Epilepsy Research

Editorial Board

2012-02-01

A meta-analysis of voxel-based morphometry studies on unilateral refractory temporal lobe epilepsy

JianPeng Li, ZhuoBo Zhang, HuiFang Shang — 2011-10-24

Summary: Purpose: To identify consistent results of voxel-based morphometry (VBM) studies in unilateral refractory temporal lobe epilepsy (TLE).Methods: Whole-brain VBM studies comparing refractory TLE patients with healthy controls (HC) were systematically searched in PubMed, ISI Web of Science, Embase, and Medline databases from January 1990 to May 2011. Coordinates were extracted from clusters with significant difference in gray matter volume (GMV) between refractory TLE patients and HC. Meta-analysis was performed using activation likelihood estimation (ALE).Key findings: A total of 6 studies, comprising 180 refractory left TLE (LTLE) patients, 142 refractory right TLE (RTLE) patients, and 283 HC, were enrolled. The included studies reported GMV reduction at 93 coordinates in refractory LTLE, and 46 coordinates in refractory RTLE, as well as GMV increase at 9 coordinates in refractory LTLE, and 8 coordinates in refractory RTLE. Given the small number of studies and coordinates that reported GMV increase, only a subgroup analysis of GMV reduction between refractory LTLE or RTLE and the HC was performed respectively. There were significant reductions in ipsilateral mesiotemporal structures and the bilateral thalamus in both refractory LTLE and refractory RTLE. Abnormalities of bilateral frontal lobe and right cingulate gyrus were also found in the refractory LTLE patients, whereas right insular atrophy was found in the refractory RTLE group.Significance: The findings suggested that unilateral refractory TLE patients had widespread GMV reduction and asymmetrical areas beyond the mesial temporal structures.

Systems biology impact on antiepileptic drug discovery

Doru Georg Margineanu — 2011-11-04

Summary: Systems biology (SB), a recent trend in bioscience research to consider the complex interactions in biological systems from a holistic perspective, sees the disease as a disturbed network of interactions, rather than alteration of single molecular component(s). SB-relying network pharmacology replaces the prevailing focus on specific drug–receptor interaction and the corollary of rational drug design of “magic bullets”, by the search for multi-target drugs that would act on biological networks as “magic shotguns”. Epilepsy being a multi-factorial, polygenic and dynamic pathology, SB approach appears particularly fit and promising for antiepileptic drug (AED) discovery. In fact, long before the advent of SB, AED discovery already involved some SB-like elements.A reported SB project aimed to find out new drug targets in epilepsy relies on a relational database that integrates clinical information, recordings from deep electrodes and 3D-brain imagery with histology and molecular biology data on modified expression of specific genes in the brain regions displaying spontaneous epileptic activity.Since hitting a single target does not treat complex diseases, a proper pharmacological promiscuity might impart on an AED the merit of being multi-potent. However, multi-target drug discovery entails the complicated task of optimizing multiple activities of compounds, while having to balance drug-like properties and to control unwanted effects. Specific design tools for this new approach in drug discovery barely emerge, but computational methods making reliable in silico predictions of poly-pharmacology did appear, and their progress might be quite rapid. The current move away from reductionism into network pharmacology allows expecting that a proper integration of the intrinsic complexity of epileptic pathology in AED discovery might result in literally anti-epileptic drugs.

The characteristics and related influencing factors of ambulatory EEGs in patients seizure-free for 3–5 years

Lian Wang, Yong-Hong Liu, Ling Wei, Yan-Chun Deng — 2011-12-26

Summary: Objective: Epileptic patients have a higher relapse risk when EEGs before the initiation of anti-epileptic drug (AED) withdrawal show epileptiform activity. The purpose of this study is to assess the characteristics of ambulatory EEGs before the decision to withdraw AEDs and to clarify potential influencing factors for abnormal EEGs.Methods: 214 epileptic patients were included in the study. These patients were seizure-free for 3–5 years on AED medication. Ambulatory 24-h EEGs were performed before the decision to withdraw AEDs. The demographical data and clinical information of the patients were used for the analysis of influencing factors for EEG findings.Results: Ambulatory EEGs showed abnormalities in 41.1% of the patients (88/214). Of 88 patients with abnormal EEGs, 43 had unequivocal epileptic discharges; and 45 only had nonspecific EEG abnormalities. In our analysis, the potential factors for abnormal EEGs included female, delayed therapy, longer duration of intractability/treatment response time and medications failed.Conclusions: In many patients ambulatory EEGs remain abnormal even after seizure-free for 3–5 years; and many factors influenced the characteristics of the EEGs. The findings can assist in establishment of therapeutic principles.

