Neuroinflammation and status epilepticus: a narrative review unraveling a complex interplay.

Status epilepticus (SE) is a medical emergency resulting from the failure of the mechanisms involved in seizure termination or from the initiation of pathways involved in abnormally prolonged seizures, potentially leading to long-term consequences, including neuronal death and impaired neuronal networks. It can eventually evolve to refractory status epilepticus (RSE), in which the administration of a benzodiazepine and another anti-seizure medications (ASMs) had been ineffective, and super-refractory status epilepticus (SRSE), which persists for more than 24 h after the administration of general anesthesia. Objective of the present review is to highlight the link between inflammation and SE. Several preclinical and clinical studies have shown that neuroinflammation can contribute to seizure onset and recurrence by increasing neuronal excitability. Notably, microglia and astrocytes can promote neuroinflammation and seizure susceptibility. In fact, inflammatory mediators released by glial cells might enhance neuronal excitation and cause drug resistance and seizure recurrence. Understanding the molecular mechanisms of neuroinflammation could be crucial for improving SE treatment, wich is currently mainly addressed with benzodiazepines and eventually phenytoin, valproic acid, or levetiracetam. IL-1ß signal blockade with Anakinra has shown promising results in avoiding seizure recurrence and generalization in inflammatory refractory epilepsy. Inhibiting the IL-1ß converting enzyme (ICE)/caspase-1 is also being investigated as a possible target for managing drug-resistant epilepsies. Targeting the ATP-P2X7R signal, which activates the NLRP3 inflammasome and triggers inflammatory molecule release, is another avenue of research. Interestingly, astaxanthin has shown promise in attenuating neuroinflammation in SE by inhibiting the ATP-P2X7R signal. Furthermore, IL-6 blockade using tocilizumab has been effective in RSE and in reducing seizures in patients with febrile infection-related epilepsy syndrome (FIRES). Other potential approaches include the ketogenic diet, which may modulate pro-inflammatory cytokine production, and the use of cannabidiol (CBD), which has demonstrated antiepileptic, neuroprotective, and anti-inflammatory properties, and targeting HMGB1-TLR4 axis. Clinical experience with anti-cytokine agents such as Anakinra and Tocilizumab in SE is currently limited, although promising. Nonetheless, Etanercept and Rituximab have shown efficacy only in specific etiologies of SE, such as autoimmune encephalitis. Overall, targeting inflammatory pathways and cytokines shows potential as an innovative therapeutic option for drug-resistant epilepsies and SE, providing the chance of directly addressing its underlying mechanisms, rather than solely focusing on symptom control.

Consensus paper on postural dysfunction: recommendations for prevention, diagnosis and therapy.

Good fundamentals of posture and balance are essential for the efficient performance of both simple daily tasks and more complex movement patterns. In particular, postural balance is the ability to keep the body in equilibrium and to regain balance after the shift of body segments: postural control mechanisms of integration of the visual, vestibular and foot afferential channels contribute to this. This document provides recommendations based on scientific evidence, clinical practice, and consensus between experts concerning the prevention, diagnosis, and treatment of postural dysfunction at the three stages of life as the developmental age, adult age, and old age > 65 years and follows the "National Guidelines on Classification and Measuring of Posture and its Dysfunctions" per the Italian Ministry of Health (December 2017). The paper answers four main questions: i) "Which measures can be adopted to prevent postural dysfunctions?" ii) "What can we do in order to make a correct diagnosis of postural dysfunction?" iii) "What are the correct treatment programs for postural dysfunctions?" iv) Which professional competencies and experiences are useful for preventing, diagnosing and treating postural dysfunctions? By the Consensus of the Experts and the scientific evidence, emerge that the approach to postural dysfunctions requires a multidisciplinary and interdisciplinary team. Furthermore, rehabilitation treatment interventions must be specific to the age groups that have been indicated, to consider the integration of the main systems and subsystems of postural control that change with age.

Post-traumatic stress, anxiety, and depressive symptoms in caregivers of children tested for COVID-19 in the acute phase of the Italian outbreak.

