Therapy For Refractory Epilepsy Research Articles

Blood–brain barrier P-glycoprotein activity in patients with therapy-refractory epilepsy before and after surgical focal resection assessed with (R)-[11C]verapamil and positron emission tomography

Blood–brain barrier P-glycoprotein activity in patients with therapy-refractory epilepsy before and after surgical focal resection assessed with (R)-[11C]verapamil and positron emission tomography

O93 – 2003 Different aspects in the evaluation of vagus nerve stimulation efficacy among children with therapy-refractory epilepsy

O93 – 2003 Different aspects in the evaluation of vagus nerve stimulation efficacy among children with therapy-refractory epilepsy

Stereo-EEG in children with therapy-refractory epilepsies: Robot-assistance plus stereotaxy combines speed with maximal precision for the implantation of multiple depth electrodes

Aims: “Stereo-EEG” is an invasive diagnostic procedure for the presurgical evaluation of therapy-refractory epilepsies, during which depth electrodes are implanted stereotactically into the brain parenchyma via multiple burr holes. A comprehensive evaluation often requires up to 20 depth electrodes in multiple brain areas, which can lead to long operations (20 to 30 minute per electrode) when conventional stereotaxy is used. Special assisting robots can make these implantations much faster (< 10 minute per electrode) by automatically defining the preplanned implantation trajectories for the surgeon. Without the use of a stereotaxic frame (“frameless”); however, the same precision as with conventional stereotaxy cannot be achieved. Here, we present the first cases of our new approach which combines both techniques, aiming at combining the speed of robot-assistance with the precision of conventional stereotaxy.

Comprehensive long-term outcome of best drug treatment with or without add-on vagus nerve stimulation for epilepsy: A retrospective matched pairs case–control study

PurposeIn the treatment of epilepsy, the recommendation to add vagus nerve stimulation (VNS) to the best available drug therapy (BDT) mostly relies on uncontrolled studies which provide limited information about VNS-specific benefits. We report findings from a retrospective matched pairs case–control study comparing the long-term (>2 years) outcomes of BDT with or without VNS. MethodsIncluded were adult patients with therapy-refractory epilepsy who had undergone the pre-surgical work-up (baseline) and subsequently received BDT with VNS (BDT+VNS) or BDT alone (BDT group). Patients were matched in pairs for age, gender and follow-up. Health outcomes were assessed at least 24 months after the baseline by comprehensive postal surveys and included established psychometric scales. ResultsWe obtained data from 20 matched pairs of case and control patients. In both groups, seizures, health-related quality of life and mood improved over time. More BDT patients experienced a complete cessation of “major” seizures (12/20 vs. 4/20) whereas, in non-seizure free patients, BDT+VNS patients showed better seizure frequency reduction (>50% reduction: 12/19 vs. 7/16). BDT+VNS patients experienced equal drug related and additional VNS related side effects. No clinically relevant effect of VNS treatment was found on any psychological/psychosocial outcome measure. ConclusionThis retrospective study provided no positive evidence for therapeutic benefits of adding VNS to BDT. The follow-up health status of BDT+VNS patients was slightly worse than in patients receiving BDT alone. Despite minor group differences at baseline the two patient groups who had failed presurgical evaluation were comparable. Therapeutic improvements during long-term BDT alone are often underestimated resulting in a misattribution of positive changes to VNS in uncontrolled studies and reviews. Currently, there is no incontrovertible evidence for the clinical effectiveness of adding VNS to BDT.

Ipsilateral Motor Control Without Mirror Movements?

