Dissecting genetics of spectrum of epilepsies with eyelid myoclonia by exome sequencing.

OBJECTIVE: Epilepsy with eyelid myoclonia (EEM) spectrum is a generalized form of epilepsy characterized by eyelid myoclonia with or without absences, eye closure-induced seizures with electroencephalographic paroxysms, and photosensitivity. Based on the specific clinical features, age at onset, and familial occurrence, a genetic cause has been postulated. Pathogenic variants in CHD2, SYNGAP1, NEXMIF, RORB, and GABRA1 have been reported in individuals with photosensitivity and eyelid myoclonia, but whether other genes are also involved, or a single gene is uniquely linked with EEM, or its subtypes, is not yet known. We aimed to dissect the genetic etiology of EEM. METHODS: We studied a cohort of 105 individuals by using whole exome sequencing. Individuals were divided into two groups: EEM- (isolated EEM) and EEM+ (EEM accompanied by intellectual disability [ID] or any other neurodevelopmental/psychiatric disorder). RESULTS: We identified nine variants classified as pathogenic/likely pathogenic in the entire cohort (8.57%); among these, eight (five in CHD2, one in NEXMIF, one in SYNGAP1, and one in TRIM8) were found in the EEM+ subcohort (28.57%). Only one variant (IFIH1) was found in the EEM- subcohort (1.29%); however, because the phenotype of the proband did not fit with published data, additional evidence is needed before considering IFIH1 variants and EEM- an established association. Burden analysis did not identify any single burdened gene or gene set. SIGNIFICANCE: Our results suggest that for EEM, as for many other epilepsies, the identification of a genetic cause is more likely with comorbid ID and/or other neurodevelopmental disorders. Pathogenic variants were mostly found in CHD2, and the association of CHD2 with EEM+ can now be considered a reasonable gene-disease association. We provide further evidence to strengthen the association of EEM+ with NEXMIF and SYNGAP1. Possible new associations between EEM+ and TRIM8, and EEM- and IFIH1, are also reported. Although we provide robust evidence for gene variants associated with EEM+, the core genetic etiology of EEM- remains to be elucidated.

Perampanel Confirms to Be Effective and Well-Tolerated as an Add-On Treatment in Patients With Brain Tumor-Related Epilepsy (PERADET Study).

Background: Epilepsy is one of the most common symptoms of brain tumors. It is often drug resistant and generally worsen patients' quality of life (QoL). Brain tumors release glutamate among other mediators, contributing to seizures onset, and this is accompanied by an increased AMPA receptors' expression on neuronal cells' membrane. Perampanel (PER) is a relatively new antiseizure medication (ASM) that acts as a selective non-competitive AMPA receptors' antagonist. Given its mechanism of action, we aimed to evaluate through a prospective, observational study, the efficacy and safety of PER as an add-on treatment in patients with brain tumor-related epilepsy (BTRE). The study was called PERADET. Methods: Thirty-six adult patients (intention to treat population-ITT) affected by BTRE, with uncontrolled focal-onset seizures treated with 1-3 ASMs were recruited from four Italian epilepsy centers. Perampanel was added-on, titrated from 2 mg/day up to a maximum of 12 mg/day. Tumor history and therapy, type, and seizures frequency, previous ASMs were collected at 6 and 12 months. A battery of QoL tests were administered at baseline, 6 and 12 months. The primary endpoint was to assess the efficacy of PER by calculating the percent change in seizure frequency and the responder rate. The secondary endpoints were tolerability, retention rate at 12 months, and improvement in quality of life. Results: At the end of 12 months, 21 patients (per protocol population-PP) were available for evaluation. In this population the responder rate (percentage of patients who experienced a 50% or greater reduction in seizure frequency) was 90.4 with 33.3% of patients being seizure-free. In the ITT group the responder rate at the end of 12 months was 66.6 with 25% of patients being seizure free. PER was well tolerated (30.6% of patients experienced an adverse event, none was severe; three needed a treatment interruptions). Conclusions: Our study indicate that PER may be efficacious against BTRE as suggested by its mechanism of action and our current knowledge on mechanisms of brain tumor epileptogenicity. Trial Registration Number (TRN): (Prot. n° 0008872.25-06-2019); RS 919/17.

Targeted re-sequencing in malformations of cortical development: genotype-phenotype correlations.

