bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human Epilepsy Can be Linked to a Defective Calcium Channel
Authors: Noebels Jeffrey L. 
Published: December 2022

Human Epilepsy Associated with Dysfunction of the Brain P/Q-type Calcium Channel Jouvenceau A, Eunson LH, Spauschus A, Ramesh V, Zuberi SM, Kullmann DM, Hanna MG Lancet 2001;358:801–807 Background The genetic basis of most common forms of human paroxysmal disorders of the central nervous system, such as epilepsy, remains unidentified. Several animal models of absence epilepsy, commonly accompanied by ataxia, are caused by mutations in the brain P/Q-type voltage-gated calcium (Ca2+) channel. We aimed to determine whether the P/Q-type Ca2+ channel is associated with both epilepsy and episodic ataxia type 2 in human beings. Methods We identified an 11-year-old boy with a complex phenotype comprising primary generalised epilepsy, episodic and progressive ataxia, and mild learning difficulties. We sequenced the entire coding region of the gene encoding the voltage-gated P/Q-type Ca2+ channel (CACNA1A) on chromosome 19. We then introduced the newly identified heterozygous mutation into the full-length rabbit cDNA and did detailed electrophysiologic expression studies of mutant and wild-type Ca2+ channels. Results We identified a previously undescribed heterozygous point mutation (C5733T) in CACNA1A. This mutation introduces a premature stop codon (R1820stop), resulting in complete loss of the C terminal region of the pore-forming subunit of this Ca2+ channel. Expression studies provided direct evidence that this mutation impairs Ca2+ channel function. Mutant/wild-type coexpression studies indicated a dominant negative effect. Conclusions Human absence epilepsy can be associated with dysfunction of the brain P/Q-type voltage-gated Ca2+ channel. The phenotype in this patient has striking parallels with the mouse absence epilepsy models.
Epilepsy Research Takes Flight
Authors: Baraban Scott C. 
Published: December 2022

Genetic Suppression of Seizure Susceptibility in Drosophila Kuebler D, Zhang H, Ren X, Tanouye MA J Neurophysiol 2001;86:1211–1225 Purpose Despite the frequency of seizure disorders in the human population, the genetic and physiologic basis for these defects has been difficult to resolve. Although many genetic defects that cause seizure susceptibility have been identified, the defects involve disparate biologic processes, many of which are not neural specific. The large number and heterogeneous nature of the genes involved make it difficult to understand the complex factors underlying the etiology of seizure disorders. Examining the effect known genetic mutations have on seizure susceptibility is one approach that may prove fruitful. This approach may be helpful both in understanding how different physiologic processes affect seizure susceptibility and in identifying novel therapeutic treatments. Methods In this study, we have taken advantage of Drosophila, a genetically tractable system, to identify factors that suppress seizure susceptibility. Of particular interest has been a group of Drosophila mutants, the bang-sensitive (BS) mutants, which are much more susceptible to seizures than are wild type. The BS phenotypic class includes at least eight genes, including three examined in this study, bss, eas, and sda. Through the generation of double-mutant combinations with other well-characterized Drosophila mutants, the BS mutants are particularly useful for identifying genetic factors that suppress susceptibility to seizures. Results We found that mutants affecting Na+ channels, mlenapts and para, K+ channels, Sh, and electrical synapses, shak-B2, can suppress seizures in the BS mutants. This is the first demonstration that these types of mutations can suppress the development of seizures in any organism. Reduced neuronal excitability may contribute to seizure suppression. The best suppressor, mlenapts, causes an increased stimulation threshold for the giant fiber (GF), consistent with a reduction in single-neuron excitability that could underlie suppression of seizures. For some other double mutants with para and ShKS133, there are no GF threshold changes, but reduced excitability also may be indicated by a reduction in GF following frequency. Conclusions These results demonstrate the utility of Drosophila as a model system for studying seizure susceptibility and identify physiologic processes that modify seizure susceptibility.
Midline Spikes Associated with Focal Epilepsy
Authors: Cascino Gregory 
Published: December 2022

