Factors influencing topiramate clearance in adult patients with epilepsy: A population pharmacokinetic analysis

Bae, E.K.,Lee, J.,Shin, J.W.,Moon, J.,Lee, K.J.,Shin, Y.W.,Kim, T.J.,Shin, D.,Jang, I.J.,Lee, S.K. Baillière Tindall ; W.B. Saunders 2016 Seizure Vol.37 No.-

<P>Purpose: To identify the factors influencing topiramate pharmacokinetics (PK) in a large population of adult patients with epilepsy using population PK analysis. Methods: Clinical data and blood samples were collected from 550 adult patients with epilepsy treated using topiramate. Nonlinear mixed effects modeling software (NONMEM, version 7.2) was used to fit the plasma concentration to a one-compartment PK model. Demographic and clinical variables tested as potential covariates were age, sex, body weight, height, serum creatinine, creatinine clearance (CLcr), total bilirubin, prothrombin time, albumin, aspartate transaminase (AST), alanine transaminase (ALT), daily dose (DOSE), and concomitant medications (phenytoin [PHT], clobazam, carbamazepine [CBZ], valproic acid, lamotrigine, levetiracetam, oxcarbazepine [OXC], pregabalin, clonazepam, and phenobarbital [PB]). Results: The final PK model was CL/F (L/h) = (1.16 + 1.36 x PHT + 1.01 x CBZ + 0.643 x OXC + 0.476 x PB) x (CLcr/90)(0.310) x (DOSE/100)(0.0929) (1 in patients co-medicated with each drug, 0 in otherwise) and V/F (L) = 109 x (WT/62). For a typical patient with CLcr of 90 mi./min and DOSE of 100 mg, co-medication with PHT, CBZ, OXC, and PB increased the CL/F to 2.52 (1.16 + 1.36) L/h, 2.17 (1.16 + 1.01) L/h, 1.803 (1.16 + 0.643) L/h, and 1.636 (1.16 + 0.476) L/h, respectively, which was 117, 87, 55, and 41% higher, respectively, than in patients without co-medication. Conclusion: The apparent clearance of topiramate increased with co-medication of PHT, CBZ, OXC, and PB. This population PK model can be applied for optimizing topiramate dosage regimens in actual clinical practice. (C) 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.</P>

Extrafrontal structural changes in juvenile myoclonic epilepsy: A topographic analysis of combined structural and microstructural brain imaging

Kim, S.H.,Lim, S.C.,Kim, W.,Kwon, O.h.,Jeon, S.,Lee, J.M.,Shon, Y.M. Baillière Tindall ; W.B. Saunders 2015 SEIZURE Vol.30 No.-

Purpose: An increasing amount of evidence has demonstrated that juvenile myoclonic epilepsy (JME) is associated with structural abnormalities in not only the thalamofrontal system but its adjacent regions such as temporal or parieto-occipital areas. The goal of this study was to systematically characterize morphological changes and the subsequent pathophysiological implications in JME patients using the combined structural and diffusion tensor MRI analysis. Methods: Comparisons of white matter (WM) water diffusivity and gray matter (GM) cortical thickness were analyzed with tract-based spatial statistics (TBSS) and a Constrained Laplacian-based Anatomic Segmentation with Proximity (CLASP) algorithm, respectively. Additionally, volumes of the bilateral thalami and hippocampi were obtained using manual volumetry (MV). Results: Compared with 22 normal controls, 18 patients with JME exhibited WM alterations in the antero-superior corona radiata, corpus callosum, both centro-parietal regions, and the left temporal lobe. JME patients also had reduced GM thickness (right paracentral lobule, precuneus, dorsolateral parietal and inferior temporal cortex; left dorsolateral frontal and anterior temporal areas). Furthermore, MV analyses revealed a significant volume reduction in the bilateral thalami and hippocampi. Conclusions: In addition to structural changes in the thalamofrontal system, there was a conspicuous alteration of WM diffusivity in widespread extra-frontal areas and an associated decreased GM thickness in temporoparietal regions, including a significant reduction of hippocampal volume. These findings suggest that the pathophysiology of JME may be not confined to the thalamofrontal circuit but may also involve extensive areas of the extra-frontal network which encompasses temporo-parietal regions.

Cognitive dysfunction with complex visual hallucinations due to focal nonconvulsive status epilepticus: A neuropsychological study and SISCOM

Kim, T.E.,Kim, H.J.,Park, J.H.,Lee, T.K.,Lee, J.D.,Park, S.A. Baillière Tindall ; W.B. Saunders 2012 SEIZURE Vol.21 No.8

A 74-year-old woman with left hemiparesis due to a previous stroke presented with the sudden development of cognitive impairment and episodic complex visual hallucinations as manifestations of nonconvulsive status epilepticus (NCSE). Neuropsychological tests performed during NCSE demonstrated deficits encompassing several cognitive domains. The short-lasting complex visual hallucinations were stereotypical, vivid, and accompanied by intense fear. The seizure activity in the right temporo-parieto-occipital region, as documented by SISCOM and electroencephalogram (EEG) recording, was thought to be due to an unusual clinical presentation of NCSE. Subcortical cerebromalacia likely blocked the propagation route, restricting the ictal activities within this area.