PURPOSE: Malformations of cortical development (MCD) are a phenotypically and genetically heterogeneous group of disorders, for which the diagnostic rate of genetic testing in a clinical setting remains to be clarified. In this study we aimed to assess the diagnostic rate of germline and pathogenic variants using a custom panel in a heterogeneous group of subjects with MCD and explore genotype-phenotype correlations. METHODS: A total of 84 subjects with different MCD were enrolled. Genomic DNA was isolated from peripheral blood. Fifty-nine tartget genes were assessed using a custom next-generation sequencing (NGS) panel. RESULTS: Genetic causes were identified in one-fourth of our cohort (21.4 %). Overall, we identified 19 pathogenic or likely pathogenic single-nucleotide variants in 11 genes among 18 subjects, including PAFAH1B1 (LIS1) (n = 3), TUBA1A (n = 3), DYNC1H1 (n = 3), ACTG1 (n = 2), TUBB2B (n = 1), TUBB3 (n = 1), DCX (n = 1), FLNA (n = 1), LAMA2 (n = 1), POMGNT2 (n = 1) and VLDLR (n = 1). The diagnostic yield was higher in patients with lissencephaly/pachygyria (60 %) (p = 0.001), cobblestone malformation (50 %), and subcortical band heterotopia (SBH) (40 %). Furthermore, five out of six subjects with suspect tubulinopathies on imaging harboured pathogenic variants in tubulin genes. Overall, germline pathogenic variants were more likely to be identified if MCD were diffuse (p = 0.002) and associated with other central nervous system malformations (p = 0.029). Moderate to severe intellectual disability was also more commonly associated with pathogenic variants (p = 0.044). CONCLUSION: Customized gene panels may support the diagnostic work-up for some specific MCD, especially when these are diffuse, bilateral and associated with other brain malformations.

Epilepsy, cerebral calcifications, and gluten-related disorders: Are anti-transglutaminase 6 antibodies the missing link?

PURPOSE: Gluten-related disorders (GRDs) are a group of immune-mediated diseases often associated to neurologic manifestations. Epilepsies with cerebral calcifications, with or without coeliac disease (CD), are rare neurological disorders characterized by childhood-onset focal seizures, often refractory to antiepileptic drugs. Transglutaminase 6 antibodies (anti-TG6) have been considered a biomarker for gluten-related ataxia and neuropathy, but their prevalence in epilepsies with cerebral calcifications is unknown. The aim of this study is to evaluate anti-TG6 prevalence in patients with epilepsies and cerebral calcifications. METHOD: this was a cross-sectional study conducted at five Italian epilepsy centres. The following groups were included. Group 1: nine patients with CD, posterior cerebral calcifications and epilepsy (CEC); group 2: nine patients with epilepsy and posterior cerebral calcifications, without CD; group 3: twenty patients with focal epilepsy of unknown etiology; group 4: twenty-two healthy controls (HC). All subjects were tested for serological evidence of anti-TG6 IgA and IgG. Differences among groups were analysed using χ ² test. RESULTS: anti-TG6 were present in 1/9 subjects (11%) of group 1, 2/9 subjects (22%) of group 2, 0/20 subjects in group 3, 3/22 (13.6%) of HC. No significant difference was found among the 4 groups. CONCLUSIONS: Anti-TG6 do not seem to be associated to epilepsies with cerebral calcifications.

Is idiopathic intracranial hypertension without papilledema a risk factor for migraine progression?

The association of chronic migraine (CM) with an idiopathic intracranial hypertension without papilledema (IIHWOP), although much more prevalent than expected in clinical series of CM sufferers, is not included among the risk factors for migraine progression. We discuss the available evidence supporting the existence of a pathogenetic link between CM and idiopathic intracranial hypertensive disorders and suggest a causative role for IIHWOP in migraine progression.

Anoxia-induced NF-kappaB-dependent upregulation of NCX1 contributes to Ca2+ refilling into endoplasmic reticulum in cortical neurons.

BACKGROUND AND PURPOSE: The 3 gene products of the Na(+)/Ca(2+) exchanger (NCX), viz, NCX1, NCX2, and NCX3, may play a pivotal role in the pathophysiology of brain ischemia. The aim of this study was to investigate the transductional and posttranslational mechanisms involved in the expression of these isoforms during oxygen and glucose deprivation and their role in endoplasmic reticulum Ca(2+) refilling in cortical neurons. METHODS: NCX1, NCX2, and NCX3 transcript and protein expression was evaluated in primary cortical neurons by reverse transcriptase-polymerase chain reaction and Western blot. NCX currents (I(NCX)) and cytosolic Ca(2+) concentrations ([Ca(2+)](i)) were monitored by means of patch-clamp in whole-cell configuration and Fura-2AM single-cell video imaging, respectively. RESULTS: Exposure of cortical neurons to 3 hours of oxygen and glucose deprivation yielded dissimilar effects on the 3 isoforms. First, it induced an upregulation in NCX1 transcript and protein expression. This change was exerted at the transcriptional level because the inhibition of nuclear factor kappa B translocation by small interfering RNA against p65 and SN-50 prevented oxygen and glucose deprivation-induced NCX1 upregulation. Second, it elicited a downregulation of NCX3 protein expression. This change, unlike NCX1, was exerted at the posttranscriptional level because it was prevented by the proteasome inhibitor MG-132. Finally, we found that it significantly increased I(NCX) both in the forward and reverse modes of operation and promoted an increase in ER Ca(2+) accumulation. Interestingly, such accumulation was prevented by the silencing of NCX1 and the NCX inhibitor CB-DMB that triggered caspase-12 activation. CONCLUSIONS: These results suggest that nuclear factor kappa B-dependent NCX1 upregulation may play a fundamental role in Ca(2+) refilling in the endoplasmic reticulum, thus helping neurons to prevent endoplasmic reticulum stress during oxygen and glucose deprivation.