BACKGROUND: The recent COVID-19 pandemic pointed out new burdens for researchers on mental health and that evidence-based (EB) studies on vulnerable populations are timely needed. The present paper aims at analysing the impact of suspicious of SARS-COV-2 infection in a cohort of parents presented at 3 major hospitals (spread between north and center of Italy) during the Italian COVID-19 pandemic phase 1. METHODS: Participants of the present cross-sectional, multicenter study were parental couples of children suspected to have COVID-19 who underwent testing with nasopharyngeal swabbing. All subjects were assessed by means of the: Impact of Event Scale-Revised (IES-R), Generalized Anxiety Disorder 7-Item (GAD-7) and Patient Health Questionnaire-9 (PHQ-9) in order to evaluate Post-traumatic stress (PTSS), anxiety, and depressive symptoms, respectively. OUTCOMES: Results evidenced that parents whose children tested positive for COVID-19 were more prone to developing PTSS, anxiety and depressive symptoms. The same results emerged for parents who had quarantined as opposed to those who had not. Moreover, patients who suffered economic damage showed a higher prevalence of anxiety and depressive symptoms, whereas PTSS was more common among unemployed subjects and among mothers. INTERPRETATION: This study identified a mental health strain represented by parenting a child who tested positive for SARS-CoV-2 infection. Further EB research is needed to develop evidence-driven strategies to reduce adverse psychological impacts and related psychiatric symptoms in caregivers of COVID-19 infected children during the next phases of the pandemic.

Rasmussen's encephalitis: From immune pathogenesis towards targeted-therapy.

Rasmussen encephalitis (RE) is a unilateral hemispheric encephalitis whose main clinical features include refractory focal epilepsy or epilepsia partialis continua, hemiparesis, and progressive cognitive decline. Despite the autoimmune pathogenesis of RE, the only definitive therapeutic option is currently represented by surgery. We review the clinical features, the immune pathogenesis, and the available therapeutic options for RE, with special focus on immunosuppressive agents. The research includes systematic reviews, meta-analyses, observational studies, clinical trials, cases series and reports, until 2020. The use of immunosuppressive agents in RE is supported by the evidence of an autoimmune involvement of the central nervous system in this condition. Although often insufficient to modify the disease course and to achieve symptomatic control, immune therapy can be effective in patients with slow disease progression or in patients in which surgery is not applicable. Moreover, the documentation of T-cell involvement in the pathogenesis of RE, with a specific cytokine pattern, opens a window of opportunity for the use of T-targeted therapies and biologic drugs (i.e. anti-TNFα agents) in the treatment of this disease.

Post-traumatic stress spectrum symptoms in parents of children affected by epilepsy: Gender differences.

PURPOSE: To investigate psychopathological reaction to traumatic stress, addressing in particular gender difference, in parental couples of children affected by epilepsy. METHODS: 50 mothers and 50 fathers, paired for one's child, of children followed at the Pediatric Unit of a major Italian University Hospital with a diagnosis of epilepsy were enrolled, screened by means of the Semi-structured Clinical Interview for DSM-5 (SCID-5) and filled the Trauma and Loss Spectrum Self-Report (TALS-SR), an international instrument to evaluate post-traumatic stress symptomatology. RESULTS: 25 % of the total sample presented a diagnosis of PTSD with a statistically higher prevalence of mothers (36 % and 14 %, respectively; p = .021). Furthermore, 44 % (48 % mothers and 40 % fathers) presented a partial PTSD. Important gender differences emerged also for all cluster dimensions of the TALS-SR except for the Avoidance. Finally, the analysis of the single items of the TALS-SR evidenced that in mothers subgroup prevail cognitive symptoms of fear and sadness as well as somatic manifestations. CONCLUSIONS: Our results point out the differences between mothers and fathers in trauma response and underline the need to develop gender targeted models of healthcare prevention and assistance.

Efficacy and tolerability of mycophenolate mofetil in a pediatric Rasmussen syndrome.

Rasmussen syndrome (RS) is a chronic encephalopathy with uncertain etiology and immune-mediated pathogenesis. The only definitive treatment is represented by functional hemispherectomy. We describe the case of a 6.5-year-old female patient who developed several episodes of focal, unilateral clonic seizures. Following laboratory and instrumental investigations, the patient was diagnosed as having RS. A treatment with corticosteroids, intravenous immunoglobulin, and the antiseizure medication (carbamazepine and levetiracetam) did not completely control the seizures. Therefore, the patient was treated with mycophenolate mofetil (MMF), showing a good clinical response, with reduction of the seizures, and stability of the radiological findings. This case suggests the potential utility of MMF in the immune approach to RS.

