Showing papers in "Epilepsy Currents in 2008"
TL;DR: It is suggested that neurobiological factors that confer increased disease severity lead to drug intractability, and the occurrence of frequent seizures at disease onset is an important factor that signals increased severity.
Abstract: For the most part, resistance to medications in epilepsy is independent of the choice of antiepileptic drug. This simple clinical observation constrains the possible biological mechanisms for drug refractory epilepsy by imposing a requirement to explain resistance for a diverse set of chemical structures that act on an even more varied group of molecular targets. To date, research on antiepileptic drug refractoriness has been guided by the “drug transporter overexpression” and the “reduced drug-target sensitivity” hypotheses. These concepts posit that drug refractoriness is a condition separate from the underlying epilepsy. Inadequacies in both hypotheses mandate a fresh approach to the problem. In this article, we propose a novel approach that considers epilepsy pharmacoresistance in terms of intrinsic disease severity. We suggest that neurobiological factors that confer increased disease severity lead to drug intractability. The occurrence of frequent seizures at disease onset is an important factor that signals increased severity.
124 citations
TL;DR: “Occasionally, after a fit, or after a series of fits, an attack of mental disturbance may come on which lasts for several days, or there may be hallucinations, with irritability and even violence.
Abstract: “Occasionally, after a fit, or, more frequently, after a series of fits, an attack of mental disturbance may come on which lasts for several days. It may be simply a demented state, or there may be hallucinations, with irritability and even violence (1).”
78 citations
TL;DR: Experimental data show that newly formed aberrant excitatory synapses on the granule cells of the fascia dentate operate by means of kainate receptor-operated signals that are not present on naivegranule cells, indicating that genuine epileptic networks rely on signaling cascades that differentiate them from naive networks.
Abstract: Do temporal lobe epilepsy (TLE) seizures in adults promote further seizures? Clinical and experimental data suggest that new synapses are formed after an initial episode of status epilepticus, however their contribution to the transformation of a naive network to an epileptogenic one has been debated. Recent experimental data show that newly formed aberrant excitatory synapses on the granule cells of the fascia dentate operate by means of kainate receptor-operated signals that are not present on naive granule cells. Therefore, genuine epileptic networks rely on signaling cascades that differentiate them from naive networks. Recurrent limbic seizures generated by the activation of kainate receptors and synapses in naive animals lead to the formation of novel synapses that facilitate the emergence of further seizures. This negative, vicious cycle illustrates the central role of reactive plasticity in neurological disorders.
62 citations
TL;DR: The question that needs to be clarified concerns clinical value: Do identification and localization of epileptiform discharges play an important role in the determination of epilepsy localization for surgery?
Abstract: Magnetoencephalography (MEG) has a long history of development for the application of epilepsy. Technical and clinical validation of spike source estimation has been demonstrated in most partial epilepsies. The question that needs to be clarified concerns clinical value: Do identification and localization of epileptiform discharges play an important role in the determination of epilepsy localization for surgery? EEG is the mainstay in the investigation of seizure disorders and will remain so because it alone possesses the attribute of long-term recordings that can capture seizures. In contrast, MEG has the unique capability of nearly instantaneous high-resolution recording, with detection sensitivity and spike localization precision beyond that of EEG. Do these distinctions matter from a clinical standpoint?
60 citations
TL;DR: This review presents the current state of the data on bioequivalence and therapeutic equivalence and proposes a series of studies to better clarify the risks of generic formulation substitution in susceptible populations.
Abstract: The Food and Drug Administration requires rigorous testing of generic formulations of antiepileptic drugs to assure bioequivalence to the brand product and asserts that all approved formulations are interchangeable. Physician surveys, case reports, and “switchback” rates from large-scale generic conversions imply that all generic formulations may not be equal to the brand drug for all patient groups. This review presents the current state of the data on bioequivalence and therapeutic equivalence and proposes a series of studies to better clarify the risks of generic formulation substitution in susceptible populations. Until such studies are completed, when switching to generic formulations, health-care providers and people with epilepsy would do well to proceed cautiously and understand the potential risks and benefits of substitution. Extra caution may be needed for patients at highest risk of seizure complications, such as the pregnant patient, patients with recurrent status epilepticus, or patients who have been seizure-free for long periods of time and are driving.
48 citations
TL;DR: Caramazepine and lamotrigine appear relatively safe; however, results are inconclusive concerning a specific risk for cleft lip/palate for both drugs as well as a dose-dependent effect for malformations associated with lamotigine.
Abstract: Recent studies demonstrate an increased teratogenic risk for valproate and a probable increased risk for phenobarbital. Carbamazepine and lamotrigine appear relatively safe; however, results are inconclusive concerning a specific risk for cleft lip/palate for both drugs as well as a dose-dependent effect for malformations associated with lamotrigine. Data regarding teratogenic risks for other antiepileptic drugs are inadequate. Additional studies are needed to delineate further the risks for all antiepileptic drugs and determine the underlying mechanisms.
33 citations
TL;DR: In human TLE with hippocampal sclerosis, astroglial, microglial and neuronal expression of C1q, C3c and C3d was observed particularly within regions where neuronal cell loss occurs, and the membrane attack protein complex (C5b-C9) was predominantly detected in activatedmicroglial cells.
