Reorganization of the Brain Extracellular Matrix in Hippocampal Sclerosis.

The extracellular matrix (ECM) is an important regulator of excitability and synaptic plasticity, especially in its highly condensed form, the perineuronal nets (PNN). In patients with drug-resistant mesial temporal lobe epilepsy (MTLE), hippocampal sclerosis type 1 (HS1) is the most common histopathological finding. This study aimed to evaluate the ECM profile of HS1 in surgically treated drug-resistant patients with MTLE in correlation to clinical findings. Hippocampal sections were immunohistochemically stained for aggrecan, neurocan, versican, chondroitin-sulfate (CS56), fibronectin, Wisteria floribunda agglutinin (WFA), a nuclear neuronal marker (NeuN), parvalbumin (PV), and glial-fibrillary-acidic-protein (GFAP). In HS1, besides the reduced number of neurons and astrogliosis, we found a significantly changed expression pattern of versican, neurocan, aggrecan, WFA-specific glycosylation, and a reduced number of PNNs. Patients with a lower number of epileptic episodes had a less intense diffuse WFA staining in Cornu Ammonis (CA) fields. Our findings suggest that PNN reduction, changed ECM protein, and glycosylation expression pattern in HS1 might be involved in the pathogenesis and persistence of drug-resistant MTLE by contributing to the increase of CA pyramidal neurons' excitability. This research corroborates the validity of ECM molecules and their modulators as a potential target for the development of new therapeutic approaches to drug-resistant epilepsy.

Predictors of Quality of Life in Patients with Drug Resistant Epilepsy after Neurosurgical Treatment: One-Year Follow-Up.

BACKGROUND: Invasive neurosurgical treatment or minimally invasive neurosurgical treatment are methods of choice for the treatment of patients with drug resistant epilepsy. The aim of this study was to evaluate the impact of neurosurgical treatment and the quality of life of patients with drug resistant epilepsy and to determine what are the potential predictors of quality of life of patients with drug resistant epilepsy one year after neurosurgical treatment. SUBJECTS AND METHODS: The research was performed at the Referral Centre for Epilepsy, Department of Neurology, University Hospital Centre Zagreb from February 2015 to February 2020 with Ethics commitee approval. The study included 96 patients with drug resistant epilepsy who were examined for the quality of life before and one year after neurosurgical treatment using the form questionnaire "Quality of life in epilepsy" (QOILE-31) validated Croatian 1.0 version and the questionnaire to assess the degree of depression "Beck Depression Inventory I" (BDI-I) validated Croatian version. RESULTS: Of 96 patients with drug resistant epilepsy one year after neurosurgical treatment 46 (47.9%) patients remained completely free from epileptis seizures. Wilcoxon equivalent pair test showed that the number of epileptic seizures one year after neurosurgical treatment was significantly lower (median before neurosurgical treatment is 10; and after neurosurgical treatment is 1, p<0.001). The most informative potential statistically significant predictor variables of quality of life based on the criterion variables QOLIE-31 and BDI-I are: total disease duration in years (p=0.034), patient age (p=0.042), number of antiepileptics one year after neurosurgical treatment (p=0.001), the number of epileptic seizures per month (p=0.016), and social welfare rights (p=0.045). CONCLUSION: Neurosurgical treatment of patients with drug resistant epilepsy significantly reduces the number of epileptic seizures which significantly improves their overall quality of life one year after neurosurgical treatment.

Sexual Dysfunction in Patients with Epilepsy.