Post-traumatic stress and major depressive disorders in parent caregivers of children with a chronic disorder.

Post-traumatic Stress Disorder (PTSD) and Major Depressive Disorder (MDD) are the most common psychiatric consequences among caregivers of pediatric patients affected by severe chronic illnesses. The aims of this study were to describe rates of PTSD and MDD in a sample of parents of epileptic children, and to examine the correlations between symptoms of post-traumatic stress and depression. Parents of children with epilepsy were enrolled and screened by means of the PTSD module of the Semi-Structured Clinical Interview for DSM-5 (SCID-5) and of the Hamilton Rating Scale for depression (HAM-D). They also completed the Trauma and Loss Spectrum Self-Report (TALS-SR), an international instrument to evaluate post-traumatic stress spectrum symptoms. Results revealed PTSD rates of 15.7% (19.5% mothers, 8,1% fathers; p = .043) and MDD rates of 7.5% (10.2% mothers,1.8% fathers; p = .064). A model of multiple linear regression indicated a significant B linear regression coefficient between being mothers (p = .012), witnessing tonic-clonic seizures (p = .015) and having higher TALS-SR total score (p < .001) as predictors of HAM-D total score. Our findings highlight the relationship between PTSD and MDD, evidencing the need for further studies on pediatric caregivers aimed to develop specific intervention programs of healthcare prevention and assistance.

Methylenetetrahydrofolate reductase polymorphism (MTHFR C677T) and headache in children: a retrospective study from a tertiary level outpatient service.

BACKGROUND: In adult studies the MTHFR C677T polymorphism has been associated with an increased risk of migraine, but little research has been done in this area in children. METHODS: A retrospective study of children referred with headache to a tertiary level Paediatric Neurology Service between 2008 and 2012. This study included only patients who had been genotyped for the MTHFR C677T polymorphism. An evaluation of homocysteine serum levels was necessary to exclude other types of migraine. CONCLUSION: Compared with the wild-type genotype, the T/T genotype was associated with an increased risk of any type of migraine, though the statistical significance was greatest in migraine with aura. The homocysteine serum levels were significantly higher in migraine with aura compared to migraine without aura. In a pediatric population MTHFR T/T homozygosity influences susceptibility to migraine.

Length measurement and spatial orientation reconstruction of single nanowires.

The accurate determination of the geometrical features of quasi one-dimensional nanostructures is mandatory for reducing errors and improving repeatability in the estimation of a number of geometry-dependent properties in nanotechnology. In this paper a method for the reconstruction of length and spatial orientation of single nanowires (NWs) is presented. Those quantities are calculated from a sequence of scanning electron microscope (SEM) images taken at different tilt angles using a simple 3D geometric model. The proposed method is evaluated on a collection of SEM images of single GaAs NWs. It is validated through the reconstruction of known geometric features of a standard reference calibration pattern. An overall uncertainty of about 1% in the estimated length of the NWs is achieved.

Generalized epilepsy and mild intellectual disability associated with 13q34 deletion: A potential role for SOX1 and ARHGEF7.

Terminal deletions of long arm of chromosome 13 are rare and poorly characterized by cytogenetic studies, making for difficult genotype-phenotype correlations. We report two siblings presenting generalized epilepsy, intellectual disability, and genitourinary tract defects. Array CGH detected a 1.3 Mb deletion at 13q34; it contains two protein-coding genes, SOX1 and ARHGEF7, whose haploinsufficiency can contribute to the epileptic phenotype.

Beyond the floor effect on the WISC-IV in individuals with Down syndrome: are there cognitive strengths and weaknesses?