Seizure Semiology and Neuroimaging Findings in Patients with Midline Spikes Kutluay E, Passaro EA, Gomez-Hassan D, Beydoun A Epilepsia 2001;42:1563–1568 Purpose Midline epileptiform discharges are rare compared with discharges at other scalp locations. Neuroimaging results and semiologic seizure characteristics of patients with midline spikes are not adequately described. The aim of this study was to describe the neuroimaging findings and detailed seizure semiologies in patients with midline spikes. Methods We reviewed the EEG database of the University of Michigan Medical Center and identified 35 patients with midline spikes. Information about seizure types and neuroimaging results was obtained from a review of medical records. The seizures were classified according to the International League Against Epilepsy (ILAE) criteria and semiologic classification. Results Twenty-nine (83%) patients had a history of seizures. Complex partial seizures and simple partial seizures were the most common seizure types, experienced by 66% of patients. The age at seizure onset was within the first 10 years in 90% of patients. According to the semiologic seizure classification, automotor seizures and tonic seizures were the most common seizure types. Neuroimaging studies were abnormal in 45% of patients. When focal abnormalities were detected, they were lateralized to one of the frontal lobes in all cases. Conclusions Our results indicate that in the majority of patients, midline spikes represent focal epileptiform activity rather than fragments of generalized discharges, and are most commonly associated with seizures of partial onset. Automotor seizures and tonic seizures are the most common semiologies. Focal radiologic abnormalities tend to be lateralized to one of the frontal lobes.
A Gene for JME at Last: The α1 GABA Receptor Subunit
Authors: Noebels Jeffrey L. 
Published: December 2022

Mutation of GABRA1 in an Autosomal Dominant Form of Juvenile Myoclonic Epilepsy Cossette P, Liu L, Brisebois K, Dong H, Lortie A, Vanasse M, Saint-Hilaire JM, Carmant L, Verner A, Lu WY, Tian Wang Y, Rouleau GA Nat Genet 2002;31:184–189 Although many genes that predispose for epilepsy in humans have been determined, those that underlie the classical syndromes of idiopathic generalized epilepsy (IGE) have yet to be identified. We report that an Ala322Asp mutation in GABRA1, encoding the alpha1 subunit of the gamma-aminobutyric acid receptor subtype A (GABA(A)), is found in affected individuals of a large French Canadian family with juvenile myoclonic epilepsy. Compared with wildtype receptors, GABA(A) receptors that contain the mutant subunit show a lesser amplitude of GABA-activated currents in vitro, indicating that seizures may result from loss of function of this inhibitory ligand-gated channel. Our results confirm that mutation of GABRA1 predisposes towards a common idiopathic generalized epilepsy syndrome in humans.
Intrinsic Bursting Alone Does Not Beget Seizures
Authors: Benardo Larry S. 
Published: December 2022

Long-Lasting Modification of Intrinsic Discharge Properties in Subicular Neurons Following Status Epilepticus Wellmer J, Su H, Beck H, Yaari Y Eur J Neurosci 2002;16:259–266 A single episode of status epilepticus (SE) induces neuropathologic changes in the brain that may lead to the development of a permanent epileptic condition. Most studies of this plasticity have focused on the hippocampus, where both synaptic function and intrinsic neuronal excitability have been shown to be persistently modified by SE. However, many other brain structures are activated during SE and also may be involved in the subsequent epileptogenic process. Here we investigated whether SE, induced in rats with pilocarpine and terminated after 40 minutes with diazepam (DZP), persistently modifies the intrinsic excitability of pyramidal neurons in the subiculum. Subicular slices were prepared from control and SE-experienced rats (2 to 5 weeks after SE). In the control group, only 4% of the neurons fired bursts in response to intrasomatic, threshold-straddling depolarizing current pulses (low-threshold bursters). The remaining neurons either fired bursts in response to strong (3 times threshold) depolarizations (35%; high-threshold bursters) or fired in a completely regular mode (61%; nonbursters). In the SE-experienced group, the fractions of low- and high-threshold bursters markedly increased to 29% and 53%, respectively. This change in firing behavior was associated with a marked increase in the size of the spike afterdepolarization, particularly in low-threshold bursters. Experimental suppression of Ca2+ currents selectively blocked low-threshold bursting but did not affect high-threshold bursting, suggesting that a dual Ca2+-dependent and Ca2+-independent mechanism controls bursting in these neurons. The persistent upregulation of intrinsic bursting in the subiculum, in concert with similar changes in the hippocampus, undoubtedly contributes to epileptogenesis after pilocarpine-induced SE.
Chronic Epilepsy Does Not Cause Measurable Structural Changes on MRI
Authors: Kanner Andres M. 
Published: December 2022