BACKGROUND: Patients with epilepsy commonly report sexual dysfunction (SD) and reproductive difficulties. This study aimed to evaluate the relationship between epilepsy, antiepileptic drugs (AEDs) and SD, and its association with the quality of life and depressive symptoms. SUBJECTS AND METHODS: This was a prospective study carried out in a tertiary healthcare centre. SD was evaluated using the internationally acclaimed questionnaire Arizona Sexual Experiences Scale (ASEX) that was successfully translated into Croatian and validated for this purpose. Depressive symptoms and quality of life were evaluated using the Hamilton Rating Scale for Depression (HAM-D17) and Quality of life in epilepsy-31 inventory (QOLIE-31). RESULTS: Of 108 patients (68 (63 %) women, 40 (37 %) men, mean age 39.54±15.91 (range18-80) years) with epilepsy, 16 (14.8%) had focal, 38 (35.2%) generalized and 44 (40.7%) both types of epilepsy. Mean overall total score on the ASEX questionnaire was 11.94±5.61 (mean total score women 12.85±6.00, mean total score men 10.4±4.55), with 48 reporting that they had sexual activity in the past week. Nine (8.33%) patients (7 (6.48%) women, 2 (1.85%) men, mean age 47.66±19.33 (range 25-80) years) had a score 19 and above, 38 (35.18%) patients (27 (25%) women, 9 (8.33%) men, mean age 46.82±17.78 (range 19-80) years) individual score 5 and above on any one item, and 33 (30.55%) patients (26 (24.07%) women, 7 (6.48%) men, mean age 48.87±17.8 (range 19-80) years) had an individual score 4 and above on any three items. Significant correlations were found between SD and older age (p=0.001) and between more pronounced symptoms regarding SD on ASEX and female gender (p=0.000). There were no significant correlations between the type of epilepsy and SD, nor between the AEDs (old generation vs. modern) and SD. Significant correlations were found between the SD and more pronounced depressive symptoms (p=0.003) and between the SD and a lower quality of life (p=0.001). CONCLUSIONS: Results of our study suggest SD is experienced by around one-third of patients in our group, which is similar to the previous percentage of SD reported in the community sample. Women were found to experience more pronounced symptoms of SD on ASEX. Symptoms of SD were found to be significantly correlated with older age, female gender, lower quality of life and depressive symptoms, while no significant correlations were found with the type of epilepsy and the AEDs.

Depression and Quality of Life in Patients with Epilepsy - Single Centre Experience.

BACKGROUND: Patients with epilepsy commonly report depressive symptoms. The main aim of this study was to evaluate the relationship between epilepsy, antiepileptic drugs (AEDs) and depression. We also wanted to evaluate possible association between depressive symptofigms in patients with epilepsy with the quality of life (QoL). MATERIAL AND METHODS: This was a prospective cross-sectional study carried out at the tertiary teaching hospital (University Hospital Centre Zagreb, Croatia) with Ethics committee approval. Questionnaires evaluating depressive symptoms and QoL were administered to consecutive patients treated in the Referral Centre of the Ministry of Health of the Republic of Croatia for Epilepsy. Depressive symptoms were evaluated using Hamilton Rating Scale for Depression (HAM-D17). Quality of life was assessed using Quality of life in epilepsy-31 inventory (QOLIE-31). RESULTS: 108 patients (63% women, 37% men; mean age 39.54±15.91 years, range 18-80 years) with epilepsy were included. 14.8% of patients had focal, 35.2% generalised and 40.7% both types of epilepsy. Majority of patients (65.74%) were on two and more AEDs and quarter was on monotherapy (25%); 42% were on newer, 19% on older and 39% on both AEDs. Mean total score on HAM-D17 was 9.94±8.18 (men - mean total score 10.16±8.85, women - mean total score 9.81±7.84). There were no significant differences on HAM-D17 regarding gender and age. We didn't find statistically significant differences regarding AEDs (older vs. newer AEDs, or both types AEDs) and results on HAM-D17, nor between the type of epilepsy and results on HAM-D17. We found strong negative correlation between the higher QoL and HAM-D17 (p=0.000). CONCLUSIONS: Results of this study evaluating depressive symptoms in patients with epilepsy demonstrate that our patients mainly experience mild depressive symptoms, with no significant differences on HAM-D17 regarding gender and age. Patients with epilepsy with less pronounced depressive symptoms were found to have higher QoL. We did not find statistically significant differences regarding the type of epilepsy and results on HAM-D17, nor between the AEDs (older vs. newer AEDs, or both types AEDs) and results on HAM-D17.

QUALITY OF LIFE IN PATIENTS WITH EPILEPSY - SINGLE CENTRE EXPERIENCE.