The prevalence and treatment gap of epilepsy in Tbilisi, Georgia

2011-09-28

Summary: Introduction: Data on the prevalence of epilepsy and the extent of its treatment gap are important for planning health care delivery for people with epilepsy. The prevalence of active epilepsy in Georgia prior to the social and political re-organization in the early 1990s was estimated at around 5.7 per 1000. Changes to the social structure of the country may have affected this. There is no previous estimate of the treatment gap.Methods: A door-to-door survey was carried out using a validated screening questionnaire to determine the prevalence of epilepsy and the extent of the treatment gap amongst a population of about 10,000 people in Tbilisi, the capital of Georgia. The diagnosis of epilepsy amongst those who screened positive was confirmed by a multidisciplinary team.Results: Lifetime prevalence was 11.4/1000. The prevalence of active epilepsy was estimated at 8.8/1000, and 5/1000 had seizures in the previous 12 months. About two thirds of people with active epilepsy had not received appropriate antiepileptic treatment in the month prior to the survey. 89% had focal epilepsy and two thirds had co-morbidity (neurological deficits, behavioral, psychiatric or somatic problems).Conclusion: The prevalence of epilepsy was higher than previously estimated and the treatment gap was substantial. Results should inform the planning of epilepsy care delivery in the country.

Levetiracetam clinical pharmacokinetics in elderly and very elderly patients with epilepsy

M. Contin, S. Mohamed, F. Albani, R. Riva, A. Baruzzi — 2011-09-26

Summary: We aimed to compare apparent steady-state oral clearance (CL/F) of the antiepileptic drug levetiracetam (LEV) in elderly (66–80 years, n=105) and very elderly (81–96 years, n=70) vs nonelderly (30–65 years, n=97) patients with epilepsy. Median weight-normalized CL/F (mLmin−1kg−1) decreased from 1.23 (nonelderly) to 0.83 (elderly) and 0.59 (very elderly) (p<0.001). LEV CL/F significantly declines with aging, elderly and very elderly patients requiring an about 30% and 50% lower dose, respectively, compared to nonelderly adults to achieve a given LEV plasma concentration.

Chronic bilateral subthalamic stimulation after anterior callosotomy in drug-resistant epilepsy: Long-term clinical and functional outcome of two cases

2011-10-03

Summary: We explored the efficacy and safety of bilateral SubThalamic Nucleus (STN) stimulation in two subjects suffering from drug-resistant epilepsy even after anterior callosotomy. Case 1 had about 65% decrease of partial motor seizures and the complete disappearance of tonic–clonic generalized attacks. Case 2, with sudden drop (atonic) attacks, partial complex seizures, atypical absences and rare tonic–clonic seizures, showed no meaningful reduction of fits and a stimulation associated atypical absence rate increase.

High incidence of pediatric idiopathic epilepsy is associated with familial and autosomal dominant disease in Eastern Newfoundland

2011-09-28

Summary: Purpose: To describe the incidence and epidemiology of pediatric idiopathic epilepsy (IE) in Newfoundland and Labrador.Methods: All children in Newfoundland and Labrador aged 0–15 years with IE were ascertained through the provincial neurology clinic at the Janeway Child Health Centre. Family history, medical history and blood samples were obtained from probands and relatives. Two genes, SCN1A and KCNQ2, were screened for mutations by direct sequencing.Results: The mean annual incidence of IE for the population of children living in the Avalon region of Newfoundland from 2000 to 2004 was 107 per 100000. This rate is approximately three-fold greater than rates reported in other developed countries. Of 117 families with IE eligible for study, 86 (74%) provided detailed pedigree data. Multiple different epilepsy phenotypes were identified. Fifty-five families (64%) had a positive family history. Eight of these had family histories compatible with autosomal dominant (AD) inheritance and these families lived in five different geographic isolates. DNA was obtained from 21 families (79 individuals). The two previously identified mutations in Newfoundland families with epilepsy were sequenced and excluded as pathogenic sites in all but one family which had a mutation in SCN1A.Conclusion: The incidence of IE is high in the Avalon Peninsula of Newfoundland and the rate of familial disease is high throughout the province of Newfoundland and Labrador. The distribution of familial and AD IE in different geographic isolates, together with the clinical heterogeneity of disease suggests substantial genetic heterogeneity. It is likely that other novel mutations will be identified in this population.