Abstract: Aronica E, Boer K, van Vliet EA, Redeker S, Baayen JC, Spliet WG, van Rijen PC, Troost D, da Silva FH, Wadman WJ, Gorter JA. Neurobiol Dis 2007;26(3):497–511. We investigated the involvement of the complement cascade during epileptogenesis in a rat model of temporal lobe epilepsy (TLE), and in the chronic epileptic phase in both experimental as well as human TLE. Previous rat gene expression analysis using microarrays indicated prominent activation of the classical complement pathway which peaked at 1 week after SE in CA3 and entorhinal cortex. Increased expression of C1q, C3 and C4 was confirmed in CA3 tissue using quantitative PCR at 1 day, 1 week and 3–4 months after status epilepticus (SE). Upregulation of C1q and C3d protein expression was confirmed mainly to be present in microglia and in a few hippocampal neurons. In human TLE with hippocampal sclerosis, astroglial, microglial and neuronal (5/8 cases) expression of C1q, C3c and C3d was observed particularly within regions where neuronal cell loss occurs. The membrane attack protein complex (C5b-C9) was predominantly detected in activated microglial cells. The persistence of complement activation could contribute to a sustained inflammatory response and could destabilize neuronal networks involved.
27 citations
TL;DR: The data suggest that changes in the relative expression of NKCC1 and KCC2 in neurons having aberrant GABAergic hyperinnervation may contribute to epileptiform activity in the subicular regions adjacent to sclerotic areas of the hippocampus.
Abstract: Munoz A, Mendez P, DeFelipe J, Alvarez-Leefmans FJ. Epilepsia 2007;48(4):663–673. Intracellular chloride concentration, [Cl]i, determines the polarity of GABAA-induced neuronal Cl currents. In neurons, [Cl]i is set by the activity of Na+, K+, 2Cl cotransporters (NKCC) such as NKCC1, which physiologically accumulate Cl in the cell, and Cl extruding K+, Cl cotransporters like KCC2. Alterations in the balance of NKCC1 and KCC2 activity may determine the switch from hyperpolarizing to depolarizing effects of GABA, reported in the subiculum of epileptic patients with hippocampal sclerosis. We studied the expression of NKCC (putative NKCC1) and KCC2 in human normal temporal neocortex by Western blot analysis and in normal and epileptic regions of the subiculum and the hippocampus proper using immunocytochemistry. Western blot analysis revealed NKCC and KCC2 proteins in adult human neocortical membranes similar to those in rat neocortex. NKCC and KCC2 immunolabeling of pyramidal and nonpyramidal cells was found in normal and epileptic hippocampal formation. In the transition between the subiculum with sclerotic regions of CA1, known to exhibit epileptogenic activity, double immunolabeling of NKCC and KCC2 revealed that approximately 20% of the NKCC-immunoreactive neurons do not express KCC2. In these same areas, some neurons were distinctly hyperinnervated by parvalbumin (PV) positive hypertrophic basket formations that innervated mostly neurons expressing NKCC (74%) and to a lesser extent NKCC-immunonegative neurons (26%). Hypertrophic basket formations also innervated KCC2-positive (76%) and -negative (24%) neurons. The data suggest that changes in the relative expression of NKCC1 and KCC2 in neurons having aberrant GABAergic hyperinnervation may contribute to epileptiform activity in the subicular regions adjacent to sclerotic areas of the hippocampus.
Huberfeld G, Wittner L, Clemenceau S, Baulac M, Kaila K, Miles R, Rivera C. J Neurosci 2007;27(37):9866–9873. Changes in chloride (Cl−) homeostasis may be involved in the generation of some epileptic activities. In this study, we asked whether Cl− homeostasis, and thus GABAergic signaling, is altered in tissue from patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis. Slices prepared from this human tissue generated a spontaneous interictal-like activity that was initiated in the subiculum. Records from a minority of subicular pyramidal cells revealed depolarizing GABAA receptor-mediated postsynaptic events, indicating a perturbed Cl− homeostasis. We assessed possible contributions of changes in expression of the potassium–chloride cotransporter KCC2. Double in situ hybridization showed that mRNA for KCC2 was absent from 30% of CaMKII (calcium/calmodulin-dependent protein kinase II)-positive subicular pyramidal cells. Combining intracellular recordings with biocytin-filled electrodes and KCC2 immunochemistry, we observed that all cells that were hyperpolarized during interictal events were immunopositive for KCC2, whereas the majority of depolarized cells were immunonegative. Bumetanide, at doses that selectively block the chloride-importing potassium–sodium–chloride cotransporter NKCC1, produced a hyperpolarizing shift in GABAA reversal potentials and suppressed interictal activity. Changes in Cl− transporter expression thus contribute to human epileptiform activity, and molecules acting on these transporters may be useful antiepileptic drugs.
22 citations
TL;DR: It is shown that autocrine/paracrine γ-aminobutyric acid (GABA) signalling by means of GABAA receptors negatively controls ES cell and peripheral neural crest stem (NCS) cell proliferation, preimplantation embryonic growth and proliferation in the boundary-cap stemcell niche, resulting in an attenuation of neuronal progenies from this stem cell niche.
Abstract: HISTONE H2AX-DEPENDENT GABAA RECEPTOR REGULATION OF STEM CELL PROLIFERATION: Andang M, Hjerling-Leffler J, Moliner A, Lundgren TK, Castelo-Branco G, Nanou E, Pozas E, Bryja V, Halliez S, Nishimaru H, Wilbertz J, Arenas E, Koltzenburg M, Charnay P, El Manira A, Ibanez CF, Ernfors P. Nature20084517177:460-46418185516 Stem cell self-renewal implies proliferation under continued maintenance of multipotency. Small changes in numbers of stem cells may lead to large differences in differentiated cell numbers, resulting in significant physiological consequences. Proliferation is typically regulated in the G1 phase, which is associated with differentiation and cell cycle arrest. However, embryonic stem (ES) cells may lack a G1 checkpoint. Regulaton of proliferation in the "DNA damage" S/G2 cell cycle checkpoint pathway is known for its role in the maintenance of chromatin structural integrity. Here we show that autocrine/paracrine gamma-aminobutyric acid (GABA) signalling by means of GABA(A) receptors negatively controls ES cell and peripheral neural crest stem (NCS) cell proliferation, preimplantation embryonic growth and proliferation in the boundary-cap stem cell niche, resulting in an attenuation of neuronal progenies from this stem cell niche. Activation of GABA(A) receptors leads to hyperpolarization, increased cell volume and accumulation of stem cells in S phase, thereby causing a rapid decrease in cell proliferation. GABA(A) receptors signal through S-phase checkpoint kinases of the phosphatidylinositol-3-OH kinase-related kinase family and the histone variant H2AX. This signalling pathway critically regulates proliferation independently of differentiation, apoptosis and overt damage to DNA. These results indicate the presence of a fundamentally different mechanism of proliferation control in these stem cells, in comparison with most somatic cells, involving proteins in the DNA damage checkpoint pathway.
