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Therapies for epilepsy mainly provide symptomatic control of seizures since most of the available drugs do not target disease mechanisms. Moreover, about one-third of patients fail to achieve seizure control. To address the clinical need for disease-modifying therapies, research should focus on targets which permit interventions finely balanced between optimal efficacy and safety. One potential candidate is the brain-specific enzyme cholesterol 24-hydroxylase. This enzyme converts cholesterol to 24S-hydroxycholesterol, a metabolite which among its biological roles modulates neuronal functions relevant for hyperexcitability underlying seizures. To study the role of cholesterol 24-hydroxylase in epileptogenesis, we administered soticlestat (TAK-935/OV935), a potent and selective brain-penetrant inhibitor of the enzyme, during the early disease phase in a mouse model of acquired epilepsy using a clinically relevant dose. During soticlestat treatment, the onset of epilepsy was delayed and the number of ensuing seizures was decreased by about 3-fold compared to vehicle-treated mice, as assessed by EEG monitoring. Notably, the therapeutic effect was maintained 6.5 weeks after drug wash-out when seizure number was reduced by about 4-fold and their duration by 2-fold. Soticlestat-treated mice showed neuroprotection of hippocampal CA1 neurons and hilar mossy cells as assessed by post-mortem brain histology. High throughput RNA-sequencing of hippocampal neurons and glia in mice treated with soticlestat during epileptogenesis showed that inhibition of cholesterol 24-hydroxylase did not directly affect the epileptogenic transcriptional network, but rather modulated a non-overlapping set of genes that might oppose the pathogenic mechanisms of the disease. In human temporal lobe epileptic foci, we determined that cholesterol 24-hydroxylase expression trends higher in neurons, similarly to epileptic mice, while the enzyme is ectopically induced in astrocytes compared to control specimens. Soticlestat reduced significantly the number of spontaneous seizures in chronic epileptic mice when was administered during established epilepsy. Data show that cholesterol 24-hydroxylase contributes to spontaneous seizures and is involved in disease progression, thus it represents a novel target for chronic seizures inhibition and disease-modification therapy in epilepsy.

Status Epilepticus (SE) is a condition resulting either from the failure of seizure termination mechanisms or from the abnormal activation of prolonged seizure mechanisms. It represents a life-threatening medical emergency associated with high morbidity and mortality that requires prompt diagnosis and treatment. SE treatment begins with a quick-acting benzodiazepine, followed by intravenous (IV) loading and a continuous infusion of antiseizure medications (ASMs). The failure of first- and second-line treatments is defined as “refractory SE” (RSE) and requires infusion of IV anaesthetics. If anaesthetics fail or SE recurs after 24 hours, SE is defined as “super refractory status epilepticus” (SRSE).

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

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Summary Objective Patients with seizures or status epilepticus (SE) access the hospital through emergency departments and may be admitted into different wards according to the level of care required. Clinicians with different expertise are in charge of taking critical therapeutic decisions. To date, very few studies have investigated the stage at which these patients are referred to neurologists or epileptologists and how guideline recommendations are applied in clinical practice. Methods A survey was used to investigate how patients with epileptic seizures or SE are managed in emergency and in subsequent hospital pathways in Italy. Results One hundred and seventy-seven physicians (mainly neurologists) from all parts of Italy filled in a questionnaire. Less than half of the participants (35%) answered that, in their hospital, patients with epilepsy were managed by epileptologists. The percentages were lower for patients presenting with acute seizures (21%) or SE (16%). Diagnostic, therapeutic, and assistance pathways (PDTA) for patients presenting with seizure(s) or SE were available for both conditions in about 50% of cases, while, in the rest of the hospitals, participants indicated informal agreements (about 25% of cases) or lack of any agreement (about 25% of cases) between clinicians. Professionals more often involved in PDTA were epileptologists/neurologists, emergency physicians, and intensivists. More than half ot the participants (55%) thought that organizational issues are the most important criticalities for such patients and need to be improved (61%). Significance There is a high variability in hospital clinical pathways for epilepsy in Italy.

Purpose Status Epilepticus can be a serious life threatening event in epileptic patients. The definition of refractory or super-refractory Status Epilepticus was based on the therapeutic response to anti-epileptic and anesthetic drugs. Vagal Nerve Stimulation showed efficacy in treating drug-resistant epilepsy but there are only few reports on emergentplacement of Vagal Nerve Stimulator for refractory or super-refractory Status Epilepticus. Methods Among 49 children implanted at our Institution with Vagal Nerve Stimulation for drug-resistant epilepsy, the authors retrospectively identified those implanted for refractory or super-refractory Status Epilepticus, according with the current definitions. Results 4 patients were operated upon at ages ranging 7 to 17 months and reached the programmed output current of 1 mA over a time ranging from 24 to 36 h (fast ramping-up). In 3 out of 4 patient we observed the abrupt of Status Epilepticus; one patient was refractory both to drugs and Vagal Nerve Stimulation and later died, without recovering from SE. At follow up, ranging from 24 to 45 months, the remaining 3 patients showed a decrease of the seizures frequency >80% without relapse of Status Epilepticus; in all the patients, output current and/or Duty Cycle were increased later. Conclusion VNS can be effective in treating refractory or super-refractory Status Epilepticus.