Polycystic ovary syndrome in women using valproate: a review.

Valproate (VPA) is a highly effective drug successfully employed in several neuropsychiatric diseases. In the last 15 years, an increased prevalence of polycystic ovary syndrome (PCOS) associated with VPA use has been reported in both women with epilepsy and women with bipolar disorders. However, data on this subject are contrasting and it is possible that different factors might play a role in the development of PCOS in these patients. The risk of developing PCOS during VPA treatment seems to be higher in women with epilepsy than in women with bipolar disorders, and this might be due to an underlying neuroendocrine dysfunction related to the seizure disorder. Gynecologists must be aware of the possibility that PCOS in these populations of patients might be related to VPA use, and a careful multi-specialist approach is required for evaluating the risks and benefits of this treatment in the presence of features of PCOS.

Cranial neuralgias: from physiopathology to pharmacological treatment.

Cranial neuralgias are paroxysmal painful disorders of the head characterised by some shared features such as unilaterality of symptoms, transience and recurrence of attacks, superficial and "shock-like" quality of pain and the presence of triggering factors. Although rare, these disorders must be promptly recognised as they harbour a relatively high risk for underlying compressive or inflammatory disease. Nevertheless, misdiagnosis is frequent. Trigeminal and glossopharyngeal neuralgias are sustained in most cases by a neurovascular conflict in the posterior fossa resulting in a hyperexcitability state of the trigeminal circuitry. If the aetiology of trigeminal neuralgia (TN) and other typical neuralgias must be brought back to the peripheral injury, their pathogenesis could involve central allodynic mechanisms, which, in patients with inter-critical pain, also engage the nociceptive neurons at the thalamic-cortical level. Currently available medical treatments for TN and other cranial neuralgias are reviewed.

Polycystic ovary syndrome and epilepsy: a review of the evidence.

Overrepresentation of polycystic ovary syndrome (PCOS) in women with epilepsy has been described since the early 1980s. While some authors attribute this association to an effect of the seizure disorder on the hypothalamic control of reproductive function, others have reported a relationship with the use of the antiepileptic drug valproic acid (VPA). In this article we review the literature on this complex issue, with a detailed analysis of the different reports which describe the reproductive endocrine assessment in women with epilepsy. In spite of the large number of patients assessed, a clear picture does not emerge, mostly because of the wide variability of methodology employed in the different study projects and of the small size of many patient samples especially when divided in subgroups. However, on the whole these studies suggest that women with epilepsy are at risk for developing reproductive endocrine disorders, even if there is not yet definite evidence that PCOS may be over-represented in these patients nor that VPA may be the cause of endocrine problems. It is likely that both the epileptic disorder and the antiepileptic treatment play different roles in the development of such disturbances. This hypothesis deserves further prospective study in large samples of patients; consistency in methodology, diagnostic criteria and presentation of results should always be encouraged in the researchers dealing with these projects. In the meantime, women with epilepsy should be carefully monitored with regard to menstrual function, bodyweight and hyperandrogenism, and evaluation of these parameters should become part of the routine evaluation in baseline and follow-up consultations.

Small hypothalamic hamartomas and gelastic seizures.

PURPOSE: To describe the clinical history of patients with gelastic seizures (GSs) related to small-size hypothalamic hamartomas (HHs), and to show some of these unusual seizures. MATERIAL AND METHODS: Patients with GSs and the MRI finding of HH < 1 cm diameter. Ictal EEG or video EEG are required. RESULTS: Three patients, among 6 with GSs and HH, had a small sessile HH. None of them had a history of precocious puberty, nor any relevant cognitive defects. All patients suffered from other seizure types, in addition to GSs. GSs were drug-resistant in all cases. CONCLUSION: since small, not easily recognizable HHs may be present in patients with GSs, a careful MRI study of the hypothalamic, infundibular and mammillary bodys areas is mandatory in these cases [published with videosequences].

Tiagabine in glial tumors.

RATIONALE AND PURPOSE: Preliminary reports have suggested a possible 'aetiology-specific' efficacy of tiagabine (TGB) in patients with drug-resistant partial epilepsy (DRPE) related to cerebral glial tumors (GTs). This efficacy should be related to selective blocking of GAT-1 transporter by TGB. We presented our open-label, add-on TGB experience in a group of patients with GTs, compared with other symptomatic DRPEs of different aetiology. MATERIAL AND METHODS: eleven patients with DRPE related to oligodendroglioma (six cases), astrocytoma (4) or multiform gliobastoma (1); 12 patients with DRPE related to a miscellanea of CNS lesions. TGB was added to previous AEDs, at dosage of 20-60 mg per die. Responders are defined by seizure frequency reduction >50% compared with baseline. RESULTS: Seven patients are responders with three seizure-free (SF) in GTs group, a rate of efficacy much higher than in matching group (63.6 vs. 16.6%). Adverse events have been observed only rarely, not leading to discontinuation, in GTs group. CONCLUSION: This preliminary observation seems to confirm the high efficacy and tolerability of TGB in DRPE related to GTs.