21 citations
TL;DR: The data do not support the idea that administration of LEV after SE prevents or reduces the long-term alterations developing after such brain insult in rats, and the behavioral alterations, e.g., behavioral hyperexcitability and learning deficits, in epileptic rats were not affected by treatment with LEv after SE.
Abstract: Brandt C, Glien M, Gastens AM, Fedrowitz M, Bethmann K, Volk HA, Potschka H, Loscher W. Neuropharmacology 2007;53(2):207–221. Levetiracetam (LEV) is a structurally novel antiepileptic drug (AED) which has demonstrated a broad spectrum of anticonvulsant activities both in experimental and clinical studies. Previous experiments in the kindling model suggested that LEV, in addition to its seizure-suppressing activity, may possess antiepileptogenic or disease-modifying activity. In the present study, we evaluated this possibility by using a rat model in which epilepsy with spontaneous recurrent seizures (SRS), behavioral alterations, and hippocampal damages develop after a status epilepticus (SE) induced by sustained electrical stimulation of the basal amygdala. Two experimental protocols were used. In the first protocol, LEV treatment was started 24 h after onset of electrical amygdala stimulation without prior termination of the SE. In the second protocol, the SE was interrupted after 4 h by diazepam, immediately followed by onset of treatment with LEV. Treatment with LEV was continued for 8 weeks (experiment #1) or 5 weeks (experiment #2) after SE, using continuous drug administration via osmotic minipumps. The occurrence of SRS was recorded during and after treatment. In addition, the rats were tested in a battery of behavioral tests, including the elevated-plus maze and the Morris water maze. Finally, the brains of the animals were analyzed for histological lesions in the hippocampal formation. With the experimental protocols chosen for these experiments, LEV did not exert antiepileptogenic or neuroprotective activity. Furthermore, the behavioral alterations, e.g., behavioral hyperexcitability and learning deficits, in epileptic rats were not affected by treatment with LEV after SE. These data do not support the idea that administration of LEV after SE prevents or reduces the long-term alterations developing after such brain insult in rats.
19 citations
TL;DR: In this article, diffusion tensor imaging evaluates the motion of water at the voxel level and can provide data on the structural integrity of brain tissue, with quantitative measures of diffusion and fractional anisotropy.
Abstract: Diffusion tensor imaging evaluates the motion of water at the voxel level and can provide data on the structural integrity of brain tissue, with quantitative measures of diffusion and fractional anisotropy. Imaging of the orientation of preferential diffusion of water in the brain can visualize major white matter pathways and infer the structural basis of cerebral networks. Thus, how these pathways and networks may be altered in specific epilepsy syndromes and in consequence to therapies can be assessed with the aid of these images.
TL;DR: Individuals with epilepsy have a higher risk of suicide, even if coexisting psychiatric disease, demographic differences, and socioeconomic factors are taken into account.
Abstract: Christensen J, Vestergaard M, Mortensen PB, Sidenius P, Agerbo E. Lancet Neurology 2007;6(8):693–698. BACKGROUND: Studies have linked epilepsy with an increased suicide risk, but the association might be modified by psychiatric, demographic, and socioeconomic factors. METHODS: Suicide cases were identified in the Cause of Death Register in Denmark from 1981 to 1997. Up to 20 controls, matched by sex, birth year, and calendar date, were assigned to each suicide case. FINDINGS: We identified 21,169 cases of suicide and 423,128 controls. In total, 492 (2.32%) individuals who committed suicide had epilepsy compared with 3,140 (0.74%) controls, corresponding to a three times higher risk (rate ratio [RR] 3.17 [95% CI 2.88–3.50]; p < 0.0001). The RR remained high after excluding those with a history of psychiatric disease and adjusting for socioeconomic factors (1.99, 1.71–2.32; p < 0.0001). The highest risk of suicide was identified in patients with epilepsy and comorbid psychiatric disease, even after adjusting for socioeconomic factors (13.7, 11.8–16.0; p < 0.0001). In individuals with epilepsy, the highest risk of suicide was found during the first half year after diagnosis was made (5.35, 3.43–8.33; p < 0.0001), and was especially high in those with a history of comorbid psychiatric disease (29.2, 16.4–51.9; p < 0.0001). INTERPRETATION: Individuals with epilepsy have a higher risk of suicide, even if coexisting psychiatric disease, demographic differences, and socioeconomic factors are taken into account. Our study identifies people with newly diagnosed epilepsy as a vulnerable group that require special attention.
Mainio A, Alamaki K, Karvonen K, Hakko H, Sarkioja T, Rasanen P. Epilepsy Behav 2007 11:389–393. Patients with epilepsy are known to have comorbid affective disorders and a higher risk for suicide compared with the general population. Epilepsy, depression, and suicidal behavior have been shown to have common pathogenic mechanisms in their etiology. We evaluated the association between epilepsy, suicidal behavior, and depression by using the comprehensive database of all suicides (n= 1,877) committed in northern Finland during the years 1988–2002 with information on all hospital-treated somatic and psychiatric disorders. Hospital-treated epilepsy occurred in 1.3% of the victims. Compared with other suicide victims, those with epilepsy were more often female, were older, and had significantly more often suffered from depression. Epilepsy was first diagnosed 8.8 (3.9–11.6) years before suicide, and depression, about 1 year after epilepsy diagnosis. Interictal depression among patients with chronic epilepsy is often classified as atypical or chronic depression, or it can mimic a dysthymic disorder. Therefore, diagnosis and treatment of depression among patients with epilepsy constitute a great challenge in clinical practice.