Interactions of pregabalin with gabapentin, levetiracetam, tiagabine and vigabatrin in the mouse maximal electroshock-induced seizure model: A type II isobolographic analysis

Jarogniew J. Luszczki, Damian Filip, Magdalena Florek-Luszczki — 2011-09-26

Summary: The aim of this study was to characterize the anticonvulsant effects of pregabalin in combination with four second-generation antiepileptic drugs (i.e., gabapentin, levetiracetam, tiagabine, and vigabatrin) in the mouse maximal electroshock (MES)-induced seizure model by using the type II isobolographic analysis.Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25mA, 500V, 50Hz, 0.2s stimulus duration) delivered via auricular electrodes.The combination of pregabalin with gabapentin at the fixed-ratio of 1:1 was supra-additive (synergistic) in terms of seizure suppression while the combinations at the fixed-ratios of 2:1 and 4:1 were additive in the mouse MES model. Similarly, the combination of pregabalin with tiagabine at the fixed-ratio of 25:1 was supra-additive, whereas the combinations at the fixed-ratios of 100:1 and 50:1 were additive in the mouse MES model. Pregabalin with levetiracetam and vigabatrin at the fixed-ratios of 1:1, 2:1 and 4:1 were additive in this seizure model.The combinations of pregabalin with gabapentin (1:1) and pregabalin with tiagabine (25:1) appear to be favorable combinations exerting supra-additive interaction in suppressing MES-induced seizures. Pregabalin in combination with levetiracetam and vigabatrin appears to be neutral producing only additivity in the mouse MES model.

Root extract of Anacyclus pyrethrum ameliorates seizures, seizure-induced oxidative stress and cognitive impairment in experimental animals

Monika Pahuja, Jogender Mehla, K.H. Reeta, Sujata Joshi, Yogendra Kumar Gupta — 2011-10-13

Summary: In Ayurveda, Anacyclus pyrethrum has been used as a brain tonic. The present study evaluates the effect of hydroalcoholic extract of A. pyrethrum (HEAP) root against seizures, seizure-induced oxidative stress and cognitive impairment in experimental models of seizures. Male Wistar rats were used in the study. HEAP was administered in doses of 50, 100, 250, 500 in pentylenetetrazole (PTZ) model and 250, 500 and 1000mg/kg in maximal electroshock (MES) model. Myoclonic jerk latency and generalized tonic clonic seizures (GTCS) were noted in PTZ whereas occurrence of tonic hind limb extension (THLE) was observed in MES seizures. Cognitive deficit was assessed using elevated plus maze and passive avoidance tests. Whole brain reduced glutathione, malondialdehyde levels and cholinesterase activity were measured. HEAP showed 50, 66.7, 83.3 and 100% protection at 50,100, 250 and 500mg/kg, respectively against GTCS in PTZ induced seizures. In MES induced seizures, HEAP produced 16.7, 33.3 and 50% protection against THLE at 250, 500 and 1000mg/kg, respectively. HEAP administration significantly prevented seizure induced oxidative stress and cognitive impairment in a dose-dependent manner. HEAP also normalized the decrease in cholinesterase activity caused by seizures. Thus, HEAP showed protective effect against seizures, seizure-induced oxidative stress and cognitive impairment in rats.

Comparison of dense array EEG with simultaneous intracranial EEG for Interictal spike detection and localization

2011-10-24

Summary: Purpose: To evaluate the clinical utility of dense array electroencephalography (dEEG) for the detection yield and localization of interictal spikes in mesial temporal lobe epilepsy.Methods: We simultaneously recorded 256-channel dEEG and intracranial electroencephalography (icEEG) implanted over the lateral and mesial temporal lobe in patients with intractable epilepsy. We calculated the dEEG spike detection rate for mesial temporal spikes which were confirmed by icEEG and applied source estimation to dEEG to compare noninvasive localization to the invasive recordings.Results: 339 of 760 interictal spikes (45%) were detected by dEEG examining the 256-channel head surface array. The average icEEG amplitude of dEEG detectable spikes was 1083μV, and that of dEEG undetectable spikes was 780μV (P<0.05). All spikes detected in dEEG were localized to the temporal lobe. 295 of 339 spikes (87%) were well localized in mesial temporal lobe, close to the position confirmed by subdural electrodes.Significance: 256-channel dEEG may provide more precise information for the localization of interictal epileptiform discharges than conventional EEG or MEG in patients with deep spike foci. 256-channel dEEG may be clinically useful in the presurgical work-up for epilepsy, providing accurate noninvasive guidance for the placement of intracranial electrodes.