Aims: Some children with unilateral-spastic cerebral palsy (=congenital hemiparesis) control their paretic hands via ipsilateral cortico-spinal projections from the contra-lesional hemisphere, which, in these cases, therefore controls both hands. This is typically associated with mirror movements both during voluntary unimanual movements of the paretic and of the non-paretic hand. It is still unclear, however, whether ipsilateral motor control can also exist without mirror movements. Methods: A former term-born child with congenital hemiparesis due to unilateral white matter damage probably resulting from intrauterine periventricular hemorrhage with venous infarction and therapy-refractory epilepsy received hemispherotomy at the age of 5 years. Results: Postoperatively, the paretic hand was still able to grasp; neurological examination at the age of 9 years showed no mirror movements despite (obvious) unihemispheric motor control of both hands. Conclusion: Since transcranial magnetic stimulation has not yet been performed in this patient, there is no formal proof for the existence of ipsilateral cortico-spinal projections from the contra-lesional hemisphere to the paretic hand. The preserved grasp function after hemispherotomy, however, is highly suggestive. Therefore, this case report demonstrates that at least in some children with ipsilateral motor control, the contra-lesional hemisphere can control both hands independently from each other, so that no mirror movements occur. Thus, the absence of mirror movements is not a valid sign for contralateral motor control; this question still requires transcranial magnetic stimulation.

Comparative efficacy of combination drug therapy in refractory epilepsy

We retrospectively examined treatment records of developmentally disabled adults with highly refractory epilepsy to determine whether any combinations of 8 of the most commonly used antiepileptic drugs (AEDs) possessed superior efficacy. We obtained the treatment records from 148 developmentally disabled adults with refractory epilepsy cared for in 2 state-run institutions. These records charted monthly convulsive seizure occurrence and AED regimen over 30 years. We studied the effects of 8 commonly used AEDs alone and in combination on seizure frequency in within-patient comparisons. Out of the 32 most frequently used AED combinations, we found that only the combination of lamotrigine and valproate had superior efficacy, measured against both an aggregate measure of other AED regimens to which patients were exposed, and in head-to-head comparisons with other AED combinations. We also found that while use of 2 concurrent AEDs provided improved efficacy over monotherapy, use of 3 AEDs at a time provided no further benefit over two. These results suggest that at least one AED regimen provides significantly better efficacy in refractory convulsive epilepsy, and that AEDs should be used no more than 2 at a time. Limitations of the study include its retrospective design, lack of randomization, and small sample sizes for some drug combinations. Future prospective trials are needed in this challenging clinical population.

Neuropathologic measurements in focal cortical dysplasias: validation of the ILAE 2011 classification system and diagnostic implications for MRI

Focal cortical dysplasias (FCD) which represent a composite group of cortical malformations are increasingly recognized as morphological substrate for severe therapy-refractory epilepsy in children and young adults. However, presurgical evaluation remains challenging as not all FCD variants can be reliably detected by high-resolution magnetic resonance imaging (MRI). Here, we studied a cohort of 52 epilepsy patients with neuropathological evidence for FCD using the 2011 classification of the International League against Epilepsy (ILAE) and systematically analysed those histopathologic features applicable also for MRI diagnostics. Histopathologic parameters included quantitative measurements of cellular profiles, cortical thickness, heterotopic neurons in white matter, and myelination that were compared between FCD subtypes and age-/localization-matched controls (n = 36) using multivariate analysis. Dysmorphic neurons in both FCD Type II variants showed significantly increased diameter of their cell bodies and nuclei. Cortical thickness was also increased with a distinct loss of myelin content specifying FCD Type IIb from IIa. The data further suggested that myelination deficits in FCD Type IIb result from compromised oligodendroglial lineage differentiation and we concluded that the "transmantle sign" is a unique finding in FCD Type IIb. In contrast, FCD Type Ia was characterized by a smaller cortical ribbon and higher neuronal densities, but these parameters failed to reach statistical significance (considering age- and location-dependent variability in controls). All FCD variants showed abnormal grey-white matter boundaries with increased numbers of heterotopic neurons. Similar results were obtained also at deep white matter location. Thus, many FCD variants may indeed escape visual MRI inspection, but suspicious areas with increased or decreased cortical thickness as well as grey-white matter blurring may be uncovered using post-processing protocols of neuroimaging data. The systematic analysis of well-specified histopathological features could be helpful to improve sensitivity and specificity in MRI detection during pre-surgical work-up of patients with drug-resistant focal epilepsies.

Characterization of the gene expression profile of human hippocampus in mesial temporal lobe epilepsy with hippocampal sclerosis.