TL;DR: It is revealed that VEGF is dramatically up-regulated in neurons and glia in hippocampus, thalamus, amygdala, and neocortex 24 h after status epilepticus, suggesting that V EGF may play a neuroprotective role following status epileptus.
Abstract: Nicoletti JN, Shah SK, McCloskey DP, Goodman JH, Elkady A, Atassi H, Hylton D, Rudge JS, Scharfman HE, Croll SD. Neuroscience 2008;151(1):232–241. Vascular endothelial growth factor (VEGF) is a protein factor which has been found to play a significant role in both normal and pathological states. Its role as an angiogenic factor is well-established. More recently, VEGF has been shown to protect neurons from cell death both in vivo and in vitro. While VEGF's potential as a protective factor has been demonstrated in hypoxia–ischemia, in vitro excitotoxicity, and motor neuron degeneration, its role in seizure-induced cell loss has received little attention. A potential role in seizures is suggested by Newton et al.'s [Newton SS, Collier EF, Hunsberger J, Adams D, Terwilliger R, Selvanayagam E, Duman RS (2003) Gene profile of electroconvulsive seizures: Induction of neurotrophic and angiogenic factors. J Neurosci 23:10841–10851] finding that VEGF mRNA increases in areas of the brain that are susceptible to cell loss after electroconvulsive-shock induced seizures. Because a linear relationship does not always exist between expression of mRNA and protein, we investigated whether VEGF protein expression increased after pilocarpine-induced status epilepticus. In addition, we administered exogenous VEGF in one experiment and blocked endogenous VEGF in another to determine whether VEGF exerts a neuroprotective effect against status epilepticus-induced cell loss in one vulnerable brain region, the rat hippocampus. Our data revealed that VEGF is dramatically up-regulated in neurons and glia in hippocampus, thalamus, amygdala, and neocortex 24 h after status epilepticus. VEGF induced significant preservation of hippocampal neurons, suggesting that VEGF may play a neuroprotective role following status epilepticus.
TL;DR: The data suggest that post-traumatic seizures represent a therapeutic target for patients with traumatic brain injury and suggest that intracranial pressure and lactate/pyruvate ratio remained elevated beyond postinjury hour 100 in the seizure group but not the nonseizure group.
Abstract: Vespa PM, Miller C, McArthur D, Eliseo M, Etchepare M, Hirt D, Glenn TC, Martin N, Hovda D. Crit Care Med 2007; [Epub ahead of print]. OBJECTIVE: To determine whether nonconvulsive electrographic post-traumatic seizures result in increases in intracranial pressure and microdialysis lactate/pyruvate ratio. DESIGN: Prospective monitoring with retrospective data analysis. SETTING: Single center academic neurologic intensive care unit. PATIENTS: Twenty moderate to severe traumatic brain injury patients (Glasgow Coma Score 3–13). MEASUREMENTS AND MAIN RESULTS: Continuous electroencephalography and cerebral microdialysis were performed for 7 days after injury. Ten patients had seizures and were compared with a matched cohort of traumatic brain injury patients without seizures. The seizures were repetitive and constituted status epilepticus in seven of ten patients. Using a within-subject design, post-traumatic seizures resulted in episodic increases in intracranial pressure (22.4 ± 7 vs. 12.8 ± 4.3 mm Hg; p < .001) and an episodic increase in lactate/pyruvate ratio (49.4 ± 16 vs. 23.8 ± 7.6; p < .001) in the seizure group. Using a between-subjects comparison, the seizure group demonstrated a higher mean intracranial pressure (17.6 ± 6.5 vs. 12.2 ± 4.2 mm Hg; p < .001), a higher mean lactate/pyruvate ratio (38.6 ± 18 vs. 27 ± 9; p < .001) compared with nonseizure patients. The intracranial pressure and lactate/pyruvate ratio remained elevated beyond postinjury hour 100 in the seizure group but not the nonseizure group (p < .02). CONCLUSION: Post-traumatic seizures result in episodic as well as long-lasting increases in intracranial pressure and microdialysis lactate/pyruvate ratio. These data suggest that post-traumatic seizures represent a therapeutic target for patients with traumatic brain injury.
TL;DR: Findings suggest that TPM, unlike LEV, may impair frontal lobe functions, and the lack of cognitive side effects related to LEV treatment may be relevant for treatment decisions.
Abstract: Gomer B, Wagner K, Frings L, Saar J, Carius A, Harle M, Steinhoff BJ, Schulze-Bonhage A. Epilepsy Behav 2007;10(3):486–494. Levetiracetam (LEV) and topiramate (TPM) are considered highly effective novel antiepileptic drugs (AEDs) in the treatment of focal epilepsies. To explore potential side effects, this study investigated their influence on cognitive functions comparatively by means of a standardized neuropsychological test battery assessing several cognitive domains. In this observational study, cognitive changes were explored in 30 consecutively recruited patients with focal epilepsy treated with LEV and in 21 patients treated with TPM, comparing functions assessed prior to gradual initiation and after reaching steady state of the individual target dosage. Before titration, patient groups did not differ significantly with respect to cognitive performance. Whereas the LEV group manifested no change in cognitive performance after AED titration, the TPM group worsened in the cognitive domains of cognitive speed and verbal fluency, as well as short-term memory. These findings suggest that TPM, unlike LEV, may impair frontal lobe functions. The lack of cognitive side effects related to LEV treatment may be relevant for treatment decisions.
