Dimitrios Chatzistefanidis

Functional impact and prevalence of polymorphisms involved in the hepatic glucuronidation of valproic acid

Metabolism of valproic acid, a widely used drug, is only partially understood. It is mainly metabolized through glucuronidation and acts as a substrate for various UDP-glucuronosyltransferases (UGTs). UGTs metabolizing valproic acid in the liver are UGT1A3, UGT1A4, UGT1A6, UGT1A9 and UGT2B7, with UGT1A6 and UGT2B7 being the most prominent. Polymorphisms in genes expressing these enzymes may have clinical consequences, regarding dosing, blood levels of the drug and adverse reactions. Not all genes are well studied and studies, where they exist, report conflicting results. Prevalence of polymorphisms and various haplotypes is also of great importance, as it may suggest different therapeutic approaches in various populations. Presented here is a review of currently known polymorphisms, their functional impact, when known, and their prevalence in different populations, highlighting the current state of understanding and areas where there is a lack of data and suggesting new perspectives for further research.

First Case of Lacosamide-Induced Psychosis

Lacosamide (LCM) is a newer antiepileptic drug with a favorable safety profile used in partial epilepsy as adjunctive therapy. The most common side effects include dizziness, headache, confusion, diplopia, nausea, nasopharyngitis, and vomiting. Although sporadic cases of drug-induced psychosis have been reported for some antiepileptic drugs, this was not the case for LCM. We describe the first case of LCM-induced psychosis in a patient with drug-resistant partial epilepsy during the first week of treatment initiation, stressing the importance of clinicians remaining alert for abnormal behavioral symptoms.

Associations of ESR2 AluI (G/A) polymorphism with ischemic stroke in Caucasians

Raising interest towards genes implicates the effect of estrogen receptor-alpha (ESR1) gene on cerebrovascular disease, but data are lacking regarding the effect of estrogen receptor-beta (ESR2) gene. We assessed the hypothesis that AluI (G/A) polymorphism of the ESR2 gene (rs 4986938) is associated with ischemic stroke in a Caucasian population. Four hundred twenty four consecutive stroke patients and 430 age and gender-matched controls were enrolled in three stroke centers in Greece over one-year period. Patients and controls were compared in regard to the prevalence of the aforementioned polymorphism. No association was found between variations in the ESR2 gene and risk of stroke or stroke subtype in men and women. Of note, a gender-specific association of G allele with the onset of stroke at a younger age in male patients was found (63.68 ± 12.687 years in G allele (GG+AG) carriers vs. 68.95 ± 10.757 years in non-carriers (AA), p=0.008). Further population independent studies are needed to establish the role of ESR2 gene polymorphisms in relation to ischemic stroke in both genders. Such studies could lead to ERβ agonists being validated in individuals with certain genotypes and/or alleles towards the development of efficient strategies to preventing ischemic stroke in both men and women.

Brand-to-generic levetiracetam switch in patients with epilepsy in a routine clinical setting

PURPOSE The therapeutic equivalence of generic and brand antiepileptic drugs, based on studies performed on healthy volunteers, has been questioned. We compare, in a routine clinical setting, brand versus generic levetiracetam (LEV) bioequivalence in patients with epilepsy and also the clinical efficacy and tolerability of the substitution. METHODS A prospective, open-label, non-randomized, steady-state, multiple-dose, bioequivalence study was conducted in 12 patients with epilepsy (5 females), with a mean age of 38.4±16.2 years. Patients treated with the brand LEV (Keppra; UCB Pharma) were closely followed for a four-week period and subsequently switched to a generic LEV (Pharmaten) and followed for another four-week period. Blood samples were collected at the end of each 4-week period, during a dose interval for each formulation, for LEV concentration measurements by liquid chromatography mass spectrometry. Steady-state area under the curve (AUC) and peak plasma concentration (Cmax) data were subjected to conventional average bioequivalence analysis. Secondary clinical outcomes, including seizure frequency and adverse events, were recorded. RESULTS Patients had epilepsy for a mean period of 14.1±10.6years and the mean daily LEV dose was 2583.3±763.7mg. The mean AUC±SD and Cmax±SD was 288.4±86.3(mg/L)h and 37.8±10.4mg/L respectively for brand LEV and 319.2±104.7(mg/L)h and 41.6±12.3mg/L respectively for the generic LEV. Statistic analysis showed no statistical significant difference in bioequivalence. Also, no change in seizures frequency and/or adverse events was recorded. CONCLUSIONS In our clinical setting, generic LEV was determined to be bioequivalent to brand LEV. Furthermore, seizures frequency or/and adverse events were not affected upon switching from brand to generic LEV.