BACKGROUND: Individuals with Down syndrome generally show a floor effect on Wechsler Scales that is manifested by flat profiles and with many or all of the weighted scores on the subtests equal to 1. METHOD: The main aim of the present paper is to use the statistical Hessl method and the extended statistical method of Orsini, Pezzuti and Hulbert with a sample of individuals with Down syndrome (n = 128; 72 boys and 56 girls), to underline the variability of performance on Wechsler Intelligence Scale for Children-Fourth Edition subtests and indices, highlighting any strengths and weaknesses of this population that otherwise appear to be flattened. RESULTS: Based on results using traditional transformation of raw scores into weighted scores, a very high percentage of subtests with weighted score of 1 occurred in the Down syndrome sample, with a floor effect and without any statistically significant difference between four core Wechsler Intelligence Scale for Children-Fourth Edition indices. The results, using traditional transformation, confirm a deep cognitive impairment of those with Down syndrome. Conversely, using the new statistical method, it is immediately apparent that the variability of the scores, both on subtests and indices, is wider with respect to the traditional method. CONCLUSION: Children with Down syndrome show a greater ability in the Verbal Comprehension Index than in the Working Memory Index.

Adult Autism Subthreshold Spectrum (AdAS Spectrum) in parents of pediatric patients with epilepsy: Correlations with post-traumatic stress symptoms.

Increasing literature has shown the usefulness of a dimensional approach to mental disorders, particularly when exploring subjects exposed to traumatic experiences such as a severe illness in one's child. Recent evidence suggests an increased vulnerability in subjects with autism spectrum symptoms to develop post-traumatic stress symptoms. The aim of the present study was to evaluate the presence of adult autism subthreshold spectrum in a sample of parents of children with epilepsy and its impact on post-traumatic stress spectrum symptoms in the same study sample. Results revealed noteworthy correlations between post-traumatic stress symptoms and adult autism subthreshold spectrum (AdAS Spectrum) only in the subgroup of the fathers. In particular, were evidenced correlations between AdAS Spectrum domain of rumination and narrow interests and some TALS-SR nuclear domains: reaction to traumatic events, reexperiencing and arousal. These findings corroborate the hypothesis that subthreshold autistic features may influence the possible psychopathological reaction to trauma.

Choosing the individual rehabilitation program for patients with intermittent claudication.

This study is aimed at identifying the collateral circulation in case of femoral-aorta-iliac axis obstruction, with the purpose of a more correct therapeutic indication being either medical or surgical or physiotherapeutic or combined.

Deep vein thrombosis of the lower limb secondary to lumbar discal hernia compression: a rarity? Review of the literature.

This case report is about a 70-years-old female patient, suffering from discal hernia, with compression of the iliac vein, that led to the formation of deep vein thrombosis of the lower limbs. The angio-CT scan revealed the starting point of the L4- L5 compression where a voluminous discal hernia caused deep vein thrombosis, with the involvement the femoro-popliteal venous axis. Blood samples and PET-CT scans excluded other possible etiologic factors. This case demonstrates how a voluminous discal hernia can cause venous thrombosis.

Percutaneous dilatational tracheostomy using a tracheoscopic ventilation tube in an experimental ex vivo animal model.

The ETView(®) tube is a standard endotracheal tube with an embedded miniature video camera that permits real-time video imaging of the tracheal lumen. We evaluated its use when performing percutaneous dilatational tracheostomy (PDT) in an ex vivo animal model. The model consisted of a pig larynyx and trachea. The ETView tube was used as an alternative to bronchoscopy, to see all manoeuvres of PDT in real time. At the end of the PDT, operative time and any complications such as trauma to the cricoid cartilage, tracheal wall or tube cuff were assessed. Nine PDT procedures were performed by two experienced operators. The mean operative time was 7.1 ± 0.9 minutes. No complications were observed. Our study supports the use of the ETView tube as a suitable alternative to bronchoscopy when performing PDT, although clinical studies are required to confirm our experimental results. .

Autosomal dominant SCN8A mutation with an unusually mild phenotype.

BACKGROUND: Mutations in SCN8A, coding for the voltage-gated sodium channel Nav 1.6, have been described in relation to infantile onset epilepsy with developmental delay and cognitive impairment, in particular early onset epileptic encephalopathy (EIEE) type 13. CASE REPORT: Here we report an infant and his father with early onset focal epileptic seizures but without cognitive or neurological impairment in whom next generation sequence analysis identified a heterozygous mutation (c.5630A > G, p. (Asn1877Ser)) in the SCN8A gene. This mutation, confirmed by Sanger sequence analysis, affects a highly conserved amino acid and in silico tools predicts that it may be pathogenic. The reported infant has a normal developmental profile at 16-month follow-up. His father also had normal development and has no cognitive impairment at 42 years. This is the second known SCN8A mutation associated with a phenotype of benign familial infantile epilepsy. Good seizure control was achieved in our patients with sodium channel blockers. CONCLUSION: Based on our proband and a recently described group of families with benign familial infantile epilepsy and SCN8A variant we suggest expanding testing to patients with infantile epilepsy and no cognitive impairment. In addition, the same SCN8A variant (c.5630A > G, p. (Asn1877Ser)) is also found in patients with epilepsy and developmental delay highlighting the phenotypic variability and the possible role of other protective genetic factors.