TL;DR: The results demonstrate that relatively brief excitatory events, not producing visible cell damage, can nevertheless cause long-lasting changes in hippocampal physiology, observable as impairments in place-cell function, LTP and spatial memory.
Abstract: Zhou JL, Shatskikh TN, Liu X, Holmes GL. Eur J Neurosci 2007;25(12):3667-3677. Patients with epilepsy are at substantial risk for memory impairment. Animal studies have paralleled these clinical observations, demonstrating impaired hippocampal function as measured by spatial memory in rodents subjected to seizures. However, the mechanism of seizure-induced hippocampal impairment is unclear. Here we investigated the effects of recurrent seizures on water-maze performance, a behavioural measure of learning and memory, long-term potentiation (LTP; considered a test of synaptic plasticity and memory) and place-cell firing patterns, a single-cell indicator of spatial memory. LTP and CA1 place-cell activity were examined in separate groups of freely moving rats, before and after 10 flurothyl-induced seizures. Water maze performance was examined in a third group of rats, five with previously induced seizures and five controls. Recurrent flurothyl seizures were associated with marked impairment in LTP and a reduction in the frequency of the peak theta power. Compared to baseline recordings, place-cell firing patterns following recurrent seizures were significantly less precise, had lower firing rates and were less stable. Impaired place-cell firing was seen as early as after two seizures and persisted at least 72 h after the last seizure. Water-maze performance was also significantly impaired in animals that underwent recurrent seizures. No cell loss or synaptic reorganization was observed in the hippocampus or in several other cortical areas that are vulnerable to seizures. These results demonstrate that relatively brief excitatory events, not producing visible cell damage, can nevertheless cause long-lasting changes in hippocampal physiology, observable as impairments in place-cell function, LTP and spatial memory.
TL;DR: HLA-B*1502 was associated with severe cutaneous reactions (SCR) induced by AEDs, which included carbamazepine, phenytoin, and lamotrigine, but was not associated with maculopapular exanthema (MPE) (p = 0.32).
Abstract: Association between HLA-B* 1502 Allele and Antiepileptic Drug-Induced Cutaneous Reactions in Han Chinese. Man CB, Kwan P, Baum L, Yu E, Lau KM, Cheng AS, Ng MH. Epilepsia 2007;48(5):1015–1018. A pr...
TL;DR: In mouse TSC models, rapamycin can prevent seizures and improve learning task performance, and provide new hope for TSC patients suffering from intractable seizures and possibly, for those with autism and cognitive disabilities.
Abstract: The recent development of several mouse models for tuberous sclerosis complex (TSC) provides in vivo systems to test new therapies for the neurological manifestations of TSC. Rapamycin is known to antagonize the effects of loss of TSC protein function in vitro and in mouse TSC models, rapamycin can prevent seizures and improve learning task performance. These findings provide new hope for TSC patients suffering from intractable seizures and possibly, for those with autism and cognitive disabilities.
TL;DR: The increased prevalence of psychiatric comorbidity antedating epilepsy onset may be consistent with the presence of underlying neurobiological influences independent of seizures, epilepsy syndrome, and medication treatment.
Abstract: Jones JE, Watson R, Sheth R, Caplan R, Koehn M, Seidenberg M, Hermann B. Dev Med Child Neurol 2007;49(7):493–497. The aim of this study was to characterize the distribution, timing, and risk factors for psychiatric comorbidity in children with recent onset epilepsy. Children aged 8 to 18 years with recent onset epilepsy (<1 year in duration) of idiopathic etiology (n= 53) and a healthy comparison group (n= 50) underwent a structured psychiatric diagnostic interview to characterize the spectrum of lifetime-to-date history of comorbid psychiatric disorder. There was no significant difference between the children with recent onset epilepsy and healthy comparison children in sex (31 males, 22 females vs 23 males, 27 females) or mean age 12.7y [SD 3.3] vs 12.7y [SD 3.2]). Children with recent onset epilepsy exhibited an elevated rate of lifetime-to-date Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) Axis I disorders compared with the comparison group. They showed significantly higher rates of depressive disorders (22.6 vs. 4%, p= 0.01), anxiety disorders (35.8 vs 22%, p<0.05), and attention-deficit-hyperactivity disorder (26.4 vs 10%, p= 0.01) with elevated but less prevalent rates of oppositional defiant and tic disorders. A subset of children with epilepsy (45%) exhibited DSM-IV Axis I disorders before the first recognized seizure, suggesting the potential influence of antecedent neurobiological factors that remain to be identified. The increased prevalence of psychiatric comorbidity antedating epilepsy onset may be consistent with the presence of underlying neurobiological influences independent of seizures, epilepsy syndrome, and medication treatment.
TL;DR: Dramatic in vivo findings demonstrate that seizures produce acute dendritic injury in neocortical neurons via calcineurin-dependent regulation of the actin cytoskeleton, suggesting novel therapeutic targets for preventing seizure-induced brain injury.
Abstract: Zeng LH, Xu L, Rensing NR, Sinatra PM, Rothman SM, Wong M. J Neurosci 2007;27(43):11604–11613. Seizures may cause brain injury via a variety of mechanisms, potentially contributing to cognitive deficits in epilepsy patients. Although seizures induce neuronal death in some situations, they may also have “nonlethal” pathophysiological effects on neuronal structure and function, such as modifying dendritic morphology. Previous studies involving conventional fixed tissue analysis have demonstrated a chronic loss of dendritic spines after seizures in animal models and human tissue. More recently, in vivo time-lapse imaging methods have been used to monitor acute changes in spines directly during seizures, but documented spine loss only under severe conditions. Here, we examined effects of secondary generalized seizures induced by kainate, on dendritic structure of neocortical neurons using multiphoton imaging in live mice in vivo and investigated molecular mechanisms mediating these structural changes. Higher-stage kainate-induced seizures caused dramatic dendritic beading and loss of spines within minutes, in the absence of neuronal death or changes in systemic oxygenation. Although the dendritic beading improved rapidly after the seizures, the spine loss recovered only partially over a 24 h period. Kainate seizures also resulted in activation of the actin-depolymerizing factor, cofilin, and a corresponding decrease in filamentous actin, indicating that depolymerization of actin may mediate the morphological dendritic changes. Finally, an inhibitor of the calcium-dependent phosphatase, calcineurin, antagonized the effects of seizures on cofilin activation and spine morphology. These dramatic in vivo findings demonstrate that seizures produce acute dendritic injury in neocortical neurons via calcineurin-dependent regulation of the actin cytoskeleton, suggesting novel therapeutic targets for preventing seizure-induced brain injury.