Apolipoprotein E polymorphisms and ischaemic stroke: a two-center Greek study.

Apolipropotein E(apoE) is a plasma protein exhibiting three common isoforms (E2, E3, E4). Its involvement in lipoprotein metabolism may have an impact on stroke occurrence. As results in the literature are inconclusive further studies are needed to elucidate its role. Our objective was to study the role of apoE isoforms and the interplay with environmental risk factors in patients with first ischaemic stroke occurrence in the Greek population.

Gender specific association of decreased bone mineral density in patients with epilepsy

OBJECTIVE To evaluate whether epilepsy or certain antiepileptic drugs render patients prone to develop low bone mineral density (BMD) and osteoporosis risk. METHODS Thirty-eight (27 males, 11 females) consecutive adult epileptic patients receiving antiepileptic drugs (AEDs) and 71 control individuals matched for race, gender, age and body mass index (BMI) were subjected to dual energy X-ray absorptiometry (DXA). RESULTS The mean lumbar spine and total hip BMD values were lower in the patients compared to control group (0.90±0.24 g/cm2 vs 1.04±0.14 g/cm2, p<0.001 and 0.92±0.14 g/cm2 vs 0.99±0.13 g/cm2, p=0.02, respectively). At the same skeletal sites, male patients had significantly reduced BMD compared to control males (0.90±0.21 g/cm2 vs 1.03±0.15 g/cm2, p=0.004 and 0.93±0.14 g/cm2 vs 1.02±0.13 g/cm2, p=0.009, respectively) while there was a trend but no significant differences in females. This BMD reduction was independent of AED type. CONCLUSION Adult epileptic, predominantly male patients have lower BMD and could be screened with densitometry for early diagnosis and prevention of osteoporosis.

A novel nonsense mutation of the EPM2A gene in northwest Greece causing myoclonic epilepsy.

Lafora disease (LD; OMIM 254780), one of the genetic progressive myoclonus epilepsies (PME), is a fatal autosomal recessive disorder. LD is characterized by periodic acid-Schiff positive (PAS+) staining intracellular inclusion bodies, which are pathognomic of the disease. Symptoms of LD are expressed in early adolescence and include generalized, mostly stimulus-sensitive, tonic–clonic and myoclonic seizures as well as absences. Progressive dementia, psychosis, cerebellar ataxia, dysarthria, amaurosis, mutism, muscle wasting and respiratory failure develop later and lead to death usually within a decade of the symptoms’ onset. The genetic basis of LD is attributed to two different genes. The EPM2A gene is located on chromosome 6q24 and encodes laforin, while the EPM2B gene located on chromosome 6p22 encodes for malin, an E3 ubiquitin ligase. The disease is treated symptomatically as there is no preventive treatment or cure.

An emerging problem in clinical practice: how to approach acute psychosis

Limbic encephalitis (LE) is rare, presents with memory impairment, seizures and behavioral disorder. We present a 44-year-old female with an agitation-depressive disorder associated with delusions and hallucinations, admitted to our hospital with the diagnosis of psychosis. A computed tomography (CT) scan of the brain and lumbar puncture on admission were normal. Because of clinical deterioration and addition of seizures in the clinical picture, further workup with serum and repeat cerebrospinal fluid studies, magnetic resonance imaging (MRI), and electroencephalogram disclosed a lesion in the left medial temporal lobe consistent with LE. The patient was treated symptomatically with antidepressive, antipsychotic and anticonvulsant drugs. Aggressive diagnostic tests for the presence of an occult cancer were negative. An 8-year follow up has not revealed a tumor to support a paraneoplasmatic origin of LE. This case, initially diagnosed and treated as psychosis, is a case of non-paraneoplasmatic, non-infective LE, probably caused by an autoimmune mechanism.