up when the patient was clinically completely asymptomatic. Studies in more patients are needed to clarify the relevance of (18)F-FDG brain PET as a possible diagnostic tool for HE.

ASAH1 gene encodes for acid ceramidase that is involved in the degradation of ceramide into sphingosine and free fatty acids within lysosomes. ASAH1 variants cause both the severe and early-onset Farber disease and rare cases of spinal muscular atrophy (SMA) with progressive myoclonic epilepsy (SMA-PME), phenotypically characterized by childhood onset of proximal muscle weakness and atrophy due to spinal motor neuron degeneration followed by occurrence of severe and intractable myoclonic seizures and death in the teenage years. We studied two subjects, a 30-year-old pregnant woman and her 17-year-old sister, affected with a very slowly progressive non-5q SMA since childhood. No history of seizures or myoclonus has been reported and EEG was unremarkable. The molecular study of ASAH1 gene showed the presence of the homozygote nucleotide variation c.124A>G (r.124a>g) that causes the amino acid substitution p.Thr42Ala. Biochemical evaluation of cultured fibroblasts showed both reduction in ceramidase activity and accumulation of ceramide compared with the normal control. This study describes for the first time the association between ASAH1 variants and an adult SMA phenotype with no myoclonic epilepsy nor death in early age, thus expanding the phenotypic spectrum of ASAH1-related SMA. ASAH1 molecular analysis should be considered in the diagnostic testing of non-5q adult SMA patients.

Background: Behavioral and cognitive impairment are common in amyotrophic lateral sclerosis (ALS) and represent a continuum with frontotemporal dementia (FTD). Olfactory dysfunction has been described in a subset of ALS patients and might be associated with frontotemporal and insular cortex dysfunction. Objective: To evaluate olfaction dysfunction in ALS patients and its relationship with either cognition or behavioral impairment. Methods: 28 consecutive ALS patients underwent an extensive cognitive and behavioral battery and were classified as patients with normal cognition (ALS-N, n = 11) or with part of the ALS-FTD spectrum (n = 17), including either cognitive or behavioral impairment or dementia. Odor verbal and visual identification and discrimination were investigated in patients and age-matched controls using a test adapted from the Sniffin' Sticks. Results: Olfactory function was significantly different between ALS-FTD spectrum patients and controls (p < 0.001) and inversely correlated with behavioral and cognitive performance. The 10-point cutoff distinguished ALS-N from ALS-FTD spectrum patients with a sensitivity and specificity of 71 and 100%, respectively. Conclusions: Hyposmia is common in a subset of ALS patients and strongly associated with behavioral and cognitive impairment. Olfactory testing may represent an early screening tool in order to identify ALS subjects with cognitive/behavioral dysfunction. Further studies in larger series are mandatory in order to better investigate clinical and pathological aspects in this group of patients.

Restless Legs Syndrome/Willis-Ekbom Disease (RLS/WED) is a common condition characterized by an irresistible urge to move the legs, concomitant with an unpleasant sensation in the lower limbs, which is typically relieved by movement. Symptoms occur predominantly at rest and prevail in the afternoon or evening. Treatment of patients with RLS/WED is indicated for those patients who suffer from clinically relevant symptoms. The management of mild forms of RLS/WED is mainly based on dopamine agonists (DA) therapy (including pramipexole and ropinirole) and α-2-δ calcium-channel ligand. Nevertheless, with passing of time, symptoms tend to become more severe and the patient can eventually develop pharmacoresistance. Furthermore, long-term treatment with dopaminergic agents may be complicated by the development of augmentation, which is defined by an increase in the severity and frequency of RLS/WED symptoms despite adequate treatment. Here, we discuss which are the best therapeutic options when RLS/WED becomes intractable, with a focus on advantages and side effects of the available medications. Prevention strategies include managing lifestyle changes and a good sleep hygiene. Different drug options are available. Switching to longer-acting dopaminergic agents may be a possibility if the patient is well-tolerating DA treatment. An association with α-2-δ calcium-channel ligand is another first-line approach. In refractory RLS/WED, opioids such as oxycodone–naloxone have demonstrated good efficacy. Other pharmacological approaches include IV iron, benzodiazepines such as clonazepam, and antiepileptic drugs, with different level of evidence of efficacy. Therefore, the final decision regarding the agent to use in treating severe RLS/WED symptoms should be tailored to the patient, taking into account the symptomatology, comorbidities, the availability of treatment and the history of the disease.