TL;DR: It is demonstrated that decreased expression of KCC2 persists for weeks after an epileptogenic injury, reducing inhibitory efficacy and enhancing dentate granule cell excitability, which may constitute a significant mechanism linking injury to the subsequent development of epilepsy.
Abstract: Pathak HR, Weissinger F, Terunuma M, Carlson GC, Hsu FC, Moss SJ, Coulter DA. J Neurosci 2007;27(51):14012–14022. GABAA receptor-mediated inhibition depends on the maintenance of intracellular Cl− concentration ([Cl−]in) at low levels. In neurons in the developing CNS, [Cl−]in is elevated, EGABA is depolarizing, and GABA consequently is excitatory. Depolarizing GABAergic synaptic responses may be recapitulated in various neuropathological conditions, including epilepsy. In the present study, rat hippocampal dentate granule cells were recorded using gramicidin perforated patch techniques at varying times (1–60 d) after an epileptogenic injury, pilocarpine-induced status epilepticus (STEP). In normal, non-epileptic animals, these strongly inhibited dentate granule cells act as a gate, regulating hippocampal excitation, controlling seizure initiation and/or propagation. For 2 weeks after STEP, we found that EGABA was positively shifted in granule cells. This shift in EGABA altered synaptic integration, increased granule cell excitability, and resulted in compromised “gate” function of the dentate gyrus. EGABA recovered to control values at longer latencies post-STEP (2–8 weeks), when animals had developed epilepsy. During this period of shifted EGABA, expression of the Cl− extruding K+/Cl− cotransporter, KCC2 was decreased. Application of the KCC2 blocker, furosemide, to control neurons mimicked EGABA shifts evident in granule cells post-STEP. Furthermore, post-STEP and furosemide effects interacted occlusively, both on EGABA in granule cells, and on gatekeeper function of the dentate gyrus. This suggests a shared mechanism, reduced KCC2 function. These findings demonstrate that decreased expression of KCC2 persists for weeks after an epileptogenic injury, reducing inhibitory efficacy and enhancing dentate granule cell excitability. This pathophysiological process may constitute a significant mechanism linking injury to the subsequent development of epilepsy.
TL;DR: Short gestational age, low birth weight, and intrauterine growth restriction are associated with an increased risk of epilepsy, and the association was modified by age but remained into early adulthood.
Abstract: OBJECTIVE: To examine outcome and explore for prognostic markers in a cohort <10 years following neonatal seizures. METHODS: We prospectively diagnosed clinical neonatal seizures with high specificity for true epileptic seizures in a population-based setting of all live newborns in the province of Newfoundland, Canada, between 1990 and 1995. Children with neonatal seizures were followed by specialized provincial health services. Follow-up data were collected on epilepsy, physical and cognitive impairments, and other heath issues. RESULTS: Data were available on 82 out of 90 subjects. We added information on six others whose outcome was clearly predictable from earlier information. Prognosis was better for term than for preterm infants (p= 0.003): term: 28 (45%) normal, 10 (16%) deaths, and 24 (39%) with impairments; preterm: 3 (12%) normal, 11 (42%) deaths, and 12 (46%) with impairments. Of survivors, 17 (27%) developed epilepsy, 16 (25%) had cerebral palsy, 13 (20%) had mental retardation, and 17 (27%) had learning disorders. Variables associated with poor prognosis were Sarnat stage III or equivalent severe encephalopathy, cerebral dysgenesis, complicated intraventricular hemorrhage, infections in the preterm infants, abnormal neonatal EEGs, and the need for multiple drugs to treat the neonatal seizures. Pure clonic seizures without facial involvement in term infants suggested favorable outcome, whereas generalized myoclonic seizures in preterm infants were associated with mortality. CONCLUSIONS: Poor prognosis for premature infants with seizures is reflected in high rates of subsequent long-term disability and mortality. The severity and timing of the pathologic process continue to be the major determinants for outcome.
The authors evaluated the association between gestational age, birth weight, intrauterine growth, and epilepsy in a population-based cohort of 1.4 million singletons born in Denmark (1979–2002). A total of 14,334 inpatients (1979–2002) and outpatients (1995–2002) with epilepsy were registered in the Danish National Hospital Register. Children who were potentially growth restricted were identified through two methods: 1) sex-, birth-order-, and gestational-age-specific z score of birth weight; and 2) deviation from the expected birth weight estimated based on the birth weight of an older sibling. The incidence rates of epilepsy increased consistently with decreasing gestational age and birth weight. The incidence rate ratios of epilepsy in the first year of life were more than fivefold among children born at 22–32 weeks compared with 39–41 weeks and among children whose birth weight was <2,000 g compared with 3,000–3,999 g. The association was modified by age but remained into early adulthood. Incidence rate ratios of epilepsy were increased among children identified as growth restricted according to either of the two methods. In conclusion, short gestational age, low birth weight, and intrauterine growth restriction are associated with an increased risk of epilepsy.
TL;DR: Protective interactions between pathogenic ion channel variants may markedly alter the clinical expression of epilepsy, highlighting the need for comprehensive profiling of this candidate gene set to improve the accuracy of genetic risk assessment of this complex disease.