A prospective study was carried out at the Zagreb University Hospital Centre to evaluate the relationship between epilepsy, antiepileptic drugs (AEDs) and quality of life (QoL) in patients with epilepsy (PE), and its association with depressive symptoms and sexual dysfunction (SD). QoL was assessed by use of the Quality of Life in Epilepsy-31 Inventory (QOLIE-31), SD by the Arizona Sexual Experiences Scale (ASEX), and depressive symptoms by the Hamilton Rating Scale for Depression (HAM-D17). The study included 108 PE (women 63% and men 37% men), mean age 39.54±15.91 years. Focal type epilepsy was diagnosed in 14.8%, generalized type in 35.2%, and both types were present in 40.7% of study patients. Drug-resistant epilepsy (DRE) was present in 44/108 and vagus nerve stimulation (VNS) was implanted in 27/44 patients. The mean response on QOLIE-31 was 62.88±17.21 with no significant differences according to gender, type of epilepsy, and age. A statistically significantly lower QoL was found in the 'Overall QoL' domain (35-55 vs. <35 age group). Patients taking both types of AEDs had a significantly lower QoL compared to those on newer types of AEDs. Higher QoL was associated with less pronounced depressive symptoms (p=0.000). Significant correlations were found between lower QoL and SD (p=0.001). In 27 patients with DRE having undergone VNS, a favorable effect of VNS implantation on the QoL and mood was observed as compared with 18 patients without VNS (p=0.041).

Impact of Invasive EEG Monitoring and Resective Neurosurgical Treatment on the Quality of Life in Patients with Drug Resistant Epilepsy - Preliminary Results.

BACKGROUND: Neurosurgical treatment is one of important way to cure drug resistant epilepsy. After invasive EEG monitoring and the invasive neurosurgical treatment (resective surgery) there are possible complications (intracranial haemorrhage, cortical lesions and infections), however there are possible neuropsyhologic outcomes such as memory outcomes, language outcomes and psychiatric outcomes. The quality of life in epilepsy (QOLIE-31) scale is a self-completed questionnaire which contains seven subscales which address the following aspects: emotional well-being, social functioning, energy/fatigue, cognitive functioning, seizure worry, medication effects and overall quality of life. Our study aimed to examine the quality of life in patients with drug resistant epilepsy who had undergone invasive EEG monitoring and resective neurosurgical treatment through the application of the QOLIE-31 scale. SUBJECTS AND METHODS: The study included 9 patients with drug resistant epilepsy who had undergone invasive EEG monitoring followed by resective neurosurgical treatment in the period from 2010 to 2016, and the control group of 15 patients with drug resistant epilepsy who had not undergone neurosurgical procedures. Clinical variables of interest for this study were obtained through phone contact, and the QOLIE-31 scale was applied. RESULTS: In the domaine of seizure worry, patients in the examined group were more concerned about the seizures (54.7) compared to the examined group (80), as well as in the overal quality of life (examined group 57.5; control group 77.5). Patients in the control group complained more in the domain of antiepileptic therapy (score 70.7) than patients in the examined group (score 100). In the other domains: emotional well-being, energy/fatigue, cognitive functioning, and social functioning there were minor deviations between the examined and control groups. CONCLUSION: There was no statistically significant difference between individual QOLIE-31 questionnaires, as well as between the two groups of respondents.

The effect of delayed anti-NMDAR encephalitis recognition on disease outcome.

Anti-NMDA receptor encephalitis is an acute form of brain inflammation that is potentially lethal but has a high probability for recovery with treatment. Although the clinical picture of anti-NMDAR encephalitis is usually recognizable due to its relatively well-known symptoms, the disorder can sometimes present itself in an unpredictable and atypical way. In this case report, we wish to present the influence of different delay times prior to the establishment of diagnosis. Thus, our first patient was diagnosed with anti-NMDAR encephalitis 4 years after the initial symptoms, the second one after 8 years, and the third one after 13 months. The outcomes of the three presented patients indicate the importance of being aware of many clinical presentations of this disorder, as its early diagnosis greatly affects the outcome and may reduce permanent damage, especially in cognitive functions.

Interaction between ABCG2 421C>A polymorphism and valproate in their effects on steady-state disposition of lamotrigine in adults with epilepsy.