The Structural Consequences of Newly Diagnosed Seizures Liu RSN, Lemieux L, Bell GS, Sisodiya SM, Bartlett PA, Shorvon SD, Sander JWAS, Duncan JS Ann Neurol 2002;52:573–580 Intractable epilepsy may be associated with widespread structural cerebral damage. We determined whether structural damage occurs to the hippocampus, cerebellum, and neocortex in the first few years after a diagnosis of seizures. Sixty-eight patients older than 14 years with newly diagnosed seizures and 90 matched controls underwent serial magnetic resonance imaging (MRI) brain scans 3.5 years apart. Using quantitative analysis of serial scans, we determined changes in hippocampal volume, hippocampal T2 relaxometry, and total and regional brain volumes. Thirty-four (50%) patients had recurrent unprovoked seizures between baseline and follow-up scans. One patient with preexisting hippocampal sclerosis (HS) did not develop progressive hippocampal damage. Group analyses found no difference in change in cerebral measures between patients and controls or between patients with and without recurrent seizures. Significant quantitative changes in individuals were largely attributable to preexisting cerebral lesions or alcohol abuse. Subtle changes detected in individuals over a 3.5-year period but were not related to a history of overt seizures. Our results show patients with newly diagnosed seizures are not generally at increased risk of seizure-induced structural cerebral damage as detected with MRI. Cerebral damage may occur before the onset of seizures or develop insidiously over a more prolonged period
Measurement and Significance of Changes in Benzodiazepine Receptors in Temporal Lobe Epilepsy
Authors: Cascino Gregory D. 
Published: December 2022

Quantitative Analysis of Benzodiazepine Receptor in Temporal Lobe Epilepsy: [125I]Iomazenil Autoradiographic Study of Surgically Resected Specimens Sata Y, Matsuda K, Mihara T, Aihara M, Yagi K, Yonekura Y Epilepsia 2002;43(9):1039–1048 Purpose To evaluate the changes of the inhibitory neurotransmitter receptor system related to epileptogenesis by measuring central benzodiazepine receptors (BZDRs) in surgically resected specimens of temporal lobe epilepsy by using [125I]iomazenil autoradiography. Methods Surgically resected specimens were obtained from 66 temporal lobe epilepsy patients [51 with mesial temporal lobe epilepsy (MTLE) and 15 with non-MTLE] receiving no BZDs and seven MTLE patients receiving BZDs. BZDR densities in brain sections were measured by using [125I]iomazenil autoradiography. Cell densities were measured from cresyl violet–stained sections. Results Compared with non-MTLE patients, non–BZD-treated MTLE patients showed remarkable reduction of BZDR density in the pyramidal cell region of cornu ammonis (CA) 1, CA3, and CA4, and a smaller but significant reduction in CA2 and the molecular and granule cell layers of dentate gyrus (mDG). In the MTLE group, the BZDR density in the mDG correlated with that in lateral cortex. Significant correlations between BZDR density and cell density were found in all hippocampal regions. A significant difference in BZDR density/cell-density ratio was observed in CA1 region between MTLE and non-MTLE. BZD-treated patients tended to have lower BZDR densities than did non–BZD-treated patients, although the differences did not reach significance. In all MTLE cases, [123I]iomazenil single-photon emission computed tomography (SPECT) showed decreased BZDR binding in MTL. Conclusions In MTLE, BZDR densities decreased parallel to reduction in cell density in most hippocampal subfields, but BZDR density appeared to decrease in excess of neuron loss in CA1. [125I]Iomazenil SPECT might be useful for detecting in vivo changes of BZDR density.
Verbal Memory Loss after ATL Based on Degree of Hippocampal Sclerosis
Authors: Harden Cynthia L. 
Published: December 2022