The detection of mood and anxiety in people with epilepsy using two-phase designs: Experiences from a tertiary care centre in Oman

2011-10-17

Summary: Background: The detection of mood and anxiety disorders is of great clinical importance in patients with chronic disease but data on the occurrence of affective dysfunction is lacking among people with epilepsy (PWE) in non-western populations. Further compounding such situation, the validity of some of the common assessment measures has not been examined.Objective: The study aims to investigate the application of the Hospital Anxiety and Depression Scale (HADS) by identifying patients with comorbid affective dysfunctions in an Omani population. The semi structured interview, Composite International Diagnostic Interview (CIDI) will be used to establish the psychometric property of HADS in the Omani population.Methods: PWE (n=150) were screened with the semi-structured, (CIDI) and the HADS. A receiver operating characteristics (ROC) curve was calculated to discriminate the power of the HADS for every possible threshold score.Results: The semi-structured interview revealed the prevalence rate of 27% for depressive disorder and 45% for anxiety disorder. The best compromise using, the cut-off score of 7 or 8, gave a sensitivity of 99% for depression and 83–91% for anxiety and a specificity of 87.5–100% for depression and 85–94% for anxiety.Conclusions: Findings suggest that HADS is a useful screening tool for this particular population. This finding is discussed from the socio-cultural perspective of Omani society.

Inter-session repeatability of cortical excitability measurements in patients with epilepsy

Radwa A.B. Badawy, Graeme D. Jackson, Samuel F. Berkovic, Richard A.L. Macdonell — 2011-10-24

Summary: Purpose: Previous studies have evaluated the inter-session variability of motor thresholds (MT), short intracortical inhibition and intracortical facilitation using paired pulse transcranial magnetic stimulation (TMS) in normal individuals. Here we evaluate the reproducibility of a range of measures of cortical excitability in patients with epilepsy.Methods: Twenty-four drug naïve patients with newly diagnosed epilepsy (13 idiopathic generalised epilepsy [IGE], 11 focal epilepsy) and seventeen non-epilepsy controls were studied. Motor threshold (MT) at rest and recovery curves constructed using paired pulse stimulation at short (2–15ms) and long (50–400ms) interstimulus intervals (ISIs) were analysed on two separate occasions, 4–20 weeks apart. The Lin's concordance correlation coefficient test was used to measure agreement between the two sessions.Results: Significant levels of agreement between the two sessions were observed at MT and all the ISIs measured. This was highest in non-epilepsy controls.Conclusion: Cortical excitability measures are repeatable over time in both patients with epilepsy and healthy controls. Increased motor cortex excitability is a stable feature in epilepsy without significant inter-session variability.

Similar response to anti-epileptic medications among epileptic siblings

Hasan H. Sonmezturk, Amir M. Arain, Juliann M. Paolicchi, Bassel W. Abou-Khalil — 2011-10-26

Summary: Background: When epilepsy does not respond to the initial anti-epileptic drug (AED) the subsequent search for an effective AED is predominantly a matter of trial and error, as only limited criteria exist for rational AED selection. Since epilepsy in siblings is likely to be relatively homogeneous, we hypothesized that an AED effective in one sibling would also be effective in the other.Methods: We reviewed the antiepileptic medication response among nine sets of epileptic siblings (19 patients) in our practice. All but one patient were drug-resistant at one point during their treatment course.Results: Eight sets of siblings (17 individuals) became seizure-free or almost seizure-free with treatment modification and using a medication proven effective for one sibling in the other siblings. The medication change that produced seizure freedom was lamotrigine monotherapy in two families, valproate monotherapy in one, lamotrigine adjunctive therapy in two, lamotrigine-levetiracetam combination in two, and lamotrigine–valproate combination in one family. In one remaining family with generalized epilepsy, one sibling was seizure-free on phenobarbital while the other had persistent seizures despite polytherapy.Conclusions: Our results indicated that siblings with epilepsy tend to respond to the same AED monotherapy or AED combination.