One of the main putative causes of therapy refractory epilepsy in mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis is the overexpression of multidrug transporters (MDTs) at the blood-brain barrier (BBB). It steps up the removal of antiepileptic drugs (AEDs) out of the brain cells across the BBB resulting in a low concentration of AEDs within the target cells. Some of the mechanisms of AED resistance are most likely to be genetically determined. To obtain more information about the underlying pathophysiology of intractability in epilepsy, we compared the global gene expression profile of human hippocampus and hippocampal-derived microvascular endothelial cells from MTLE with HS patients and controls. At the level of MDT, a significant up-regulation was found for ABCB1 (P-gp), ABCB2, ABCB3, and ABCB4, which was mainly related to endothelial cells. The data on the MDT were validated and extended by quantitative RT-PCR. Surprisingly, inflammatory factors such as interleukins (IL-1α, IL-1β, IL-6, and IL-18) and cytokines (TNF-α and TGF-β1) were found to be up-regulated in hippocampal parenchyma. The overexpression of P-gp, IL-1β, and IL-6 was also confirmed by immunohistochemistry (IHC). Our results suggest that complex expression changes of ABC-transporters may play a decisive role in pharmacoresistance in MTLE. Further studies on the new and unexpected overexpression of inflammatory cytokines may unlock hitherto undiscovered pathways of the underlying pathophysiology of human MTLE.

Experimental re-evaluation of flunarizine as add-on antiepileptic therapy

Background:Experimental studies have found several calcium channel blockers with anticonvulsant property. Flunarizine is one of the most potent calcium channel blockers, which has shown anticonvulsant effect against pentylenetetrazole (PTZ) and maximal electroshock (MES)-induced seizures. However, further experimental and clinical trials have shown varied results. We conducted a PTZ model experimental study to re-evaluate the potential of flunarizine for add-on therapy in the management of refractory epilepsy.Materials and Methods:Experiments were conducted in PTZ model involving Swiss strain mice. Doses producing seizures in 50% and 99% mice, i.e. CD50 and CD99 values of PTZ were obtained from the dose-response study. Animals received graded, single dose of sodium valproate (100–300 mg/kg), lamotrigine (3–12 mg/kg) and flunarizine (5–20 mg/kg), and then each group of mice was injected with CD99 dose of PTZ (65mg/kg i.p.). Another group of mice received single ED50 dose (dose producing seizure protection in 50% mice) of sodium valproate and flunarizine separately in left and right side of abdomen. Results were analysed by Kruskal–Wallis ANOVA on Ranks test.Results:As compared to control, sodium valproate at 250 mg/kg and 300 mg/kg produced statistical significant seizure protection. At none of the pre-treatment dose levels of lamotrigine, the seizure score with PTZ differed significantly from that observed in the vehicle-treated group. Pre-treatment with flunarizine demonstrated dose-dependent decrease in the seizure score to PTZ administration. As compared to control group, flunarizine at 20 mg/kg produced statistical significant seizure protection.Conclusion:As combined use of sodium valproate and flunarizine has shown significant seizure protection in PTZ model, flunarizine has a potential for add-on therapy in refractory cases of partial seizures. It is therefore, we conclude that further experimental studies and multicenter clinical trials involving large sample size are needed to establish flunarizine as add-on therapy in refractory epilepsy.

What is Depression in Epilepsy?

Psychiatry, in terms of neuropsychiatry, has experienced an impressive revival in the field of neurology over the past two decades. This especially holds true for epileptology (Reynolds and Trimble, 2009). A large number of studies have addressed depressive and other affective disorders in patients with seizures. Depression is now widely acknowledged as a frequent psychiatric comorbidity of seizure disorders (Barry et al., 2008; LaFrance et al., 2008). Here we critically explore the concept of depression as a comorbidity in epilepsy (see also Hoppe and Elger, 2011). First, we address criteria which differentiate between transiently altered mood states and psychiatric mood disorders. We then show that depression in epilepsy provides a perfect model for the biopsychosocial etiology of depression and discuss related therapeutic approaches. Finally, we provide some general remarks on what is required to maintain or restitute emotional well-being in patients with therapy–refractory epilepsy.

