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.

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.

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.

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.

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.

Recurrence patterns in patients with early stage cervical cancer treated with radical hysterectomy and external pelvic irradiation.

One hundred and fifty patients with clinical FIGO stage IB-II cervical cancer who underwent radical surgery followed by external pelvic irradiation between 1978 and 1991 were reviewed. Until June 1994, 28 (18.7%) patients developed recurrent disease. Seventeen (60.7%) of them experienced a pelvic failure, 7 (25.0%) an extrapelvic failure and 4 (14.3%) both a pelvic and an extrapelvic failure. The median time to recurrence was 16 months for patients with pelvic failure (range = 4-50 months), 27 months for those with extrapelvic failure (range = 6-49 months), and 21 months for those with both pelvic and extrapelvic failure (range u 8-56 months). Recurrence rates were significantly related to surgical-pathologic stage, tumor size and lymph node status, but not to histologic type. An extrapelvic recurrence, alone or associated with a pelvic failure, was found in 0.9% of 117 patients with negative lymph nodes, 6.2% of 16 patients with one or two positive lymph nodes, and 52.9% of 17 patients with three or more positive lymph nodes, (p = 0.0001). It is worth noting that 9 (81.8%) out of the 11 patients who developed extrapelvic recurrences had three or more involved lymph nodes. The number of positive lymph nodes (p = 0.0001) and the tumor size (p = 0.0046) were independent prognostic variables for disease-free survival.

Analysis of treatment failures in patients with early-stage uterine leiomyosarcoma.

This retrospective study aimed to investigate the treatment failures in 26 patients with stages I-II uterine leiomyosarcoma (> or = 10 mitoses per 10 high-power field (HPF) who underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy +/- adjuvant external pelvic irradiation. Thirteen (50%) patients developed recurrent disease, after a median time of 10 months from surgery (range = 4-72 months). Recurrence was pelvic in 3 (23%) patients, extrapelvic in 9 (69%) patients, and both pelvic and extrapelvic in 1 (8%) patient. Disease-free survival was better for premenopausal than for postmenopausal patients (p = 0.002) and for patients with < 20 mitoses per 10 HPF than for those with > or = 20 mitoses per 10 HPF (p = 0.006). In conclusion, patients with early-stage disease who had undergone locoregional treatment experienced a high recurrence rate. Most of the treatment failures were extrapelvic. Multicentric randomized trials on the role of adjuvant chemotherapy are advocated.

Serum interleukin-6 levels in uterine malignancies. Preliminary data.

Interleukin-6 (IL-6) was measured with an enzyme-immunoassay in blood samples drawn at diagnosis from 37 patients with endometrial cancer, 36 with cervical cancer, 9 with cervical intraepithelial neoplasia (CIN) and 68 with benign uterine disease. The minimal detectable dose of IL-6 was 3 pg/mL. Detectable serum IL-6 levels were found in 9% of patients with benign uterine diseases, 11% of patients with CIN, 44% of patients with cervical cancer and 11% of patients with endometrial cancer. As regards cervical cancer, serum IL-6 levels > 3 pg/mL were found in 36.0% of 25 patients with stage Ib-IIa disease and in 64% of 11 patients with stage IIb-IV disease. As regards endometrial cancer, serum detectable IL-6 levels were observed in 0% of 30 patients with stage I-II disease and in 57% of 7 patients with stage III-IV disease (p = 0.0005). These preliminary data suggest that IL-6 may be involved in the progression of uterine malignancies.