Novel GATOR1 variants in focal epilepsy.

INTRODUCTION: Variants in GATOR1 genes are well established in focal epilepsy syndromes. A strong association of GATOR1 variants with drug-resistant epilepsy as well as an increased risk of sudden unexplained death in epilepsy warrants developing strategies to facilitate the identification of patients who could potentially benefit from genetic testing and precision medicine. We aimed to determine the yield of GATOR1 gene sequencing in patients with focal epilepsy typically referred for genetic testing, establish novel GATOR1 variants and determine clinical, electroencephalographic, and radiological characteristics of variant carriers. PATIENTS AND METHODS: Ninety-six patients with clinical suspicion of genetic focal epilepsy with previous comprehensive diagnostic epilepsy evaluation in The Neurology Clinic, University Clinical Center of Serbia, were included in the study. Sequencing was performed using a custom gene panel encompassing DEPDC5, NPRL2, and NPRL3. Variants of interest (VOI) were classified according to criteria proposed by the American College of Medical Genetics and the Association for Molecular Pathology. RESULTS: Four previously unreported VOI in 4/96 (4.2%) patients were found in our cohort. Three likely pathogenic variants were determined in 3/96 (3.1%) patients, one frameshift variant in DEPDC5 in a patient with nonlesional frontal lobe epilepsy, one splicogenic DEPDC5 variant in a patient with nonlesional posterior quadrant epilepsy, and one frameshift variant in NPRL2 in a patient with temporal lobe epilepsy associated with hippocampal sclerosis. Only one VOI, a missense variant in NPRL3, found in 1/96 (1.1%) patients, was classified as a variant of unknown significance. CONCLUSION: GATOR1 gene sequencing was diagnostic in 3.1% of our cohort and revealed three novel likely pathogenic variants, including a previously unreported association of temporal lobe epilepsy with hippocampal sclerosis with an NPRL2 variant. Further research is essential for a better understanding of the clinical scope of GATOR1 gene-associated epilepsy.

Influence of COVID-19 pandemic on quality of life in patients with epilepsy - Follow-up study.

OBJECTIVE: To perform a follow-up study of the quality of life in patients with epilepsy in the era of the COVID-19 crisis. METHODS: Two months before the first case of the COVID-19 in Serbia, we obtained the Serbian Version of Quality of Life Inventory for Epilepsy 31 (SVQOLIE-31) and Neurological Disorders Depression Inventory for Epilepsy scores (SVNDDI-E) for another study. We retested the same patients one year after in COVID-19 pandemic. In addition to SVQOLIE-31, and SVNDDI-E we used a generic questionnaire compiled from items related to the COVID-19. RESULTS: We retested 97 out of 118 patients (82.2%) for the follow-up analysis. The average age was 36.1 ±â€¯12.2 (range: 18-69), and 49 were women (50.5%). The median duration of epilepsy was 13 years (range: 1.5-48). The structural etiology of epilepsy was noted in 41 (42.3%), unknown etiology in 41 (42.3%), and genetic etiology in 15 (15.4%) patients. Fewer patients (27.8%) experienced at least one seizure three months before follow-up testing when compared to patients who experienced at least one seizure three months in initial testing (36.0%) (p = 0.15). All patients reported full compliance with anti-seizure medication in the follow-up. The SVQOLIE-31 score during the COVID-19 pandemic visit (64.5 ±â€¯14.6) was significantly lower than the SVQOLIE-31 score before the pandemic (p < 0.001). The SVNDDI-E score during the COVID-19 pandemic (10.5 ±â€¯3.5) was significantly higher than the SVNDDI-E score before it (p < 0.001). Multiple linear regression analyses revealed fear of seizures, and fear of a reduction in household income, significantly associated with SVQOLIE-31 and SVNDDI-E overall score. These variables accounted for 66% and 27% of the variance of SVQOLIE-31 and SVNDDI-E overall score. SIGNIFICANCE: Lower quality of life, higher prevalence of depression, healthcare availability issues, and perceived fears during pandemic all suggest COVID-19 has negatively impacted lives of patients with epilepsy.

Validation of the Serbian version of the Liverpool Adverse Events Profile of antiseizure therapy in patients with epilepsy.