Operative and Technical Complications of Vagus Nerve Stimulator Implantation

The treatment of refractory epilepsy by vagus nerve stimulation (VNS) is a well-established therapy option for patients not suitable for epilepsy surgery and therapy refractory depressions. To analyze surgical and technical complications after implantation of left-sided VNS in patients with therapy-refractory epilepsy and depression. One hundred five patients receiving a VNS or VNS-related operations (n = 118) from 1999 to 2008 were investigated retrospectively. At the time of operation, 84 patients were younger than 18 years, with a mean age of 10.5 years. Twenty (19%) patients had technical problems or complications. In 6 (5.7%) patients these problems were caused by the operation. The device was removed in 8 cases. The range of surgically and technically induced complications included electrode fractures, early and late onset of deep wound infections, transient vocal cord palsy, cardiac arrhythmia under test stimulation, electrode malfunction, and posttraumatic dysfunction of the stimulator. VNS therapy is combined with a wide spread of possible complications. Technical problems are to be expected, including electrode fracture, dislocation, and generator malfunction. The major complication in younger patients is the electrode fracture, which might be induced by growth during adolescence. Surgically induced complications of VNS implantation are comparably low. Cardiac symptoms and recurrent nerve palsy need to be taken into consideration.

Prevalence of visual field loss following exposure to vigabatrin therapy: A systematic review

Vigabatrin is an efficacious antiepileptic drug licensed as add-on therapy in refractory epilepsy and used in infantile spasms. Eight years after licensing, there emerged a strong and possibly causative association with bilateral visual field loss. We report a systematic review ascertaining the magnitude of risk of vigabatrin associated visual field loss (VAVFL) and any clinical predictors of risk. Electronic searches, including MEDLINE (1966-2009), EMBASE (1974-2009), and CINAHL (1982-2009), were conducted. Reports, published in full, of observational studies investigating the prevalence of visual field loss in patients with partial epilepsy treated with vigabatrin were included. Outcomes were the proportion with visual field loss, and the relative risk of VAVFL compared to similar nonexposed patients with epilepsy. Thirty-two studies were identified, which included 1,678 patients exposed to vigabatrin and 406 controls. Of the 1,678 exposed patients, 738 (44%) had visual field loss compared to just 30 (7%) among the 406 controls. The random-effects estimate for the proportion of adults with visual field loss was 52% [95% confidence interval (CI) 46-59]. The estimate for children was lower at 34% (95% CI 25-42). The relative risk for field loss in vigabatrin-exposed patients was 4.0 (95% CI 2.9-5.5). Larger mean cumulative dose of vigabatrin and increasing age were associated with a higher proportion of patients with visual field loss. Vigabatrin should be reserved for patients with epilepsy for whom there is no other alternative or for patients who have determined the benefit of ongoing treatment to outweigh the risk of VAVFL.

Febrile infection–related epilepsy syndrome (FIRES): A nonencephalitic encephalopathy in childhood

Encephalitis is generally presumed, even when seizures follow banal febrile infection, and pathogen detection in cerebrospinal fluid fails. This retrospective multicenter case series reports on 22 previously healthy children aged 3-15 years (median 6.5 years) with prolonged or recurrent seizures occurring 2-14 days (median 5 days) after fever onset (19 children with respiratory or nonspecific infections). Cerebrospinal fluid studies revealed 2-42 cells/microl (median 5 cells/microl) and no pathogens. Electroencephalography showed diffuse slowing or multifocal discharges. Neuroimaging demonstrated normal findings in 10 children. Brain biopsies were performed in seven children showing gliosis but no inflammation. Anesthetic barbiturates were used in 14 children with refractory status epilepticus, and immunotherapy in 9. Two children died, eight remained in a state of impaired consciousness, eight developed therapy-refractory epilepsies, two had behavioral disturbances, and two recovered. The lack of evidence for encephalitis suggests another infection-related pathogenesis of this disastrous epileptic encephalopathy. Therefore, we propose the term "febrile infection-related epilepsy syndrome" (FIRES).