Myotonic dystrophy type 2 (DM2) is a common adult onset muscular dystrophy caused by a dominantly transmitted (CCTG)( n ) expansion in intron 1 of the CNBP gene. In DM2 there is no obvious evidence for an intergenerational increase of expansion size, and no congenital cases have been confirmed. We describe the clinical and histopathological features, and provide the genetic and molecular explanation for juvenile onset of myotonia in a 14-year-old female with DM2 and her affected mother presenting with a more severe phenotype despite a later onset of symptoms. Histological and immunohistochemical findings correlated with disease severity or age at onset in both patients. Southern blot on both muscle and blood samples revealed only a small increase in the CCTG repeat number through maternal transmission. Fluorescence in situ hybridization, in combination with MBNL1 immunofluorescence on muscle sections, showed the presence of mutant mRNA and MBNL1 in nuclear foci; the fluorescence intensity and its area appeared to be similar in the two patients. Splicing analysis of the INSR, CLCN1 and MBNL1 genes in muscle tissue demonstrates that the level of aberrant splicing isoforms was lower in the daughter than in the mother. However, in the CLCN1 gene, a heterozygous mutation c.501CG p.F167L was present in the daughter's DNA and found to be maternally inherited. Biomolecular findings did not explain the unusual young onset in the daughter. The co-segregation of DM2 with a recessive CLCN1 mutation provided the explanation for the unusual clinical findings.

The pathophysiology of restless legs syndrome (RLS) isn’t completely understood. Small Fiber Neuropathy (SFN) patients may have RLS-like sensory symptoms. The aim of this study was to assess the prevalence and clinical features of RLS in patients with SFN, compared with Large Fibres Neuropathy (LFN) patients and healthy controls. All patients underwent nerve-conduction studies and electromyography, and a skin biopsy to confirm SFN. RLS was diagnosed according to international criteria. We compared: frequency of RLS, age of onset, severity as measured by IRLS, insomnia and diabetes comorbidity. We included 39 SFN patients, 37 LFN patients and 40 matched controls. Peripheral nerve-conduction velocities were normal in SFN patients and controls. SFN patients had a 25.60% prevalence of RLS, compared to 10.80% in LFN and 7.50% in controls. Age of onset was 42.91 years, versus 62.67 in LFN and 58.50 in controls. Mean IRLS was 15.6 versus 19.5 in LFN and 18.6 in controls. The occurrence of insomnia was similar between SFN and LFN (43.58% and 43.24%), but higher than in controls (20%). Biopsy-proven SFN patients had a higher risk for an early-onset RLS. They show a less severe RLS, but it can frequently cause insomnia.

The three-dimensional (3D) temporomandibular joint (TMJ) model derives from a study of the cranium by 3D virtual reality and mandibular function animation. The starting point of the project is high-fidelity digital acquisition of a human dry skull. The cooperation between the maxillofacial surgeon and the cartoonist enables the reconstruction of the fibroconnective components of the TMJ that are the keystone for comprehension of the anatomic and functional features of the mandible. The skeletal model is customized with the apposition of the temporomandibular ligament, the articular disk, the retrodiskal tissue, and the medial and the lateral ligament of the disk. The simulation of TMJ movement is the result of the integration of up-to-date data on the biomechanical restrictions. The 3D TMJ model is an easy-to-use application that may be run on a personal computer for the study of the TMJ and its biomechanics.

