Lack of Association between Polymorphism in ABCC2 Gene and Response to Antiepileptic Drug Treatment in Croatian Patients with Epilepsy

Despite advances in antiepileptic drug (AED) therapy, about one-third of patients with epilepsy are resistant to drug treatment. Functional impact of polymorphisms in drug-efflux transporter genes may contribute to multidrug resistance theory. Studies on ABCB1 gene gave contradictory results and available data suggest that this polymorphism may not directly cause altered P-glycoprotein (Pgp) transport activity but may be associated with one or more causal variants in the stretch of linkage disequilibrium or is caused by multiple gene polymorphisms. Genetic polymorphisms also occur frequently in other transmembrane transport systems including the multidrug resistance proteins (MRPs, ABCC2). The aim of this research was to investigate the possible association of ABCC2 gene polymorphisms G1249A in exon 10 and C24T in exon 1 with the development of drug resistance. This cross-sectional study is a part of ongoing pharmacogenomic study of epilepsy in Croatian population. All patients enrolled in the study had an established diagnosis of partial complex epilepsy with or without secondary generalization with non lesional brain MRI with epilepsy protocol and have been suffering for more than two years. They were divided into two groups. The first group comprised 52 patients refractory to the current therapy, while the second group consisted of 45 patients with well-controlled seizures. Our data did not identify any significant association between genetic polymorphisms of exon 1 (24C>T) and exon 10 (1249G<A) of ABCC2 gene or any combined effect in response to AED treatment and development of drug resistance in patients with partial complex epilepsy. Statistical significant difference was not found in genotype based analysis, allele frequency, haplotype and combined genotype analysis

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

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

Abstract 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.</p

The influence of C3435T polymorphism of ABCB1 gene on penetration of phenobarbital across the blood-brain barrier in patients with generalized epilepsy

BACKGROUND: Epilepsy is refractory to medical treatment in about one-third of the patients. The exact pathological mechanism of epilepsy pharmacoresistance is still unclear, but a decreased antiepileptic drug (AED) uptake into the brain is suspected to play a role. P-glycoprotein (Pgp), a transmembrane transporter encoded by ABCB1 gene and located at the endothelial cells of the blood-brain barrier (BBB), has been associated with epilepsy pharmacoresistance. ----- OBJECTIVE: To analyze the effect of two ABCB1 gene polymorphisms, C3435T and G2677T/A, on phenobarbital (PB) concentrations in the cerebrospinal fluid (CSF) and serum (S) and to assess the relationship of ABCB1 polymorphisms to phenobarbital penetration across BBB in vivo and seizure frequency. ----- METHODS: CSF PB and S PB concentrations were measured in 60 patients with idiopathic primary generalized epilepsy receiving phenobarbital monotherapy. CSF/S PB concentration ratio was calculated as an index of phenobarbital penetration across BBB. The patients were genotyped for the ABCB1 gene C3435T and G2677T/A polymorphisms. Seizure frequency was recorded during the 6-month phenobarbital monotherapy. ----- RESULTS: Patients with different C3435T polymorphism had significantly different CSF PB concentrations and CSF/S PB concentration ratio. In comparison with CT heterozygotes and TT homozygotes, CC homozygotes had a significantly lower CSF PB concentration (p=0.006) and CSF/PB concentration ratio (p<0.001). G2677T/A polymorphism showed no such effect (p=0.466). CC genotype and low CSF/S PB concentration ratio correlated with increased seizure frequency. ----- CONCLUSIONS: C3435T polymorphism of ABCB1 gene was demonstrated in vivo to significantly influence the CSF/S PB concentration ratio and seizure frequency

The provision of epilepsy care across Europe 2017:a 17-year follow-up survey

\u3cp\u3eObjective: To assess the resources available in the provision of epilepsy care across Europe and the developments since the International League Against Epilepsy (ILAE) survey published in 2003 (data collected in 2000). Methods: An updated online version of the European Epilepsy Services Inventory was distributed to all European chapters of the ILAE (N = 47) and responses were obtained from 33 chapters (response rate 70%). To assess trends and allow comparisons with the survey published in 2003, the responding countries were divided into 4 groups (Western, Central, Southern, and Eastern). Responses from European Union (EU) member states are reported as a subgroup (N = 23), since the current survey is a part of the EU-funded European Study on the Burden and Care of Epilepsy (ESBACE, www.esbace.eu). Results: The total number of physicians involved in epilepsy care had increased since 2000, with the largest increase seen for neurologists. The gap between the best- and the least-provided areas with regard to the competence of the providers had diminished. However, the density of comprehensive multidisciplinary epilepsy teams had not changed to any greater degree. The main problems reported by the chapters were to a large extent the same as in 2000 and included lack of specialists and specialist care, lack or underuse of epilepsy surgery, and problems regarding financing and resource allocation. Several chapters also highlighted problems with healthcare structure and organization. Significance: Although there have been some improvements concerning the availability of care for people with epilepsy in Europe over the last 17 years, there are still a number of problem areas with little improvement or where there are important regional differences.\u3c/p\u3