Antiepileptic drug combinations—Have newer agents altered clinical outcomes?

Linda J. Stephen, Murray Forsyth, Kevin Kelly, Martin J. Brodie — 2011-10-10

Summary: In 2000, 332 (20.5%) of 1617 patients registered with the Western Infirmary Epilepsy Unit required antiepileptic drug (AED) polytherapy to remain seizure-free for at least 1 year. The analysis was repeated 10 years later. Of 2379 seizure-free patients, 20.4% (n=486 – 254 women, 232 men, aged 18–95 years [median age 49 years]) were receiving combination therapy. Two AEDs were taken by 395 (81.3%) patients in 2010, and by 287 (86.4%) in 2000. Sodium valproate with lamotrigine was the commonest of 64 successful pairings. As a combination, mean daily doses of both AEDs were lower (n=96; sodium valproate 1200mg, lamotrigine 155mg) than when sodium valproate was taken with carbamazepine or levetiracetam (n=42; 1621mg; p<0.001), and lamotrigine was combined with topiramate or levetiracetam (n=33; 430mg; p<0.001), suggesting possible synergism. In 2010, a higher percentage of patients (n=85) remained seizure-free on 3 AEDs (17.5% in 2010, 12.7% in 2000) in 57 separate regimens. Only 0.9% (n=3) of patients in 2000, and 1.2% (n=6) in 2010 responded to 4 AEDs. Levetiracetam (n=109; 10.2%) and topiramate (n=81; 7.6%) were the newer agents most commonly represented in successful combinations. These data tend to imply that drug substitution rather than addition has largely led to these marginally improved results. In the last decade, when used as adjunctive therapies, newer agents appear not to have impacted substantially on the likelihood of producing seizure freedom. An alternative approach to AED development may be required to change this disappointing scenario.

A genetic epidemiological survey of idiopathic epilepsy in the Chinese Han population

2011-10-13

Summary: Background: Idiopathic epilepsy (IE) is a syndrome that comprises epilepsy only, with no underlying structural brain lesion or other neurological signs or symptoms. Numerous studies have shown that genetic factors play an important role in IE. IE is a common disease in the Chinese Han population. However, the genetic epidemiological characteristics of IE in the Chinese population, such as its heritability and genetic models remain unclear.Purpose: To study the clinical and epidemiological profile of IE, to estimate the heritability and determine the possible genetic models for IE in the Chinese Han population.Methods: A case–control family-based study was carried out in a rural Chinese county. We collected data from eligible IE patients, controls, and their relatives by a uniform structured questionnaire, and then established an epidemiologic database of epilepsy using Access2010. General statistical and genetic epidemiological analyses (Falconer's-method-based heritability, simple segregation ratio and complex segregation analysis) were performed using SAS9.1 and the SAGE-SEGREG program.Results: (1) The prevalence of IE among the relatives of probands with IE (2.75‰) was higher than that among the relatives of the control group (0.61‰). The prevalence of IE among the first-, second-, and third-degree relatives of the probands with IE was 11.45‰, 2.64‰ and 0.98‰, respectively, which were all higher than the corresponding prevalences in the relatives of controls. Trend-chi-squared tests indicated that the prevalence of epilepsy increased among the relatives of probands with decreasing kinship distance (χ2=97.16, P=0.00). (2) The heritability of IE among first-, second-, and third-degree relatives was 55.06%, 50.72% and 16.98%, respectively. The weighted mean heritability was 46.07%. (3) The simple segregation ratio of IE was 0.03, significantly lower than the Mendelian recessive segregation ratio of 0.25. Complex segregation analysis showed that the population we studied accepted a Mendelian genetic model (dominant, recessive, additive, and a major gene model) and excluded the general model, non-transmitted model, and environment-only model. A Mendelian additive inheritance model was ultimately the best-fit because it had the lowest Akaike Information Criteria score.Conclusion: In the Chinese Han population, IE follows a pattern of polygenic Mendelian additive inheritance rather than single-gene inheritance. Nearly half of the total variance can be explained by genetic factors.