Mutations within EDA1 gene, which encodes for the ectodysplasin, cause X-linked anhidrotic ectodermal dysplasia. In this study, 23 Italian patients with anhidrotic ectodermal dysplasia were analyzed for mutations in EDA1 gene. We set up a rapid protocol through denaturing high-performance liquid chromatography, followed by sequencing, that allowed the characterization of 18 mutations, 14 novel and 4 recurrent: 8 missense mutations (p.L51Q, p.H54R, p.R156H twice, p.C332F, p.D316H, p.T378M, and p.A349T), 3 in-frame deletions (p.G82_P84del, p.A179_P191del, and p.L354del), 1 gross deletion (p.G168_G265del, identified through direct sequencing and PCR), 4 altered splicing (c.949-13T > C, c.741 + 1G/T, c.793 + 4A > T, and c.924 + 1G/T), 1 nonsense (p.Y3X), and 1 synonymous mutation (c.741G > A). Moreover, structural analysis of three missense mutations shows that alteration of the electrostatic surface of the protein (p.D316N), the break of intermonomer interactions (p.A349T) and destabilization of the single monomer structure (p.T378M), may irreversibly invalidate the EDA-A1 binding properties. Our data confirm and extend the large spectrum of EDA1 mutations and provide a rapid and efficient molecular protocol for testing EDA1 mutations in EDA patients.

Rapid eye movement (REM) sleep behavior disorder (RBD) can occur in the absence of any other obvious asso- ciated neurologic disorder or in association with a neurodegenerative disease, in which case it is considered as symptomatic RBD. RBD is frequently associated with Parkinson’s disease (PD), Lewy body dementia or multiple system atrophy (MSA), and in several cases may even antedate the occurrence of motor symptoms by decades. When no neurologic disorder is obvious, RBD can be considered as idiopathic (iRBD). Several studies have looked at neurophysiologic and neuropsychological functions in iRBD and have found evidence of CNS dysfunc- tion during both wakefulness and sleep in a variable proportion of these patients, challenging the concept of iRBD. Identifying subjects with a high risk of developing a neurodegenerative process may be crucial in order to develop early intervention strategies. Some prospective results in iRBD showed that potential markers of neuro- degeneration are the following: 1) marked EEG slowing on spectral analysis; 2) decreased striatal 123I-FPCIT; 3) impaired color vision.

Parasomnias are unpleasant or undesirable behaviours or experiences that occur predominantly during or within close proximity to sleep. Pharmacological treatments of parasomnias are available, but their efficacy is established only for few disorders. Furthermore, most of these disorders tend spontaneously to remit with development. Nonpharmacological treatments therefore represent valid therapeutic choices. This paper reviews behavioural and cognitive-behavioural managements employed for parasomnias. Referring to the ICSD-3 nosology we consider, respectively, NREM parasomnias, REM parasomnias, and other parasomnias. Although the efficacy of some of these treatments is proved, in other cases their clinical evidence cannot be provided because of the small size of the samples. Due to the rarity of some parasomnias, further multicentric researches are needed in order to offer a more complete account of behavioural and cognitive-behavioural treatments efficacy.

International audience; Settled uneaten feed causes the most intense impact under sea cages, and settling velocity of the feed pellets represents a key parameter for waste dispersion models. Even if some data about physical properties of feed pellets have been published in the framework of salmonid rearing, there is a complete lack of information related to the Mediterranean Sea, as regards typical values of temperature, salinity and feed composition for Gilthead Sea Bream (Sparus aurata L.) and Sea Bass (Dicentrarchus labrax L.). In this study we try to fill this lack, determining dimensions, water adsorption properties, floating times and settling velocities of a typical growing sequence of pellets for the species mentioned above, under defined laboratory conditions reproducing Mediterranean Sea water. The settling velocity increases with pellet size from 0.087, for the smallest pellet (3 mm), to 0.144 m s(-1), for the 5 mm pellet. The biggest extruded pellet (6 mm) falls slower (0.088 m s(-1)). The floating time before pellet's fall is found to be a critical parameter in determining settling velocity. The latter depends on pellet's size, water temperature and salinity. The examined pellets reach a 42% of weight increase after 10 min of immersion, while no appreciable dimension change is observed. Our results are in part different from previous ones and could play a role in evaluating and modelling Mediterranean aquaculture environmental impact.