17q12 microduplications: a challenge for clinicians.

In the recent years, some cases of 17q12 deletions and duplications have been reported, but the clinical impact of these imbalances is still to be fully elucidated. In particular, 17q12 duplications elude syndrome classification, since they are associated with a wide phenotypic spectrum, ranging from very mild to quite severe phenotypes. Here, two unrelated patients with the same 1.2 Mb microduplication of 17q12 are reported. Comparing these patients' phenotype with those previously published, it emerges that the more patients reported, the more difficult is finding common characteristics, even in presence of exactly the same genetic anomaly. The role of the genes duplicated in this region and the impact of this chromosomal imbalance are discussed.

Beyond the floor effect on the Wechsler Intelligence Scale for Children--4th Ed. (WISC-IV): calculating IQ and Indexes of subjects presenting a floored pattern of results.

BACKGROUND: It is now widely known that children with severe intellectual disability show a 'floor effect' on the Wechsler scales. This effect emerges because the practice of transforming raw scores into scaled scores eliminates any variability present in participants with low intellectual ability and because intelligence quotient (IQ) scores are limited insofar as they do not measure scores lower than 40. METHOD: Following Hessl et al.'s results, the present authors propose a method for the computation of the Wechsler Intelligence Scale for Children--4th Ed. (WISC-IV)'s IQ and Indexes in intellectually disabled participants affected by a floored pattern of results. The Italian standardization sample (n = 2200) for the WISC-IV was used. The method presented in this study highlights the limits of the 'floor effect' of the WISC-IV in children with serious intellectual disability who present a profile with weighted scores of 1 in all the subtests despite some variability in the raw scores. RESULTS: Such method eliminates the floor effect of the scale and therefore makes it possible to analyse the strengths and weaknesses of the WISC-IV's Indexes in these participants. CONCLUSIONS: The Authors reflect on clinical utility of this method and on the meaning of raw score of 0 on subtest.

Evaluation of the cephalometrics modification of growing Class II Division I patients after treatment with the PUL appliance: a pilot study.

AIM: The aim of this preliminary study was to evaluate short-term dentoskeletal changes obtained with a functional appliance for Class II Division I malocclusions called propulsor universal light (PUL). METHODS: Fifteen Class II Division 1 patients (10.6±1.2 years) were consecutively treated by one expert operator with PUL appliance and they were compared with a longitudinal group of Class II Division I untreated patients (9.9±1.9 years) matched for pubertal growth spurt stage and sex. Lateral cephalograms were taken before PUL therapy and at the end of treatment. The mean duration of treatment was 11.2±0.3 months; t-test or Mann-Whitney U-test was used (P <0.05). RESULTS: Statistically significant reduction of the overjet, WITS and ANB was noticed in treated group as well as a significant improvement of CoGo and Ramus. CONCLUSION: Class II Division I malocclusion in the short term was efficiently treated by PUL appliance with both skeletal and dentoalveolar changes.

A phase diagram for microfabrication of geometrically controlled hydrogel scaffolds.

Hydrogels are considered as excellent candidates for tissue substitutes by virtue of their high water content and biphasic nature. However, the fact that they are soft, wet and floppy renders them difficult to process and use as custom-designed scaffolds. To address this problem alginate hydrogels were modeled and characterized by measuring stress-strain and creep behavior as well as viscosity as a function of sodium alginate concentration, cross-linking time and calcium ion concentration. The gels were then microfabricated into scaffolds using the pressure-assisted microsyringe. The mechanical and viscous characteristics were used to generate a processing window in the form of a phase diagram which describes the fidelity of the scaffolds as a function of the material and machine parameters. The approach can be applied to a variety of microfabrication methods and biomaterials in order to design well-controlled custom scaffolds.