The duration of sustained convulsive seizures determines the pattern of hippocampal neurogenesis and the development of spontaneous epilepsy in rats

2011-10-20

Summary: The duration of sustained seizures (SS) plays a crucial role in the occurrence of spontaneous recurrent seizures (SRS) in experimental animals. We tested whether rats with varying durations of initial convulsive SS exhibited differential neurogenesis patterns in the hippocampal dentate gyrus that may be related to subsequent epileptogenesis. Sprague-Dawley rats with pilocarpine-induced convulsive SS were divided into short SS (30min) and long SS (2h) groups. Their behavior was monitored to identify convulsive SRS. From 1 to 28 days post-SS, cell proliferation was evaluated by 5′-bromo-2′-deoxyuridine (BrdU) labeling and immature neuroblasts in the dentate gyrus were identified by doublecortin immunohistochemistry. Convulsive SRS was detected in 8 out of the 9 long SS rats, but not in the 9 short SS rats. During day 1–3, proliferative cells were diffusely localized throughout the hippocampus in the long SS rats but were primarily confined within the subgranular zone in the short SS rats. Within the subgranular zone, a significant increase in the number of BrdU-positive cells was found at days 3 and 7 after the long SS and on day 1 after the short SS. Notably, abnormal dendritic outgrowth and hilar-ectopic localization of doublecortin-positive cells were present in the long SS rats. In conclusion, aberrant hippocampal neurogenesis following long SS may contribute to the development of SRS.

Rats with different thresholds for DMCM-induced clonic convulsions differ in the sleep-time of diazepam and [3H]-Ro 15-4513 binding

2011-10-17

Summary: The current study investigated the possible inherent relationship between convulsions and sleep involving the GABAA/benzodiazepine site complex. The aim of this study was to determine if rats with high (HTR) and low (LTR) thresholds for clonic convulsions induced by DMCM, a benzodiazepine inverse agonist, differ in the following aspects: (1) sensitivity to the hypnotic effects of the GABAA positive allosteric modulators diazepam, pentobarbital and ethanol and (2) in the binding of [3H]-flunitrazepam, a benzodiazepine agonist, measured by autoradiography, and [3H]-Ro 15-4513, a benzodiazepine partial inverse agonist, to membranes from discrete brain regions. The LTR subgroup presented a shorter diazepam-induced sleeping time compared to that of the HTR subgroup. Biochemical assays revealed that the LTR subgroup did not differ in [3H]-flunitrazepam binding compared to the HTR subgroup. With respect to the binding of [3H]-Ro 15-4513, the LTR subgroup had higher binding in the brainstem and lower binding in the striatum compared to the HTR subgroup. These results suggest that differences in the benzodiazepine site on the GABAA receptor may underlie the susceptibility to DMCM-induced convulsions and sensitivity to the hypnotic effect of diazepam.

Association between equivalent current dipole source localization and focal cortical dysplasia in epilepsy patients

2011-10-24

Summary: We analysed the association between focal cortical dysplasia (FCD) visible in MRI and the location of equivalent current dipole (ECD) of single interictal scalp EEG spikes (IIS) in 11 epilepsy patients. We calculated several indicators of distance of ECDs to the FCD border. The results confirm some previous studies suggesting that the epileptogenic zone associated to the location of ECDs extends beyond the FCD visible in MRI. The analysis suggests the ECDs to be in a shell parallel to part of the FCD surface.

The efficacy of topiramate in adult refractory status epilepticus: Experience of a Tertiary Care Center

2011-10-17

Summary: Refractory status epilepticus (RSE) occurs in patients with SE when they fail to respond to traditional medical therapy. Because there are very few case reports of topiramate (TPM) treatment of RSE in adult patients, we examined our experience with TPM with regard to its safety and efficacy in seizure termination in RSE in an adult patient population. We report a retrospective review of 35 adult patients with RSE who were treated with TPM in addition to other antiepileptic drugs (AEDs) between 2003 and 2010. After failure of initial treatments of benzodiazepines and weight-based intravenous loading doses of standard AEDs, TPM tablets were crushed and administered via nasogastric tube. Data were collected on age, gender, history of epilepsy, etiology of RSE, daily dose of TPM, co-therapeutic agents, treatment response, and disposition. Following initiation of TPM use and discontinuation of continuous intravenous anesthetics with no additional AEDs administered, cumulative cessation of RSE in patients was 4/35 (11%) at one day, 10/35 (29%) at two days, and 14/35 (40%) at three days. However, when including all patients and comparing the two patient groups in which RSE was or was not terminated within three days of initiating TPM as the last or not last AED given, there was no significant difference. Time to TPM response was not associated with the type of seizures, etiology of SE, or whether there was a history of epilepsy. There were no documented side effects or complications of therapy with TPM. This study provides support for the use of TPM as an adjunctive agent in the treatment of RSE.