Headache is a common presenting complaint in the Emergency Department. The aim of this study was to delineate the demographic profile of patients presenting a chief complaint of headache and to assess the application of diagnostic algorithms for the management of these patients. We examined patients admitted to the Spedali Civili Hospital ED between January 2005 and December 2009 who complained of headache not related to trauma and all patients hospitalized for headache in Neurological Clinic, from ED, between January 2008 and December 2009. 7495 patients were examined at ED for headaches. 72 % of patients were discharged, 22 % were admitted. From 2005 to 2009, there was a definite decrease in the rate of hospitalization due to headache (15 vs 9.9 % in Department of Neurology and 26 vs 18.9 % in all Departments). Considering the decrease year by year, this reduction was significant from 2007 to 2008, when the algorithms were adopted. The most common diagnosis in the ED was “Non-specific headache” (41 %), followed by “Primary headaches and complications of primary headaches” (20.8 %), “Secondary headaches not associated with risk of serious disease” (20.4 %) and “Secondary headache associated with risk of serious disease” (5 %). Over 2-year period (2008–2009) we found an increase in the diagnosis of “Primary headaches and complications of primary headaches” and “Secondary headaches associated with risk of serious disease” compared with a decrease of “nonspecific headache” and “secondary headaches not associated with risk of serious disease”. The use of the diagnostic algorithms and collaborative network between the ED and the Headache Center can improve the management of patients with headache in ED.

sporadic motor neuron disorder that differs from the spinal ALS because it remains largely restricted to the upper limbs over time. Only a few cases are described in the literature with a follow-up ranging between two and 11 years (3,4). We report on a 69-years-old patient having a 35-year history of progressive bilateral weakness of the proximal segments of upper limbs and shoulders, which started insidiously on the left side and involved the right side 15 years later. No lower limb involve-ment was reported. No injury of rotator cuff muscles and tendons was noted. Neuromuscular family history was unremarkable. Clinical evaluation showed severe weakness and atrophy of muscles of the upper limb girdle (Figure 1). Distal segments of upper limbs as well as lower limbs were normal. Fasciculations were not present. Deep tendon refl exes were absent at the upper limbs and normal at the lower ones. Dear Sir, Man-in-the-barrel syndrome (MIBS) is characterized by brachial diplegia with motor function preserved in the legs and facial musculature, giving to a patient the clinical appearance of seeming constrained in a barrel (1). MIBS was early observed in patients with bilat-eral ischaemia in the border zones of the anterior and medial cerebral arteries, pontine lesion, multiple sclerosis lesions, cerebral metastases and head trauma. A less recognized variant of MIBS is the neurogenic form that can result from different causes, i.e. amyotrophic lateral sclerosis and myelopathies with purely motor presentation including cervical spinal cord infarction, cervical spondylosis and post radiation (1,2). The term ‘ brachial amyotrophic diplegia ’ has been used to identify a MIBS related to a primary

Hashimoto's encephalopathy (HE) is a rare neuropsychiatric syndrome associated with antithyroid antibodies. It may have an acute onset (episodes of cerebral ischemia, seizure, and psychosis) or it may present as an indolent form (depression, cognitive decline, myoclonus, tremors, and fluctuations in level of consciousness). We here describe a case of encephalopathy presenting as non-convulsive status epilepticus associated with Hashimoto's thyroiditis (HT), unresponsive to corticosteroid therapy, with improvement after plasma exchange treatment. A previously healthy 19-year-old woman, presented generalized tonic-clonic seizures. About a month later, she manifested a speech disorder characterized by difficulties in the production and comprehension of language. Within a few days she also developed confusion and difficulties in recognizing familiar places, with gradual worsening over time. EEG revealed a non-convulsive status epilepticus (NCSE). CSF examination showed slightly elevated cell count and four oligoclonal bands. MRI was unremarkable, and (18)F-FDG brain PET showed widespread hypometabolism, mostly in posterior regions bilaterally. Laboratory and ultrasound findings showed signs of HT. Treatment with steroid was introduced without any improvement. After five sessions of plasma exchange there was a decrease of antithyroid antibodies, as well as EEG and clinical improvement. Three months after discharge (18)F-FDG brain PET showed a complete normalization of the picture, and the patient was asymptomatic. This report emphasizes the successful treatment of HE with plasma exchange in a patient who presented with NCSE. Based on the actual evidence, the term "Encephalopathy associated with Hashimoto's thyroiditis" may be the most proper. Furthermore, to our knowledge, this is the first case of an adult patient studied twice with an (18)F-FDG brain PET: prior to treatment with plasma exchange, and at 3 months follow-up when the patient was clinically completely asymptomatic. Studies in more patients are needed to clarify the relevance of (18)F-FDG brain PET as a possible diagnostic tool for HE.