Fructose-1,6-diphosphate inhibits seizure acquisition in fast hippocampal kindling

Inhibition of glycolytic metabolism may provide a new therapy for refractory epilepsy. Fructose-1,6-diphosphate (FDP), which inhibits glycolysis and diverts glucose into the pentose phosphate pathway, has strong inhibitory action on seizures induced by chemical convulsants. Here, we investigated the effect of FDP on a rat model of rapid hippocampal kindling. After determining the after-discharge threshold (ADT), the seizure severity and after-discharge duration (ADD) were measured to study the antiepileptogenic effects of FDP (0.5 or 1.0 g/kg i.p. for 4 days). The mRNA expression levels of the brain-derived neurotrophic factor (BDNF) and its principal receptor TrkB, which are key modulators of seizure activity, were determined in the ipsilateral hippocampus by real-time polymerase chain reaction (RT-PCR). High-dose FDP (1.0 g/kg) delayed kindling development together with shortened ADD, and high-dose treated rats also needed more kindling stimulations and more cumulative ADD to stage 4. However, it showed no significant antiepileptogenic effect at a lower dose of 0.5 g/kg. In addition, FDP attenuated BDNF and TrkB expression before and during kindling procedure; this result indicated that BDNF/TrkB signaling pathway may participate in the antiepileptogenic action of FDP. Our data demonstrates that FDP has a significant antiepileptogenic effect in kindling seizures and that it may be a potential antiepileptic drug in the future.

Add-on lamotrigine in pediatric epilepsy in India

Lamotrigine is a newer antiepileptic drug useful as oral adjunctive therapy in refractory epilepsy. Indian data on use of lamotrigine is limited. This study was conducted to evaluate add-on lamotrigine in Indian children with epilepsy. Twenty children (median age 90 months) receiving lamotrigine as add-on therapy for mean 26.7 (19.1) months, were followed for a median period of 7.9 (6-10) months. Follow-up was done every two weeks. The most common seizures types were either generalized tonic-clonic (6, 30%) or myoclonic (8, 40%). The average dose used was 3.86 mg/kg/day (with concomitant valproate). Good response (>50% reduction) or complete seizure control was seen in 72% patients. Side effects were seen in 27.5% patients and were mild in more than half of these. Lamotrigine was stopped in two patients due to adverse reactions, which resolved on stopping the drug. Lamotrigine was observed to be an effective, add-on, broad-spectrum antiepileptic with 'mild' side effects in Indian children.

Carisbamate as adjunctive treatment of partial onset seizures in adults in two randomized, placebo‐controlled trials

To assess the efficacy, safety, and tolerability of the investigational drug carisbamate as adjunctive treatment for partial-onset seizures (POS). Two identical, randomized, placebo-controlled, double-blind studies were conducted in adults with POS uncontrolled for >or=1 year. Therapy-refractory epilepsy patients (>or=16 years) remained on stable doses of prescribed antiepileptic drugs (<or=2) for an 8-week prospective baseline phase and were then randomized (1:1:1) to carisbamate 200 mg/day, carisbamate 400 mg/day, or placebo, for a 12-week double-blind phase. Primary efficacy end points were percent reduction in seizure frequency and responder rate (patients with >or=50% reduction in POS frequency) during the double-blind phase compared with the prospective baseline phase. Of the 565 patients randomized in study 1, 93% completed the study; of the 562 randomized in study 2, 94% completed the study. Patient characteristics were similar across both studies and treatment arms: mean age, 35 years (study 1, range 16-75 years) and 36 years (study 2, range 16-74 years); approximately 50% were men. Treatment with carisbamate 400 mg/day resulted in significant improvement (p < 0.01) in both efficacy measures compared with placebo in study 1 but not in study 2. Carisbamate 200 mg/day did not differ statistically from placebo in either study. Among the most common treatment-emergent adverse events (>or=5% in any group), those with an incidence exceeding placebo (>or=3%) were dizziness (400 mg/day group) and somnolence. Carisbamate 400 mg/day was effective in patients with refractory partial-onset seizures in one of these global studies. More than 200 mg/day of carisbamate is required for efficacy. Carisbamate was well-tolerated in both studies.