Synthesis and anticonvulsant evaluation of dimethylethanolamine analogues of valproic acid and its tetramethylcyclopropyl analogue

Tawfeeq Shekh-Ahmad, Meir Bialer, Eylon Yavin — 2011-11-07

Summary: Background: Valproic acid (VPA) is a major antiepileptic drug (AED) that is less potent than other AEDs. 2,2,3,3-Tetramethylcyclopropanecarboxylic acid (TMCA) is an inactive cyclopropyl analogue of VPA that serves as a starting material for the synthesis of CNS-active compounds.Methods: New conjugation products between N,N′-dimethylethanolamine to VPA and TMCA to form N,N-dimethylethanolamine valproate (DEVA) and N,N-dimethylethanolamine 2,2,3,3-tetramethylcyclopropionate were synthesized and their anticonvulsant activity was assessed in the maximal electroshock seizure (MES) and subcutaneous metrazol (scMet) seizure tests and the hippocampal kindling model in mice and/or rats. An amide analogue of DEVA (DEVAMIDE) was also synthesized and evaluated. The pharmacokinetics of DEVA and DEVAMIDE was comparatively evaluated in rats.Results: In rats DEVA acted as a prodrug of VPA and had ED50 values of 73mg/kg and 158mg/kg in the MES and the hippocampal kindling models, respectively. At these two anticonvulsant models DEVA was seven-times more potent than VPA. DEVAMIDE was active in the MES test at doses of 100mg/kg (mice) and its rat-MES-ED50=38.6mg/kg however, its protective index (PI=TD50/ED50) was twice lower than DEVA's PI. The TMCA analogues were inactive at the mice MES and scMet models. DEVA underwent rapid metabolic hydrolysis to VPA and consequently, in its pharmacokinetic analysis only VPA plasma levels were monitored. In contrast, DEVAMIDE was stable in whole blood.Conclusion: DEVA acts in rats as a prodrug of VPA yet shows a more potent anticonvulsant activity than VPA. DEVAMIDE acted as the drug on its own and was more potent than DEVA at the rat-MES test.

Olanzapine-associated myoclonus

Jennifer Block Rosen, Mark J. Milstein, Sheryl R. Haut — 2011-12-26

Summary: Olanzapine is an atypical antipsychotic drug that infrequently has been reported to cause seizures and myoclonus despite a small proconvulsant risk. This is the first report of generalized myoclonus induced in a patient who had been maintained on low dose olanzapine for over seven years without any change in her dose. Olanzapine was discontinued, and the myoclonic jerks completely resolved within 48h.

Diffusion tensor imaging of subependymal heterotopia

2011-09-26

Summary: A magnetic resonance (MR) diffusion tensor imaging (DTI) study was performed in a newborn with bilateral subependymal heterotopia (SE). White matter fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD) were compared to values obtained in four newborns with moderate perinatal asphyxia and normal MRI findings. The reduction of FA and increase of AD and RD in the newborn with SE were the in vivo late expression of alterations in the intermediate zone, with an underlying arrest of neuronal migration.

Memory in paediatric temporal lobe epilepsy: Effects of lesion type and side

2011-10-31

Summary: This study investigated the role of underlying pathology on memory function of children with temporal lobe epilepsy (TLE). Memory was assessed in 44 children with TLE resulting from hippocampal sclerosis (HS) or dysembryoplastic neuroepithelial tumours (DNT), and 22 control children. Delayed story and paired associate recall performance was significantly more impaired in children with HS compared to those with DNT, irrespective of the affected side. Semantic memory was impaired in both HS groups, and also in the left DNT group. These results suggest a role for type, and to a lesser extent, side of pathology in the memory profile of children with TLE.

Initial post marketing experience with lacosamide in adult patients with epilepsy

Cynthia L. Harden, Aaron Cohn, Merredith Lowe, Enrique Serrano — 2011-10-24

Summary: The outcomes of adult epilepsy patients prescribed lacosamide for additional seizure control. Responders were defined as having at least a 50% decrease in seizure frequency Sixty-seven patients were evaluated. Forty-six out of 67 patients (69%) were responders. Twelve of 14 patients not taking sodium channel-acting AEDs were responders (86%) and 34/53 patients taking sodium channel-acting AEDs were responders (64%) (difference not significant).