The Liverpool Adverse Event Profile (LAEP) is a useful instrument in assessing the consequences of adverse events in patients using antiseizure medication. The LAEP scale has been validated in several languages to date. The aim of our study was to validate the LAEP scale in the Serbian language (SVLAEP). Validation of the SVLAEP scale was conducted by translating the original English version into the Serbian language and backtranslated into the English language. The translation was accepted when the two versions of the text were compatible. The questionnaire is then given to a group of patients with epilepsy treated with a stable dose of antiseizure medication. For the assessment of the quality of life and depression, we used the Serbian version of the Quality of Life in Epilepsy Inventory-31 (SVQOLIE-31) and the Serbian version of the Neurological Disorders Depression Inventory for Epilepsy (SVNDDI-E). From a total of 166 patients, 118 patients were included, and the remaining 48 were excluded because of other comorbidities and using other psychotropic drugs. Internal consistency (Cronbach's α = 0.87) and test-retest reliability (intraclass correlation coefficient (ICC) = 0.80) were satisfactory. The SVLAEP and SVQOLIE-31 had a strong negative statistical correlation (rs = -0.73; p < 0.001). The SVLAEP and SVNDDI-E final scores had a positive moderate correlation (rs = 0.52; p < 0.001). A moderate negative statistical correlation was found between SVNDDI-E and SVQOLIE-31 (rs = -0.56; p < 0.001). Our study showed that the LAEP scale is a useful indicator for the frequency of the adverse events in antiepileptic drug (AED) usage, despite a minor overlap with the symptoms of depression.

Clusters of cognitive impairment among different phenotypes of myotonic dystrophy type 1 and type 2.

Neuropsychological examinations in myotonic dystrophy (DM) patients show a great variability of results from a condition of intellectual disability to the subtle cognitive impairments. It is unclear if different clusters of neuropsychological deficits appear in different phenotypes of DM, or if there are patients with no cognitive deficit at all. The aim of this study is to assess cognitive impairments among patients with different phenotypes of DM type 1 (DM1) and type 2 (DM2), and to potentially define cognitive clusters in these disorders. Study comprised 101 DM1 and 46 DM2 adult patients who were genetically confirmed. Patients underwent analysis of five cognitive domains (visuospatial, executive, attention, memory and language). Virtually all DM1 patients had cognitive defect with approximately 2-3 cognitive domains affected. On the other hand, one-third of DM2 patients had completely normal neuropsychological findings, and in other two-thirds approximately 1-2 domains were affected. Cluster analysis showed that in both diseases visuospatial and executive dysfunctions seemed to be the main cognitive defects, while memory and language impairments appeared in more severe phenotypes. Our results showed that a single form of DM1 or DM2 may consist of several cognitive clusters. Understanding of cognitive impairments in DM is very important to follow positive and side effects in ongoing and future clinical trials.

Metals and electrolytes in sclerotic hippocampi in patients with drug-resistant mesial temporal lobe epilepsy.

An altered metal and electrolyte profile has been implicated in the pathologic mechanisms of chronic epilepsy; however, no study has comprehensively measured hippocampal concentrations of these elements in patients with mesial temporal lobe epilepsy and hippocampal sclerosis (mTLE-HS). We therefore analyzed hippocampi of 24 patients with drug-resistant mTLE-HS (mean age 35.6 ± 9.4 years) who underwent anterior temporal lobe resection and amygdalohippocampectomy and 17 hippocampi obtained by autopsy from 13 controls (mean age 40.5 ± 12.9 years), using inductively coupled plasma optical emission spectrometry (ICP-OES). Epileptic hippocampi showed significantly lower concentrations (µg/g of tissue) of copper (HS: 2.34 ± 0.12; control [C]: 3.57 ± 0.33; p < 0.001), manganese (HS: 0.205 ± 0.030; C: 0.409 ± 0.064; p = 0.004), and potassium (HS: 2,001 ± 59; C: 2,322 ± 61; p < 0.001), and increased sodium levels (HS: 1,131 ± 22; C: 1,040 ± 25; p = 0.010). Zinc, iron, calcium, and magnesium levels did not differ in HS and controls. In summary, copper and manganese levels are deficient, whereas iron level is unchanged in hippocampi from patients with mTLE-HS. Our results provide a basis for understanding the potential involvement of different metals and electrolytes in the pathology of HS.

Familial occurrence of seizure disorders across MRI defined structural focal epilepsy etiology.