Abstract: Glasscock E, Qian J, Yoo JW, Noebels JL. Nat Neurosci 2007;10(12):1554–1558. Inherited errors in ion channel genes comprise the largest subset of monogenic causes of idiopathic epilepsy, and pathogenic variants contribute to genetic risk in the complex inheritance of this common disorder. We generated a digenic mouse model of human idiopathic epilepsy by combining two epilepsy-associated ion channel mutations with mutually opposing excitability defects and overlapping subcellular localization. We found that increasing membrane excitability by removing Shaker-like K+ channels, which are encoded by the Kcna1 gene, masked the absence epilepsy caused by a P/Q-type Ca2+ channelopathy due to a missense mutation in the Cacna1a gene. Conversely, decreasing network excitability by impairing Cacna1a Ca2+-channel function attenuated limbic seizures and sudden death in Kcna1-null mice. We also identified intermediate excitability phenotypes at the network and axonal levels. Protective interactions between pathogenic ion channel variants may markedly alter the clinical expression of epilepsy, highlighting the need for comprehensive profiling of this candidate gene set to improve the accuracy of genetic risk assessment of this complex disease.
TL;DR: Adjunctive levetiracetam is an effective and well-tolerated antiepileptic drug for treating generalized tonic-clonic seizures in patients with idiopathic generalized epilepsies.
Abstract: Berkovic SF, Knowlton RC, Leroy RF, Schiemann J, Falter U; On behalf of the Levetiracetam N01057 Study Group. Neurology. 2007;68 [Epub ahead of print]. OBJECTIVE: To assess the efficacy and tolerability of adjunctive levetiracetam in patients with uncontrolled generalized tonic-clonic (GTC) seizures associated with idiopathic generalized epilepsies (IGE). METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study enrolled adults and children (4 to 65 years) with IGE experiencing 3 GTC seizures during the 8-week baseline period (4-week retrospective and 4-week prospective), despite receiving stable doses of one or two antiepileptic drugs (AEDs). Patients were randomized to levetiracetam (target dose 3,000 mg/day for adults; 60 mg/kg/day for children) or placebo and a 4-week titration period was followed by a 20-week evaluation period. RESULTS: Of 229 patients screened, 164 were randomized (levetiracetam, n = 80; placebo, n = 84). Levetiracetam produced a greater mean reduction in GTC seizure frequency per week over the treatment period (56.5%) than placebo (28.2%; p= 0.004). The percentage of patients who had 50% reduction of GTC seizure frequency per week (responders) during the treatment period was 72.2% for levetiracetam and 45.2% for placebo (p < 0.001; OR 3.28; 95% CI 1.68 to 6.38). During the first 2-week treatment 64.6% of patients on levetiracetam and 45.2% on placebo (p= 0.018) were classified as responders. During the evaluation period the percent of patients free of GTC seizures (34.2% vs 10.7%; p < 0.001) and all seizure types (24.1% vs 8.3%; p= 0.009) was greater for levetiracetam than placebo. Levetiracetam was well tolerated with 1.3% of patients discontinuing therapy due to adverse events vs 4.8% on placebo. CONCLUSION: Adjunctive levetiracetam is an effective and well-tolerated antiepileptic drug for treating generalized tonic-clonic seizures in patients with idiopathic generalized epilepsies.
TL;DR: VPA seems to be a safe, effective treatment of SE/SA, but efficacy is dependent on time lapse between symptoms and VPA treatment, and administration of a sufficiently high loading dose.
Abstract: Olsen KB, Tauboll E, Gjerstad L. Acta Neurol Scand Suppl 2007;187:51–54. OBJECTIVE: Status epilepticus (SE) and serial attacks (SA) represent neurological emergencies, and mortality rate for SE/SA is high, ranging from 3% to 25%, depending on cause and co-morbidity. As SE/SA become more refractory to treatment over time, rapid, appropriate treatment is extremely important. Here, we report a prospective registration of the effect of intravenous (IV) valproate (VPA) on SE/SA in a group of Norwegian patients. PATIENTS AND METHODS: Forty-one adult patients (18 males, 23 females) were included in the study. All had previously been unsuccessfully treated with diazepam. For 19, the main SE/SA seizure type was generalized tonic-clonic, while 16 had complex-partial seizures. Six had seizures that were difficult to classify. The treatment protocol recommended 25 mg/kg of VPA loading dose over 30 min, followed by continuous infusion of 100 mg/h for at least 24 h, then per oral administration. If seizures persisted after the loading dose, general anaesthesia (barbiturates/propofol/midazolam) was administered. RESULTS: No serious side effects were reported. In 76% of the cases (31 of 41), SE/SA stopped and anaesthesia was not required. Of the patients treated within 3 h, only 5% needed anaesthesia, whereas of those treated after 3–24 h, 38% needed anaesthesia. Of those who waited for more than 24 h before treatment, 60% required anaesthesia. Furthermore, 60% of the patients who needed anaesthesia were given loading doses below 2100 mg. CONCLUSIONS: VPA seems to be a safe, effective treatment of SE/SA, but efficacy is dependent on time lapse between symptoms and VPA treatment, and administration of a sufficiently high loading dose.
TL;DR: A specific attack by cytotoxic T lymphocytes is suggested as a possible mechanism responsible for astrocytic degeneration in RE and the loss of astracytes might play a role in neuronal dysfunction, seizure induction, and enhancement of neuronal cell death.
Abstract: Astrocytes Are a Specific Immunological Target in Rasmussen's Encephalitis. Bauer J, Elger CE, Hans VH, Schramm J, Urbach H, Lassmann H, Bien CH. Ann Neurol 2007;62(1):67–80.ObjectiveThe current hi...
TL;DR: The results indicate that adjunctive VNS therapy is a favorable treatment option for patients with drug-resistant IGE.