AIMS: To investigate the impact of glucuronidation enzyme (UGT1A4*3 142T>G, UGT1A4*2 70C>A, UGT2B7 -161C>T) and transporter (MDR1/ABCB1 1236C>T, ABCG2 421C>A) polymorphisms on steady-state disposition of lamotrigine and on the lamotrigine-valproate interaction. METHODS: Adults with epilepsy on lamotrigine monotherapy (n = 131) or lamotrigine + valproate treatment (n = 74) were genotyped and steady-state lamotrigine and valproate morning troughs were determined as a part of routine therapeutic drug monitoring. RESULTS: No effect of UGT and MDR1/ABCB1 polymorphisms was observed. In the entire cohort, ABCG2 421A allele had no effect however an interaction between the variant allele and valproate was observed: (i) in lamotrigine-only patients, variant allele (vs. wild type homozygosity) was independently (adjustments: age, sex, body mass index, lamotrigine dose, other polymorphisms) associated with mildly lower lamotrigine troughs [geometric means ratio (GMR) = 0.76, 95% confidence interval (CI) 0.59-0.98], whereas in lamotrigine + valproate patients it was associated with higher troughs (GMR = 1.72, 95%CI 1.14-2.62); (ii) valproate cotreatment was overall associated with markedly higher troughs vs. lamotrigine monotherapy (GMR = 3.49, 95%CI 2.73-4.44), but more so in variant allele carriers (GMR = 5.24, 95%CI 3.38-8.15) than in wild type homozygotes (GMR = 2.32, 95%CI 1.89-2.83); (iii) variant allele effects in two treatment subsets and valproate effects in two genotype subsets differed by 2.36-fold (95%CI 1.39-3.67); (iv) increase in lamotrigine troughs associated with increasing valproate troughs was greater in variant allele carriers than in wild type homozygotes, i.e. variant allele effect increased with increasing valproate troughs. CONCLUSION: This study is first to indicate a potentially relevant interaction between ABCG2 421C>A polymorphism and valproate in their effects on lamotrigine disposition.

Effect of antiepileptic drug comedication on lamotrigine concentrations.

AIM: To estimate the effect size of concomitant antiepileptic therapy on the concentrations of lamotrigine, a drug often prescribed in combination with other antiepileptic drugs (AED), which can act as enzyme inducers or inhibitors. METHODS: A total of 304 patients with epilepsy, aged 18-70 years, were divided into a lamotrigine monotherapy group and groups receiving lamotrigine with AEDs that act as enzyme inducers, enzyme inhibitors, or both. We compared lamotrigine monotherapy serum concentrations with those where lamotrigine was administered with a metabolic inhibitor valproate, metabolic inducers carbamazepine, oxcarbazepine, phenobarbital, phenytoin, or topiramate, and both an inducer and an inhibitor. RESULTS: Comparison of trough lamotrigine monotherapy concentrations and lamotrigine polytherapy concentrations showed an almost similar median concentration in case of drug-inducers, and higher lamotrigine concentration in case of comedication with valproate as an inhibitor. A significant difference was confirmed after dose correction (P<0.001). Significant positive correlations of lamotrigine trough serum concentrations with valproate were observed before and after the dose correction (r=0.480, P<0.001 and r=0.561, P<0.001, respectively). Positive correlations between the dose-corrected lamotrigine trough concentration and carbamazepine (r=0.439; PP<0.001) or monohydroxy metabolite of oxcarbazepine (MHD) (r=0.675; PP<0.001) were also significant. CONCLUSION: Higher valproate levels resulted in higher inhibition potency and higher lamotrigine levels. Increased dose-corrected concentrations of inducers carbamazepine and MHD, after the process of induction was finished, did not lower lamotrigine concentrations. These findings can be of clinical significance for optimal AED dosing.

Many Faces of Déjà Vu: a Narrative Review.

French expression standing for the phrase "already seen" is a déjà vu. It is thought that as much as 97% of the population have experienced déjà vu at least once in their lifetime and 67% experience it regularly. The explanations of this phenomenon in novels and poems include reincarnation, dreams, organic factors, and unconscious memories. In this narrative review connection between déjà vu and various other conditions has been mentioned: false memories, temporal lobe epilepsy and other neurological conditions. In psychiatric patients déjà vu phenomenon is more often seen in patients with anxiety and people with derealisation/ depersonalization. It seems that temporal region is the origin of déjà vu phenomena in both healthy individuals and in individuals with neurological and psychiatric conditions, but the exact mechanism of this phenomenon is however still unknown. More attention should also be given to déjà vu from philosophical and religious perspectives as well. Déjà vu is still an enigma which could only be revealed with multidisciplinary approach through cooperation between neurologists, brain scientists, psychiatrists and experimental psychologists.

Genetics of Pediatric Epilepsy: Next-Generation Sequencing in Clinical Practice.