Aquaporin-4-dependent edema clearance following status epilepticus

2011-10-14

Summary: We investigated the role of aquaporin-4 in the development of cerebral edema following kainic acid-induced status epilepticus (SE) using specific gravimetry and T2 MRI techniques at 6h, 1 day, 4 days and 7 days after SE. Our results indicate significantly greater tissue edema and T2 MRI changes in AQP4−/− compared to AQP4+/+ mice that peaks at about 1 day after SE (greater in hippocampus relative to cortex). These results have implications for the mechanisms of edema formation and clearance following intense seizure activity.

Changed constitution without change in brand name – The risk of generics in epilepsy

Vishal Patel, Dennis J. Cordato, Manu Dias, Roy G. Beran — 2011-10-26

Summary: Purpose: Lamotrigine (LTG) is an anti epileptic medication (AEM) for which blood levels are helpful for optimal dosing. In late 2010, patients attending an epilepsy clinic were becoming toxic without obvious cause. This paper reports altered levels without change in regimen and provides unexpected findings.Methods: Patients with elevated LTG blood levels were assessed to determine change in AEM regimen or generic substitution. Method of blood level determination was reviewed and the company (GlaxoSmithKline) contacted regarding change in source of medication.Principal results: The sample comprised 18 patients; mean age 40±16years, mean daily LTG dose 493±218mg. Mean serum LTG concentrations from August 2010 to February 2011 [91.8±17.7μmolL−1, range 69.9–133.7μmolL−1] were significantly higher than those from January 2010 to July 2010 [50.3±9.1μmolL−1, range 32–60.1μmolL−1), p<0.0001]. All patients received parent product (Lamictal®) and the method of LTG blood level determination was unchanged. GlaxoSmithKline confirmed that Lamictal® was sourced from a different site.Conclusions: These results indicate that, even using a parent compound, AEM levels can fluctuate if the product source has changed, resulting in toxicity. It also highlights the value of determining AEM levels and the risks attached to generic substitution.

Four novel and two recurrent NHLRC1 (EPM2B) and EPM2A gene mutations leading to Lafora disease in six Turkish families

2011-11-02

Summary: Lafora disease (LD) is a type of autosomal recessive, progressive myoclonus epilepsy resulting mostly from mutations in the EPM2A and NHLRC1 genes. Mutational analysis in both genes was initiated with the aim of establishing LD DNA diagnosis in Turkey. Four novel NHLRC1 (p.G131X, p.P69S and p.D82H) and EPM2A (p.V7A) and two recurrent NHLRC1 (p.D146N) and EPM2A (p.R241X) mutations were identified in six families. The delineation of causative mutations in patients provided early disease diagnosis for other family members and contributed to the knowledge of LD pathogenesis.

Are patients referred for presurgical evaluation drug resistant according to the new consensus definition? A study in a tertiary center

2011-12-19

Summary: We performed a retrospective chart review of the last consecutive 40 patients admitted in our Epilepsy Unit for presurgical evaluation to find out if they met criteria for drug resistant epilepsy according to the recently published consensus definition. 276 drug trials had been performed in the 40 patients. In total, 196 trials were considered “uninformative” versus 80 informative and adequate trials. Finally, a firm diagnosis of drug resistant epilepsy could be made only in 13/40 patients (32.5%, 90% confidence interval for proportion 21.7–45.5%), due to insufficient information regarding previous drug trials. The definition should be spread among general neurologists for earlier and more complete referrals.

Phenytoin intoxication induced by Mandrax (methaqualone)

Rajesh Verma, Naveen Tiwari — 2011-10-24

Phenytoin is most commonly prescribed drug for management of epilepsy, particularly in developing countries. Phenytoin therapy is known to cause toxic central nervous system reactions, due to its peculiar non-linear pharmacokinetic property in clinical background of alcoholism, consumption of concomitant drugs which can cause drug interactions and elderly individuals (). In this submission, we described a young male suffering from primary generalized epilepsy who presented as acute vestibulo-cerebellar syndrome due to phenytoin toxicity induced by Mandrax (methaqualone).