Background Ring chromosome 14 syndrome is a rare chromosomal disorder characterized by early onset refractory epilepsy, intellectual disability, autism spectrum disorder and a number of diverse health issues. Results The aim of this work is to provide recommendations for the diagnosis and management of persons affected by ring chromosome 14 syndrome based on evidence from literature and experience of health professionals from different medical backgrounds who have followed for several years subjects affected by ring chromosome 14 syndrome. The literature search was performed in 2016. Original papers, meta-analyses, reviews, books and guidelines were reviewed and final recommendations were reached by consensus. Conclusion Conventional cytogenetics is the primary tool to identify a ring chromosome. Children with a terminal deletion of chromosome 14q ascertained by molecular karyotyping (CGH/SNP array) should be tested secondarily by conventional cytogenetics for the presence of a ring chromosome. Early diagnosis should be pursued in order to provide medical and social assistance by a multidisciplinary team. Clinical investigations, including neurophysiology for epilepsy, should be performed at the diagnosis and within the follow-up. Following the diagnosis, patients and relatives/caregivers should receive regular care for health and social issues. Epilepsy should be treated from the onset with anticonvulsive therapy. Likewise, feeding difficulties should be treated according to need. Nutritional assessment is recommended for all patients and nutritional support for malnourishment can include gastrostomy feeding in selected cases. Presence of autistic traits should be carefully evaluated. Many patients with ring chromosome 14 syndrome are nonverbal and thus maintaining their ability to communicate is always essential; every effort should be made to preserve their autonomy.

Neurofibromatosis type 2 (NF2) is a dominantly inherited syndrome caused by mutations of the tumour-suppressor NF2, which encodes the merlin protein. Mutations are associated with a predisposition to development of benign tumours in the central nervous system. Even though cerebral cortical lesions are frequently associated with seizures, epilepsy is rarely described in NF2. Here, we describe an adult case of NF2 in which the onset of symptoms was characterised by status epilepticus. In this patient, we identified the novel c.428_430delCTTdel mutation in NF2, involving the amino-terminal FERM domain, which is fundamental for the correct tumour suppressor function of the protein. Bioinformatic analyses revealed an important structural perturbation of the FERM domain, with a predicted impairment of the anti-tumour activity.

Based on data from the EURAP observational International registry of antiepileptic drugs (AEDs) and pregnancy, we assessed changes in seizure control and subsequent AED changes in women who underwent attempts to withdraw valproic acid (VPA) during the first trimester of pregnancy. Applying Bayesian statistics, we compared seizure control in pregnancies where VPA was withdrawn (withdrawal group, n = 93), switched to another AED (switch group, n = 38), or maintained (maintained-therapy group, n = 1,588) during the first trimester. The probability of primarily or secondarily generalized tonic-clonic seizures (GTCS) was lower in the maintained-therapy group compared with the other two groups, both in the first trimester and for the entire duration of pregnancy. GTCS were twice as common during pregnancy in the withdrawal (33%) and switch groups (29%) compared with the maintained-treatment group (16%). Limitations in the data and study design do not allow to establish a cause-effect relationship between treatment changes and seizure outcome, but these observations provide a signal that withdrawal of, or switch from, VPA during the first trimester could lead to loss of seizure control, and highlight the need for a specifically designed prospective observational study.

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3-year-old girl was admitted for the first time to our hospital because of status epilepticus. The girl was born to healthy, unrelated parents, who had an unremarkable family history, and her birth parameters were within the normal range. The girl had started to walk and had used single words at around 12 months. At 6 months, she had a right hemiclonic seizure 48 hours after being given pentavalent (pertussis, tetanus, diphtheria, inactivated polio, and haemophilus) vaccination. An electroencephalogram was normal. Between 7 and 10 months, she had nine prolonged (20–30 min) clonic or hemiclonic seizures, involving alternating sides, which occurred during febrile illness. An electroencephalogram at 13 months showed generalised spike waves, slowed background activity, and photosensitivity. Despite therapy with phenobarbital, the convulsive seizures reoccurred during fever, and she had atypical absences and myoclonus at rest from 20 months old. Delayed psychomotor development, which involved motor and linguistic activities, was also evident. At 2 years and 9 months, the girl had five prolonged febrile or afebrile convulsive seizures. Valproate was added to her regimen, and seizure control was almost complete, apart from weekly atypical absences. However, owing to a mild increase in serum amylase concentrations (112 U/L [normal range 15–110]), her general practitioner replaced valproate with lamotrigine. The girl had intense myoclonus in the arms, neck, and lower limbs 6 weeks after starting lamotrigine (150 mg/day). The dose was lowered to 100 mg/day, and the myoclonus was dramatically reduced; 4 weeks later, the dose was increased to 200 mg/day, and the myoclonic jerks reoccurred, culminating within 5 days in a myoclonic state. On admission to our department, the patient had intense, continuous, erratic myoclonus that affected different parts of the body. An electroencephalogram showed slowed background activity and multifocal spikes. The patient was hypothermic (35·0°C) and had signs of respiratory insufficiency. Blood and CSF analysis showed severe metabolic acidosis and high concentrations of serum transaminases (alanine transaminase 259 U/L, aspartate transaminase 214 U/L [normal range ≤40]) and creatine kinase (897 U/L [normal range 30–180]). Brain MRI was unremarkable. The myoclonic status did not respond to oral clonazepam and intravenous lorazepam, and the patient was transferred to the intensive care unit where, after intubation and ventilation, thiopental was given