Abstract: Is Vagus Nerve Stimulation a Treatment Option for Patients with Drug-Resistant Idiopathic Generalized Epilepsy? Kostov H, Larsson PG, Roste GK. Acta Neurol Scand Suppl 2007;187:55–58.BackgroundThe ...
TL;DR: The experiments in a slice mimicked epileptic and cognitive dysfunction induced by thrombin in the brain, and suggest that these effects are mediated by activation of the PAR1 receptor.
Abstract: Maggio N, Shavit E, Chapman J, Segal M. J Neurosci 2008;28(3):732–736. The effects of thrombin, a blood coagulation serine protease, were studied in rat hippocampal slices, in an attempt to comprehend its devastating effects when released into the brain after stroke and head trauma. Thrombin acting through its receptor, protease-activated receptor 1 (PAR1), produced a long-lasting enhancement of the reactivity of CA1 neurons to afferent stimulation, an effect that saturated the ability of the tissue to undergo tetanus-induced long-term potentiation. This effect was mediated by activation of a PAR1 receptor, because it was shared by a PAR1 agonist, and was blocked by its selective antagonist. An independent effect of thrombin involved the lowering of the threshold for generating epileptic seizures in CA3 region of the hippocampus. Thus, the experiments in a slice mimicked epileptic and cognitive dysfunction induced by thrombin in the brain, and suggest that these effects are mediated by activation of the PAR1 receptor.
TL;DR: The data indicate that substrate recognition or transport efficacy by P-gp differs between human and mouse for certain AEDs, and that multidrug resistance proteins (MRPs) have been proposed to be involved in the efflux transport of VPA at the BBB.
Abstract: Baltes S, Gastens AM, Fedrowitz M, Potschka H, Kaever V, Loscher W. Neuropharmacology 2007;52(2):333–346. In view of the important role of P-glycoprotein (P-gp) and other drug efflux transporters for drug distribution and resistance, the identification of compounds as substrates of P-gp-mediated transport is one of the key issues in drug discovery and development, particularly for compounds acting on the central nervous system. In vitro transport assays with P-gp-transfected kidney cell lines are widely used to evaluate the potential of compounds to act as P-gp substrates or inhibitors. Furthermore, such cell lines are also frequently utilized as a substitute for more labor-intensive in vitro or in vivo models of the blood–brain barrier (BBB). Overexpression of P-gp or members of the multidrug resistance protein (MRP) family at the BBB has been implicated in the mechanisms underlying resistance to antiepileptic drugs (AEDs) in patients with epilepsy. Therefore, it is important to know which AEDs are substrates for P-gp or MRPs. In the present study, we used monolayers of polarized MDCKII dog kidney or LLC-PK1 pig kidney cells transfected with cDNA containing either human MDR1, MRP2 or mouse mdr1a and mdr1b sequences to measure the directional transport of AEDs. Cyclosporin A (CsA) and vinblastine were used as reference standards for P-gp and MRP2, respectively. The AEDs phenytoin and levetiracetam were directionally transported by mouse but not human P-gp, whereas CsA was transported by both types of P-gp. Carbamazepine was not transported by any type of P-gp and did not inhibit the transport of CsA. In contrast to vinblastine, none of the AEDs was transported by MRP2 in transfected kidney cells. The data indicate that substrate recognition or transport efficacy by P-gp differs between human and mouse for certain AEDs. Such species differences, which are certainly not restricted to human and mouse, may explain, at least in part, the controversial data that have been previously reported for AED transport by P-gp in preparations from different species. However, because transport efficacy of efflux transporters such as P-gp or MRP2 may not only differ between species but also between tissues, the present data do not exclude that the AEDs examined are weak substrates of P-gp or MRP2 at the human BBB.
Baltes S, Fedrowitz M, Tortos CL, Potschka H, Loscher W. J Pharmacol Exp Ther 2007;320(1):331–343. The antiepileptic drug valproic acid (VPA) is widely used in the treatment of epilepsy, bipolar disorders, and migraine. However, rather high doses are required for the clinical effects of VPA, which is due to its relatively inefficient delivery to the brain. The poor brain distribution of VPA is thought to reflect an asymmetric transport system at the blood–brain barrier (BBB). Based on recent data from in vitro experiments, multidrug resistance proteins (MRPs) have been proposed to be involved in the efflux transport of VPA at the BBB. In the present study, we used different experimental in vitro and in vivo strategies to evaluate whether VPA is a substrate for MRPs or the efflux transporter P-glycoprotein (P-gp). In contrast to known P-gp or MRP substrates, such as cyclosporin A or vinblastine, no directional transport of VPA was observed in cell monolayer efflux assays using the kidney cell lines Madin Darby canine kidney II and LLC-PK1, which had been transfected with either human or mouse cDNAs for the genes encoding P-gp, MRP1, or MRP2. Likewise, no indication for efflux transport of VPA was obtained in a rat microdialysis model, using inhibitors of either P-gp or MRPs. Furthermore, a significant role of MRP2 in brain efflux of VPA was excluded by using MRP2-deficient rats. Our data do not support the hypothesis that MRP1 or MRP2 is involved in the efflux of VPA from the brain. Thus, the molecular identity of the putative transporter(s) mediating the active efflux of VPA from the brain remains to be elucidated.
TL;DR: It was found that neither decreasing temperature nor increasing glucose concentrations (above 2 mM) significantly increased hippocampal glycogen content, and that low glycogencontent, per se, may not predispose to the generation of hypoglycemic seizures.
Abstract: Factors Which Abolish Hypoglycemic Seizures Do Not Increase Cerebral Glycogen Content In Vitro. Abdelmalik PA, Liang P, Weisspapir M, Samoilova M, Burnham WM, Carlen PL. Neurobiol Dis 2008;29(2):20...