BACKGROUND: Previous studies have established familial occurrence of epilepsy and seizure disorders and early age of epilepsy onset as predictors of genetic epilepsy, but have not evaluated the rate of their occurrence in patients with different epilepsy etiology. Our study determines the distribution of familial occurrence and age of epilepsy onset across structural focal epilepsy (FE) etiology in a large FE cohort. METHODS: Records of 1354 consecutive patients evaluated for epilepsy and seizure disorders in The Neurology Clinic, University Clinical Center of Serbia from 2008 to 2019 were screened for FE. Structural etiology, lobar diagnosis, familial occurrence, and age at epilepsy onset were determined. Patients with a. nonlesional focal epilepsy (NLFE), b. hippocampal sclerosis (HS) and c. congenital or perinatal etiology (CPE) were classified as NAFE, while patients with an identified acquired focal epilepsy (AFE) constituted the control group. RESULTS: We identified 965 patients with FE, 329 (34.1 %) with NLFE, 213 (22.1 %) with HS, 174 (18.0 %) with CPE and 249 (25.8 %) with AFE. Familial occurrence was identified in 160 (16.6 %), 19.1 % of patients with NAFE and 9.2 % of AFE (p = 0.003). Patients with NAFE had a younger age of epilepsy onset (13 vs. 18 years, p < 0.001). The highest proportion of familial occurrence was found in patients with NLFE (23.7 %), while the youngest median age of epilepsy onset was identified in patients with HS (12 years) and CPE (11 years). CONCLUSION: Patients with NAFE frequently have familial occurrence of epilepsy and have an earlier age of epilepsy onset than patients with AFE.

Novel variants in established epilepsy genes in focal epilepsy.

INTRODUCTION: Next generation sequencing (NGS) has greatly expanded our understanding of genetic contributors in multiple epilepsy syndromes, including focal epilepsy. Describing the genetic architecture of common syndromes promises to facilitate the diagnostic process as well as aid in the identification of patients who stand to benefit from genetic testing, but most studies to date have been limited to examining children or adults with intellectual disability. Our aim was to determine the yield of targeted sequencing of 5 established epilepsy genes (DEPDC5, LGI1, SCN1A, GRIN2A, and PCHD19) in an extensively phenotyped cohort of focal epilepsy patients with normal intellectual function or mild intellectual disability, as well as describe novel variants and determine the characteristics of variant carriers. PATIENTS AND METHODS: Targeted panel sequencing was performed on 96 patients with a strong clinical suspicion of genetic focal epilepsy. Patients had previously gone through a comprehensive diagnostic epilepsy evaluation in The Neurology Clinic, University Clinical Center of Serbia. Variants of interest (VOI) were classified using the American College of Medical Genetics and the Association for Molecular Pathology criteria. RESULTS: Six VOI in eight (8/96, 8.3%) patients were found in our cohort. Four likely pathogenic VOI were determined in six (6/96, 6.2%) patients, two DEPDC5 variants in two patients, one SCN1A variant in two patients and one PCDH19 variant in two patients. One variant of unknown significance (VUS) was found in GRIN2A in one (1/96, 1.0%) patient. Only one VOI in GRIN2A was classified as likely benign. No VOI were detected in LGI1. CONCLUSION: Sequencing of only five known epilepsy genes yielded a diagnostic result in 6.2% of our cohort and revealed multiple novel variants. Further research is necessary for a better understanding of the genetic basis in common epilepsy syndromes in patients with normal intellectual function or mild intellectual disability.

Focal to bilateral motor seizures in temporal lobe epilepsy during video-EEG monitoring: effects on surgical outcome.

The aim of this study was to determine whether the occurrence of focal to bilateral motor seizures in the course of partial drug withdrawal during video-EEG monitoring (FTBMS-M) had a predictive value for seizure recurrence in surgically treated patients with mesial temporal lobe epilepsy (MTLE). We analyzed the outcomes of 59 patients who underwent temporal lobe resection at 12 month postoperative follow up. In total, 48 out of 59 patients were rendered seizure free (81.4%). We analyzed seizure recurrence after surgery with reference to: (i) occurrence of seizures after partial drug withdrawal during video-EEG monitoring (FTBMS-M); (ii) history of secondarily generalized seizures during antiepileptic drug treatment prior to presurgical evaluation (FTBMS-H) and (iii) other possible confounding factors (sex, age, epilepsy duration, side of surgery, presence of hippocampal sclerosis, and history of febrile seizures). We found no differences in the frequency of seizure recurrences between patients with FTBMS-M and patients without FTBMS-M (4/20 vs. 7/39; p = 0.848). Conversely, the frequency of seizure recurrence was significantly higher among the patients with FTBMS-H than among the patients without FTBMS-H (7/20 vs. 4/39; p = 0.021). The predictive value of FTBMS-H for postoperative seizure recurrence was confirmed in logistic regression analysis. We found a statistically significant influence of FTBMS-H on poor outcome after surgery, but not of FTBMS-M or other confounding variables, which suggests that withdrawal seizures do not affect postsurgical seizure control.

Focal-to-bilateral motor seizures in temporal lobe epilepsy during video-EEG monitoring: effects on surgical outcome.