Amygdala volume loss in patients with dysphoric disorder of epilepsy

A categorical approach to the study of amygdala volumes in specific neuropsychiatric disorders leads to contradictory findings. In an alternative dimensional approach, we tested the hypothesis that amygdala volume loss represents specific dimensions of affective syndromes in patients with epilepsy. One hundred sixty patients with chronic therapy-refractory epilepsy were carefully diagnosed for psychiatric symptoms. Fifty-three patients without any lifetime psychopathology ( n = 24), with dysphoric disorder of epilepsy ( n = 12), or with major depressive disorder ( n = 17) were included. Amygdala and hippocampal volumes were measured using established protocols. Amygdala volumes were significantly reduced in patients with dysphoric disorder of epilepsy and correlated significantly with core symptoms of dysphoric disorder of epilepsy, that is, emotional instability, dysphoria, irritability, and aggression. Our finding supports a dimensional concept of the meaning of brain alterations and validates the clinical concept of dysphoric disorder of epilepsy.

Neuropathology of focal epilepsies: A critical review

A broad spectrum of structural lesions can be histopathologically identified in surgical brain specimens obtained from patients with focal, therapy-refractory epilepsies. In our experience with 4512 tissue samples collected at the German Neuropathological Reference Center for Epilepsy Surgery, three clinicopathological entities are most common: mesial temporal sclerosis (40%), long-term epilepsy-associated tumors (27%), and malformations of cortical development (13%). Notwithstanding, a systematic histopathological and molecular-genetic analysis is mandatory to unravel the underlying pathogenic mechanism of epilepsy-associated lesions and may contribute to our current understanding of pharmacoresistance and epileptogenesis. However, an interdisciplinary approach is necessary to further explore predictive parameters with respect to postsurgical seizure relief and memory impairment, and also to identify new pharmacological targets.

Association of ABCB1 genetic variants 3435C&gt;T and 2677G&gt;T to ABCB1 mRNA and protein expression in brain tissue from refractory epilepsy patients

There is evidence from studies in rodents that P-glycoprotein (P-gp) overexpression is implicated in the causation of refractory epilepsy. Genetic variants in the human ABCB1 (MDR1) gene were shown to affect the expression levels of the transporter in various tissues and to be associated with refractory epilepsy. However, the effect of the genetic variants on the P-gp level in epileptogenic brain tissue is poorly investigated. In the present study, we examined the impact of putatively functional polymorphisms 3435C>T and 2677G>T in the ABCB1 gene on the ABCB1 mRNA expression and P-gp content in human brain tissue from epileptogenic foci of the patients with refractory epilepsy. Fresh brain tissue specimens were obtained from therapy-refractory epilepsy patients during neurosurgery of the epileptogenic focus. We determined the ABCB1 mRNA expression in 23 samples using 5' exonuclease-based real-time polymerase chain reaction (PCR) as well as the P-gp content in 32 samples determined by immunohistochemistry, genotyping was performed by PCR/restriction fragment length polymorphism (RFLP). There was lack of association of 3435C>T and 2677G>T as well as diplotype configurations on ABCB1 mRNA expression and P-gp content in epileptogenic brain tissues. We cannot exclude an association of ABCB1 variants on P-gp function, but our results suggest that brain ABCB1 mRNA and protein expression is not substantially influenced by major ABCB1 genetic variants thus explaining in part results from case-control studies obtaining lack of association of ABCB1 polymorphisms to the risk of refractory epilepsy.

Smooth mosaics

Lissencephaly (LIS) is a diffuse cortical malformation caused by an incomplete neuronal migration disorder in early brain development.1 There is a continuum of structural alterations ranging from complete agyria and thickened cortex to variable extent of agyria or pachygyria, and subcortical band heterotopia (SBH) as the mildest form.2 Severe phenotypes include marked mental retardation, therapy refractory epilepsy, and cerebral palsy leading to reduced life expectancy whereas milder phenotypes encompass less severe epilepsy and mild to moderate intellectual impairment. A majority of patients with a clinical and neuroradiologic manifestation of the lissencephaly spectrum harbor a mutation either in the LIS1 gene or in the doublecortin ( DCX or XLIS ) gene.3 Classic LIS (type I) is associated with mutations in the LIS1 gene whereas patients with typical SBH are prone to carry mutations in the X-chromosomal DCX …