Blockade of endothelin B receptor improves the efficacy of levetiracetam in chronic epileptic rats

Ko, A.R.,Kang, T.C. Baillière Tindall ; W.B. Saunders 2015 SEIZURE Vol.31 No.-

Purpose: To elucidate the mechanisms that regulate p-glycoprotein (PGP) expression and function in pharmacoresistant epilepsy, we investigated the effect of an ET<SUB>B</SUB> receptor antagonist (BQ788) and a p38 mitogen-activated protein kinase (p38MAPK) inhibitor (SB202190) on intractable seizures in chronic epileptic rats. Methods: Lithium-pilocarpine-induced chronic epileptic rats were used in the present study. Animals were given levetiracetam (LEV), LEV+SB202190, LEV+BQ788, SB202190 or BQ788 over a 3-day period using an osmotic pump. Seizure activity was recorded by video-EEG monitoring with 2h of recording per day at the same time of day. We also performed western blot after EEG analysis. Results: Compared to control animals, PGP, ET<SUB>B</SUB> receptor and p38MAPK expression was increased in the hippocampus of epileptic animals. Neither SB202190 nor BQ788 affected the spontaneous seizure activity in epileptic rats. Three of ten rats were responders and achieved complete seizure control or significant reduction in seizure activity by LEV. In four of ten rats, seizure frequency was unaltered by LEV (non-responders). LEV+SB202190 reduced seizure duration, but not seizure frequency, in both responders and non-responders. LEV+BQ788 alleviated seizure frequency and seizure duration in both responders and non-responders. Compared to responders, PGP and ET<SUB>B</SUB> receptor expression was enhanced in the hippocampus of non-responders. Conclusion: To the best of our knowledge, these findings are the first indications of the role of ET<SUB>B</SUB> receptor in pharmacoresistant epilepsy. Therefore, the present data suggest that the regulation of the ET<SUB>B</SUB> receptor-mediated signaling pathway may be important for identification of new therapeutic strategies for improving antiepileptic drug efficacy.

A newly discovered LGI1 mutation in Korean family with autosomal dominant lateral temporal lobe epilepsy

Lee, M.K.,Kim, S.W.,Lee, J.H.,Cho, Y.J.,Kim, D.E.,Lee, B.I.,Kim, H.M.,Lee, M.G.,Heo, K. Baillière Tindall ; W.B. Saunders 2014 SEIZURE Vol.23 No.1

Purpose: A new leucine-rich glioma-inactivated 1 gene (LGI1) mutation inducing an amino acid sequence substitution was found in a Korean family with autosomal dominant lateral temporal lobe epilepsy (ADLTE). We report the clinical features and characteristics of this newly identified LGI1 mutation. Methods: Clinical data were collected from a large ADLTE family. All exons and flanking regions of the LGI1 gene were directly sequenced. 243 healthy controls were screened for the putative mutation. The 'Sorting Tolerant From Intolerant' algorithm was employed for the prediction of mutated LGI1 protein stability. LGI1 protein secretion was confirmed in vitro by immunoblotting assay. Results: The main clinical characteristics included a young age at onset (mean, 12.4 years), diverse phenotypic manifestations, the occurrence of generalized tonic-clonic seizures, and a favorable prognosis. The genetic analysis detected a nonsynonymous single nucleotide polymorphism of c.137G>T coding for p.C46F in the five affected family members. This variant was not found in the normal control population and one unaffected family member. All the amino acids substituted for cysteine at position 46 of the LGI1 protein were predicted to damage protein stability in in silico analysis. Mutated C46F protein was retained within the cell at the immunoblotting assay. Conclusion: We identified a new LGI1 mutation in a large Korean ADLTE family which appeared to be involved in the development of epilepsy through suppressing LGI1 protein secretion.

Comparison of MRI features and surgical outcome among the subtypes of focal cortical dysplasia

Kim, D.W.,Kim, S.,Park, S.H.,Chung, C.K.,Lee, S.K. Baillière Tindall ; W.B. Saunders 2012 SEIZURE Vol.21 No.10

Purpose: Focal cortical dysplasia (FCD) is the most common pathological diagnosis in patients who have undergone surgical treatment for intractable neocortical epilepsy. However, presurgical identification of MRI abnormalities in FCD patients remains difficult, and there are no highly sensitive imaging parameters available that can reliably differentiate among FCD subtypes. The purpose of our study was to investigate the surgical outcome in FCD patients with identifiable MRI abnormalities and to evaluate the prognostic role of the various MRI features and the characteristics of FCD pathology. Methods: We retrospectively recruited epilepsy patients who had undergone surgical treatment for refractory epilepsy with focal MRI abnormalities and the pathological diagnosis of FCD. We evaluated the surgical outcome according to the pathological subtypes, and studied the prognostic roles of various MRI features. We used recently proposed three-tiered FCD classification system which included FCD type III when FCD occurs in association with other potentially epileptogenic pathologies. Results: A total of 69 patients were included, and 68.1% of patients became seizure free. Patients with FCD type III had a lower chance for achieving seizure freedom (7/15) than in patients with isolated FCD (FCD types I and II) (40/54, p=0.044). Cortical thickness and blurring of gray-white matter junction were more common in isolated FCD than in FCD type III, but most MRI features failed to differentiate between FCD types I and II, and only the transmantle sign was specific for FCD type II. We failed to find a prognostic value of specific MRI abnormalities of prognostic value in terms of post-epilepsy surgery outcome in FCD patients. Conclusions: Our study showed that patients with FCD III have poor surgical outcome. Typical MRI features of isolated FCD such as cortical thickness and blurring of gray-white matter junction were less common in FCD type III and only transmantle sign was helpful in differentiating between FCD types I and II.