Risk to Verbal Memory After Anterior Temporal Lobectomy in Patients with Severe Left-Sided Hippocampal Sclerosis Martin RC, Kretzmer T, Palmer C, Sawrie S, Knowlton R, Faught E, Morawetz R, Kuzniecky R Arch Neurol 2002;59:1895–1901 Background Previous investigations indicate low risk for memory loss after anterior temporal lobectomy (ATL) in patients with severe hippocampal sclerosis (HS) compared with patients with mild HS. However, these conclusions have been established primarily with group-level analyses. Purpose To investigate individual base rate risk for verbal memory loss after ATL in patients who have pathologically verified mild, moderate, or severe HS. Methods One hundred fifteen patients with unilateral temporal lobe epilepsy (68 with left-sided and 47 with right-sided epilepsy) were included. Acquisition, retrieval, and recognition components of verbal memory, as measured by the California Verbal Learning Test, were assessed before and after ATL. Postoperatively, the degree of neuronal loss and reactive gliosis of the hippocampus was assessed with a three-tiered rating system establishing mild, moderate, and severe pathologic features. Patients with preoperative magnetic resonance imaging-based evidence of lesions outside the mesial temporal area (side of surgical resection) were excluded. Results Neither seizure laterality nor severity of HS was associated with preoperative verbal memory performance. Postoperatively, the left-sided ATL group demonstrated significant decline across the acquisition ( P < 0.01), retrieval ( P < 0.001), and recognition ( P < 0.001) verbal memory components compared with the right-sided ATL group. Patients who underwent left-sided ATL and had mild HS displayed the largest magnitude and percentage proportion of postoperative decline across all verbal memory components. However, 28 (48%) of the 58 patients who underwent left-sided ATL and who had moderate and severe HS displayed statistically reliable declines on retrieval aspects of verbal memory. Most patients undergoing right-sided ATL, regardless of the extent of hippocampal pathologic features, displayed no postoperative memory change. Conclusions Substantial individual heterogeneity of memory outcome exists across groups of patients undergoing ATL, with various degrees of pathologically verified HS. Patients undergoing left-sided ATL who have mild HS seem at greatest risk for broad-spectrum verbal memory decline. However, in examining outcome on a patient-by-patient basis, many patients undergoing left-sided ATL who have moderate to severe HS were also vulnerable to verbal memory loss. This risk seems selective to a retrieval-based aspect of verbal memory.
Sleep and Epilepsy: Something Else We Did Not Know
Authors: Bazil Carl 
Published: December 2022

Sleep Deprivation Does Not Affect Seizure Frequency During Inpatient Video-EEG Monitoring Malow BA, Passaro E, Milling C, Minecan DN, Levy K Neurology 2002;59:1371–137 Purpose To determine whether acute sleep deprivation facilitates seizures during inpatient monitoring in a controlled protocol. Methods Eighty-four patients with medically refractory partial epilepsy undergoing inpatient monitoring were assigned in consecutive blocks to either sleep deprivation every other night or to normal sleep. In both groups, subjects were requested to stay awake during the day, from 6 am to 10 pm. In the sleep-deprivation group, patients also stayed awake between 10 pm and 6 am every other night beginning with day 2. Patients were removed from sleep deprivation if they had two or more secondarily generalized seizures within 24 hours. Patients were removed from the normal sleep group and were sleep deprived if they did not have a complex partial or secondarily generalized seizure by day 6 of monitoring. In these patients removed from sleep deprivation or from normal sleep, data were analyzed up to and including the day of removal from the protocol. Results The sleep deprivation and normal sleep subjects did not differ in age, sex, seizure localization, or percentage dosage reduction in antiepileptic drugs from baseline at days 1 to 3 of monitoring. Protocol duration was 6.5 ± 2.4 days (mean ± SD) for the sleep-deprivation group and 5.8 ± 2.0 days for the normal sleep group. Seizures per day for complex partial, secondarily generalized, and combined complex partial and secondarily generalized, calculated from admission until end of protocol, did not differ significantly between the two groups. Conclusions Acute sleep deprivation did not affect seizure frequency during inpatient monitoring in our patients with intractable complex partial seizures with secondary generalization.
Neurotransmitter Supply and Demand in Epilepsy
Authors: Huguenard John 
Published: December 2022