Epilepsy is one of the most common neurological disorders with diverse phenotypic characteristics and high genetic heterogeneity. Epilepsy often occurs in childhood, so timely diagnosis and adequate therapy are crucial for preserving quality of life and unhindered development of a child. Next-generation-sequencing (NGS)-based tools have shown potential in increasing diagnostic yield. The primary objective of this study was to evaluate the impact of genetic testing and to investigate the diagnostic utility of targeted gene panel sequencing. This retrospective cohort study included 277 patients aged 6 months to 17 years undergoing NGS with an epilepsy panel covering 142 genes. Of 118 variants detected, 38 (32.2%) were not described in the literature. We identified 64 pathogenic or likely pathogenic variants with an overall diagnostic yield of 23.1%. We showed a significantly higher diagnostic yield in patients with developmental delay (28.9%). Furthermore, we showed that patients with variants reported as pathogenic presented with seizures at a younger age, which led to the conclusion that such children should be included in genomic diagnostic procedures as soon as possible to achieve a correct diagnosis in a timely manner, potentially leading to better treatment and avoidance of unnecessary procedures. Describing and discovering the genetic background of the disease not only leads to a better understanding of the mechanisms of the disorder but also opens the possibility of more precise and individualized treatment based on stratified medicine.

Brain MRI post-processing with MAP07 in the preoperative evaluation of patients with pharmacoresistant epilepsy - Croatian single centre experience.

OBJECTIVE: This study aimed to determine the role of brain MRI post-processing method MAP07 (Morphometric Analysis Program) in detecting epileptogenic brain lesions in patients with pharmacoresistant epilepsy (PE). MAP07 is a sophisticated diagnostic program that offers several morphometric maps and facilitates the detection and localization of hippocampal sclerosis (HS), focal cortical dysplasias (FCD), and other types of cortical malformations, which could be undetected by conventional visual MRI analysis (CVA). METHODS: 120 patients aged > 16 years with PE have been recruited. 3 T MRI was performed according to epilepsy imaging protocol followed by image postprocessing with a fully automated MATLAB script, MAP07, by applying SPM5 algorithms. Statistical analysis was performed in IBM SPSS Statistics, version 25.0. RESULTS: Analysis in our patients showed a high sensitivity of MAP07 with low specificity and with a high proportion of false-positive patients. After MRI analysis, out of 120 patients, 32 were found to have no structural abnormalities by conventional visual analysis in whom after MAP07 in 5 patients structural lesions were found (in one HS, in one FCD, in two perinatal vascular lesions, and in one hippocampal hyperintensity). There was a quite high overall coincidence of the findings of MAP07 and MRI for the detection of FCD, HS, perinatal ischemia/chronic vascular lesions, heterotopias, and polymicrogyria (kappa coefficient above 0.700). CONCLUSIONS: MAP07 analysis is a useful, additional, and automated method that may guide re-evaluation of MRI by highlighting suspicious cortical regions, as a complementary method to CVA, by enhancing the visualization of cortical malformations and lesions.

Patient with neuromyelitis optica and inflammatory demyelinating lesions comprising whole spinal cord from C2 level till conus: case report.

BACKGROUND: Neuromyelitis optica (NMO) is an idiopathic, severe, inflammatory demyelinating disease of the central nervous system, that causes severe optic neuritis and myelitis attacks. Early discrimination between multiple sclerosis (MS) and NMO is important, as optimum treatment for both diseases may differ considerably. CASE PRESENTATION: We report a case of a patient who initially presented as longitudinally extensive transverse myelitis (LETM), having spastic upper extremities diparesis and spastic paraplegia, C2/C3 sensory level and urinary incontinence, as well as extensive inflammatory spinal cord lesions from C2 level to conus. After 5 months the patient had another attack of transverse myelitis, had electrophysiological findings consistent with optic neuritis, was seropositive for NMO-IgG (aquaporin-4 IgG) and thus fulfilled NMO diagnostic criteria. Following treatment of disease attacks with pulse corticosteroid therapy and intravenous immunoglobulins, we included oral azathioprine in a combination with oral prednisone in the therapy. Since there was no significant clinical improvement, we decided to use cyclophosphamide therapy, which resulted in good clinical improvement and gradual decrease of cord swelling. CONCLUSION: In this NMO case report we wanted to emphasize the extensiveness of inflammatory spinal cord changes in our patient, from C2 level to conus. In the conclusion it is important to say that accurate, early diagnosis and distinction from MS is critical to facilitate initiation of immunosuppressive therapy for attack prevention.