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.
Klasifikacija epilepsije Petelin - Gadže, Željka
Medicus (Zagreb, Croatia : 1992),
02/2019, Letnik:
28, Številka:
1 Neurologija
Journal Article
Recenzirano
Odprti dostop
Epilepsija je jedna od najčešćih neuroloških bolesti, odnosno moždani poremećaj karakteriziran trajnom predispozicijom za nastanak epileptičnih napadaja te s neurobiološkim, kognitivnim, psihološkim ...i socijalnim posljedicama tog stanja. Posljednjih godina prati se znatno širenje našeg razumijevanja etiologije i patofiziologije ove bolesti, zahvaljujući napretku ponajprije neuroslikovnih dijagnostičkih metoda i molekularno-genskog testiranja. Određivanje kliničke semiologije epileptičnih napadaja te klasifikacije epilepsije, odnosno epileptičnog sindroma, vrlo je važno pri postavljanju ispravne dijagnoze te odabiru prikladnoga terapijskog algoritma. U klasifikaciji epileptičnih napadaja donedavno se upotrebljavala pojednostavnjena verzija klasifikacije Međunarodne lige protiv epilepsije (engl. International League Against Epilepsy – ILAE) iz 1981. i 1989. godine, koja znači klasifikaciju elektrokliničkih značajka. Godine 2010. ILAE predlaže reviziju klasifikacije u skladu s novim shvaćanjem epilepsije kao poremećaja mozgovne mreže uz prijedlog promjene terminologije, slijedom koje je 2017. godine objavljena nova operativna (praktična) klasifikacija epileptičnih napadaja. Potonja klasifikacija ne donosi fundamentalne promjene, ali dopušta veću fleksibilnost i transparentnost u imenovanju tipova epileptičnih napadaja. U ovom se radu, kao nastavak na novu terminologiju i podjelu epilepsije prema preporukama ILAE-a, predlaže terminologija klasifikacije epilepsije na hrvatskom jeziku.
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.
Purpose
To estimate whether epilepsy patients with variant
UGT2B7 -161C
>
T
(rs7668258) or
UGT1A4*3 c.142 T
>
G
(rs2011425) alleles differ from their wild-type (wt) peers in exposure to ...lamotrigine.
Methods
Consecutive adults on lamotrigine monotherapy or lamotrigine + valproate co-treatment undergoing routine therapeutic drug monitoring, otherwise generally healthy and free of interacting drugs, were genotyped for
UGT2B7 -161C
>
T
and
UGT1A4*3 c.142 T
>
G.
Heterozygous, variant homozygous, or combined heterozygous/variant homozygous subjects were compared to their wt controls for dose-adjusted lamotrigine troughs with adjustment for age, sex, body weight, rs7668258/rs2011425, polymorphisms of efflux transporter proteins
ABCG2 c.421C
>
A
(rs2231142) and
ABCB1 1236C
>
T
(rs1128503), and level of exposure to valproate using covariate entropy balancing.
Results
Of the 471 included patients, 328 (69.6%) were on monotherapy and 143 were co-treated with valproate. Dose-adjusted lamotrigine troughs in
UGT2B7 -161C
>
T
heterozygous (CT,
n
= 237) or variant homozygous (TT,
n
= 115) subjects were closely similar to those in their wt controls (CC,
n
= 119): geometric means ratios (GMRs) (frequentist and Bayes) 1.00 (95%CI 0.86–1.16) and 1.00 (95%CrI 0.83–1.22) for CT vs. CC; and 0.97 (0.81–1.17) and 0.97 (0.80–1.20) for TT vs. CC subjects. Lamotrigine troughs were also closely similar in
UGT1A4*3 c.142 T
>
G
variant carriers (
n
= 106: 102 TG + 4 GG subjects) and wt controls (TT,
n
= 365): GMR = 0.95 (0.81–1.12) frequentist, 0.96 (0.80–1.16) Bayes. GMRs for variant carriers vs. wt controls were around unity also at different levels of exposure to valproate.
Conclusion
Dose-adjusted lamotrigine troughs in epilepsy patients with variant
UGT2B7 -161C
>
T
or
UGT1A4*3 c.142 T
>
G
alleles are equivalent to those in their respective wt peers.
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.
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.
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.
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 Bošnjak Pašić, Marija; Horvat Velić, Emina; Fotak, Luka ...
Psychiatria Danubina,
03/2018, Letnik:
30, Številka:
1
Journal Article
Odprti dostop
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.
BACKGROUNDPatients 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 METHODSThis 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). RESULTSOf 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). CONCLUSIONSResults 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.
Epilepsy is a neurological condition that accompanies mankind probably since its inception. About 400 years before Christ, the disease was already known by Hippocrates, who wrote the book "On The ...Sacred Disease". Classically, epilepsy has been defined as a chronic condition characterized by an enduring propensity to generate seizures, which are paroxysmal occurring episodes of abnormal excessive or synchronous neuronal activity in the brain. Out of all brain disorders, epilepsy is the one that offers a unique opportunity to understand normal brain functions as derived from excessive dysfunction of neuronal circuits, because the symptoms of epileptic seizures are not the result of usual loss of function that accompanies many disease that affect the brain. I am therefore extremely honoured to present this book. The 15 very interesting chapters of the book cover various fields in epileptology - they encompass the etiology and pathogenesis of the disease, clinical presentation with special attention to the epileptic syndromes of childhood, principles of medical management, surgical approaches, as well as social aspects of the disease.
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.
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.
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).
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.
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