Block of Glutamate-Glutamine Cycle Between Astrocytes and Neurons Inhibits Epileptiform Activity in Hippocampus Bacci A, Sancini G, Verderio C, Armano C, Pravettoni E, Fesce R, Franceschetti S, Matteoli M J Neurophysiol 2002;88:2302–2310 Recurrent epileptiform activity occurs spontaneously in cultured CNS neurons and in brain slices in which γ-aminobutyric acid (GABA) inhibition has been blocked. We demonstrate here that pharmacologic treatments, resulting in either the block of glutamine production by astrocytes or the inhibition of glutamine uptake by neurons, suppress or markedly decrease the frequency of spontaneous epileptiform discharges both in primary hippocampal cultures and in disinhibited hippocampal slices. These data point to an important role for the neuron-astrocyte metabolic interaction in sustaining episodes of intense rhythmic activity in the CNS, and thereby reveal a new potential target for antiepileptic treatments. A Neuronal Glutamate Transporter Contributes to Neurotransmitter GABA Synthesis and Epilepsy Sepkuty JP, Cohen AS, Eccles C, Rafiq A, Behar K, Ganel R, Coulter DA, Rothstein JD J Neuroscience 2002;22:6372–6379. The predominant neuronal glutamate transporter, EAAC1 (excitatory amino acid carrier-1), is localized to the dendrites and somata of many neurons. Rare presynaptic localization is restricted to γ-aminobutyric acid (GABA) terminals. Because glutamate is a precursor for GABA synthesis, we hypothesized that EAAC1 may play a role in regulating GABA synthesis and thus could cause epilepsy in rats when inactivated. Reduced expression of EAAC1 by antisense treatment led to behavioral abnormalities, including staring-freezing episodes and electrographic (EEG) seizures. Extracellular hippocampal and thalamocortical slice recordings showed excessive excitability in antisense-treated rats. Patch-clamp recordings of miniature inhibitory postsynaptic potentials (mIPSCs) conducted in CA1 pyramidal neurons in slices from EAAC1 antisense-treated animals demonstrated a significant decrease in mIPSC amplitude, indicating decreased tonic inhibition. A 50% loss of hippocampal GABA levels was associated with knockdown of EAAC1, and newly synthesized GABA from extracellular glutamate was significantly impaired by reduction of EAAC1 expression. EAAC1 may participate in normal GABA neurosynthesis and limbic hyperexcitability, whereas epilepsy can result from a disruption of the interaction between EAAC1 and GABA metabolism
Neuroimaging Markers of Epileptogenesis
Authors: White H. Steve 
Published: December 2022

Predictive Value of Cortical Injury for the Development of Temporal Lobe Epilepsy in 21-Day-Old Rats: An MRI Approach Using the Lithium-Pilocarpine Model Roch C, Leroy C, Nehlig A, Namer IJ Epilepsia 2002;43(10):1129 Purpose Patients with temporal lobe epilepsy (TLE) usually had an initial precipitating injury in early childhood. However, epilepsy does not develop in all children who have undergone an early insult. As in patients, the consequences of the lithium-pilocarpine–induced status epilepticus (SE) are age dependent, and only a subset of 21-day-old rats will develop epilepsy. Thus with magnetic resonance imaging (MRI), we explored the differences in the evolution of lesions in these two populations of rats. Methods SE was induced in 21-day-old rats by the injection of lithium and pilocarpine. T2-weighted images and T2 relaxation-time measurements were used for detection of lesions from 6 hours to 4 months after SE. Results Three populations of rats could be distinguished. The first one had neither MRI anomalies nor modification of the T2 relaxation time, and these rats did not develop epilepsy. In the second one, a hypersignal appeared at the level of the piriform and entorhinal cortices 24 hours after SE (increase of 49% of the T2 relaxation time in the piriform cortex) that began to disappear 48 to 72 hours after SE; epilepsy developed in all these animals. The third population of rats showed a more moderate increase of the T2 relaxation time in cortices (14% in the piriform cortex) that could not be seen on T2-weighted images. Epilepsy developed in all these rats. Only in a subpopulation of the 21-day-old rats with epilepsy did hippocampal sclerosis develop. Conclusions These results suggest that the injury of the piriform and entorhinal cortices during SE plays a critical role for the installation of the epileptic networks and the development of epilepsy.
Epileptogenesis beyond the Hippocampus
Authors: Stafstrom Carl E. 
Published: December 2022

On the Origin of Interictal Activity in Human Temporal Lobe Epilepsy In Vitro Cohen I, Navarro V, Clemenceau S, Baulac M, Miles R Science 2002;298(5597):1418–1421 The origin and mechanisms of human interictal epileptic discharges remain unclear. Here we describe a spontaneous, rhythmic activity initiated in the subiculum of slices from patients with temporal lobe epilepsy. Synchronous events were similar to interictal discharges of patient electroencephalograms. They were suppressed by antagonists of either glutamatergic or γ-aminobutyric acid (GABA)ergic signaling. The network of neurons discharging during population events comprises both subicular interneurons and a subgroup of pyramidal cells. In these pyramidal cells, GABAergic synaptic events reversed at depolarized potentials. Depolarizing GABAergic responses in neurons downstream to the sclerotic CA1 region contribute to human interictal activity.