The aim of this study was to determine whether the occurrence of focal-to-bilateral motor seizures in the course of partial drug withdrawal during video-EEG monitoring (FTBMS-M) had a predictive value for seizure recurrence in surgically treated patients with mesial temporal lobe epilepsy (MTLE). We analyzed the outcomes of 59 patients who underwent temporal lobe resection and had postoperative follow-up from 6 to 58 months. In total, 48 out of 59 patients were rendered seizure free (81.4%). We analyzed seizure recurrence after surgery with reference to: (i) occurrence of seizures after partial drug withdrawal during video-EEG monitoring (FTBMS-M); (ii) history of secondarily generalized seizures during antiepileptic drug treatment prior to presurgical evaluation (FTBMS-H) and (iii) other possible confounding factors (sex, age, epilepsy duration, side of surgery, presence of hippocampal sclerosis, and history of febrile seizures). We found no differences in the frequency of seizure recurrences between patients with FTBMS-M and patients without FTBMS-M (4/20 vs. 7/39; p = 0.848). Conversely, the frequency of seizure recurrence was significantly higher among the patients with FTBMS-H than among the patients without FTBMS-H (7/20 vs. 4/39; p = 0.021). The predictive value of FTBMS-H for postoperative seizure recurrence was confirmed in logistic regression analysis. We found a statistically significant influence of FTBMS-H on poor outcome after surgery, but not of FTBMS-M or other confounding variables, which suggests that withdrawal seizures do not affect post-surgical seizure control.

New-onset musicogenic epilepsy after temporal lobe epilepsy surgery.

Musicogenic epilepsy is a reflex epilepsy provoked by listening to or playing music. The epileptogenic network involves temporal regions, usually mesiotemporal structures. We present a 31-year-old female patient who experienced musicogenic seizures after a right temporal lobectomy with amygdalohippocampectomy that was performed in order to treat preexisting right mesio-temporal epilepsy.

Heart involvement in patients with myotonic dystrophy type 2.

Myotonic dystrophy type 2 (DM2) is a slowly progressive, autosomal-dominant disease. This is a multisystemic disorder that affects the heart, which is one of the main causes of morbidity and mortality in DM2. The aim of the study was to define cardiac impairments in patients with DM2 and its association with sociodemographic and clinical features of patients. This retrospective study comprised 62 adult patients with DM2 hospitalized at the Neurology Clinic, Clinical Center of Serbia from 2013 until 2018, who underwent electrocardiography (ECG) and echocardiography examinations. Hypertension was observed in 42% of DM2 patients. One-fifth of DM2 patients had bradycardia, while other conduction and rhythm impairments were rare. Only one patient had a pacemaker implanted because of the first degree AV block associated with incomplete left bundle branch block. Echocardiography showed diastolic dysfunction of the left ventricle in 44% of patients, while systolic dysfunction was found in only 4%. Cardiomyopathy was observed in 18% of patients, of whom three-fourth had dilated type. Cardiac conduction and rhythm defects are relatively rare in DM2, while diastolic dysfunction is common. This suggests that regular ECG and echocardiography screening is needed in DM2. Adequate therapy should be introduced in patients with DM2 on time to reduce the frequency of heart complications and to prevent premature death.

Cortical thickness, surface area and folding in patients with psychogenic nonepileptic seizures.

OBJECTIVE: To determine cortical thickness (CTh), cortical surface area (CSA), curvature and sulcal depth (SD) in patients with psychogenic nonepileptic seizures (PNES). METHODS: Freesurfer software was used to identify differences between active and control group in Cth, CSA, curvature, and SD. Neuropsychological tests intending to document possible frontal lobe deficit were applied. RESULTS: We included 37 patients with PNES (age 37.3±13.8; female/male 31/6; age of disease onset 26.1±10.6; age of disease duration 11.1±11.1), and 37 healthy controls (age 38.4; ±12.7; female/male 26/11). No difference in CSA and curvature was detected between groups. Patients with PNES had increased CTh in the left insula, left and right medial-orbitofrontal, and left lateral-orbitofrontal, and decreased CTh in the left and right precentral, right enthorinal, and right lateral-occipital region than healthy controls. SD was increased at the level of the left and right insula, right rostral anterior cingulate, right posterior cingulate, and left cuneus, and reduced at the level of the right and left medial-orbitofrontal sulci in patients with PNES compared to healthy controls. CONCLUSION: Individuals with PNES display a distinct profile of changes in CTh, in association with increase in SD in both insula as compared to controls. Our results may contribute to the understanding of the neurobiological background of PNES. Further research, to include replication of the findings and directed to understand the role of insula is needed.