Why do complex-partial seizures in temporal lobe epilepsy (TLE) cause a loss of consciousness? Abnormal function of the medial temporal lobe is expected to cause memory loss, but it is unclear why profoundly impaired consciousness is so common in temporal lobe seizures. Recent exciting advances in behavioral, electrophysiological, and neuroimaging techniques spanning both human patients and animal models may allow new insights into this old question. While behavioral automatisms are often associated with diminished consciousness during temporal lobe seizures, impaired consciousness without ictal motor activity has also been described. Some have argued that electrographic lateralization of seizure activity to the left temporal lobe is most likely to cause impaired consciousness, but the evidence remains equivocal. Other data correlates ictal consciousness in TLE with bilateral temporal lobe involvement of seizure spiking. Nevertheless, it remains unclear why bilateral temporal seizures should impair responsiveness. Recent evidence has shown that impaired consciousness during temporal lobe seizures is correlated with large-amplitude slow EEG activity and neuroimaging signal decreases in the frontal and parietal association cortices. This abnormal decreased function in the neocortex contrasts with fast polyspike activity and elevated cerebral blood flow in limbic and other subcortical structures ictally. Our laboratory has thus proposed the “network inhibition hypothesis,” in which seizure activity propagates to subcortical regions necessary for cortical activation, allowing the cortex to descend into an inhibited state of unconsciousness during complex-partial temporal lobe seizures. Supporting this hypothesis, recent rat studies during partial limbic seizures have shown that behavioral arrest is associated with frontal cortical slow waves, decreased neuronal firing, and hypometabolism. Animal studies further demonstrate that cortical deactivation and behavioral changes depend on seizure spread to subcortical structures including the lateral septum. Understanding the contributions of network inhibition to impaired consciousness in TLE is an important goal, as recurrent limbic seizures often result in cortical dysfunction during and between epileptic events that adversely affects patients’ quality of life.
cortex; EEG; fMRI; septal nuclei; slow waves; attention; temporal lobe epilepsy; thalamus
Consciousness is essential to normal human life. In epileptic seizures consciousness is often transiently lost making it impossible for the individual to experience or respond. This has huge consequences for safety, productivity, emotional health and quality of life. To prevent impaired consciousness in epilepsy it is necessary to understand the mechanisms leading to brain dysfunction during seizures. Normally the “consciousness system”—a specialized set of cortical-subcortical structures—maintains alertness, attention and awareness. Recent advances in neuroimaging, electrophysiology and prospective behavioral testing have shed new light on how epileptic seizures disrupt the consciousness system. Diverse seizure types including absence, generalized tonic-clonic and complex partial seizures converge on the same set of anatomical structures through different mechanisms to disrupt consciousness. Understanding these mechanisms may lead to improved treatment strategies to prevent impaired consciousness and improve quality of life in people with epilepsy.
Currently, there is intense clinical research into various aspects of the medical risks relating to epilepsy, including total and cause-specific mortality, accidents and injuries in patients with epilepsy and mortality related with seizures. Seizures occurring in precarious situations and resulting in injuries are still an important concern for patients with epilepsy, their employers and their care-givers. Submersion injuries, motor vehicle accidents, burns, and head injuries are among the most feared epilepsy-related injuries. These concerns seem valid because the hallmark of epilepsy, episodic impairment of consciousness and motor control, may occur during interictal EEG epileptiform discharges, even in the absence of a clinical seizure. In addition, psychomotor comorbidity and side effects of antiepileptic drugs may contribute to the risk of injuries in patients with epilepsy. Published risk factors for injuries include the number of antiepileptic drugs, history of generalized seizures, and seizure frequency. In general, epidemiological information about incidence of injuries has been conflicting and sparse. In general, studies focusing on populations with more severe forms of epilepsy tend to report substantially higher risks of injuries than those involving less selected populations. On the other hand, studies based on non-selected populations of people with epilepsy have not shown an increased frequency of injuries in people with epilepsy compared with the general population. Some studies have shown that patients with epilepsy are more frequently admitted to the hospital following an injury. Possible explanations include: more cautious attitude of clinicians toward injuries occurring in the setting of seizures; hospitalization required because of seizures and not to the injuries themselves; and hospitalization driven by other issues, such as comorbidities, which are highly prevalent in patients with epilepsy. Potentially the high rate of hospitalizations could be related with the severity of the injury. This article reviews the best available epidemiological information about injuries, including incidence and risk factors. Also this article reviews information about specific types of injuries such as fractures, burns, concussions, dislocations, etc. Information about accidents in people with epilepsy is also discussed.
Impaired consciousness requires altered cortical function. This can occur either directly from disorders that impair widespread bilateral regions of the cortex or indirectly through effects on subcortical arousal systems. It has therefore long been puzzling why focal temporal lobe seizures so often impair consciousness. Early work suggested that altered consciousness may occur with bilateral or dominant temporal lobe seizure involvement. However, other bilateral temporal lobe disorders do not impair consciousness. More recent work supports a ‘network inhibition hypothesis’ in which temporal lobe seizures disrupt brainstem–diencephalic arousal systems, leading indirectly to depressed cortical function and impaired consciousness. Indeed, prior studies show subcortical involvement in temporal lobe seizures and bilateral frontoparietal slow wave activity on intracranial electroencephalography. However, the relationships between frontoparietal slow waves and impaired consciousness and between cortical slowing and fast seizure activity have not been directly investigated. We analysed intracranial electroencephalography recordings during 63 partial seizures in 26 patients with surgically confirmed mesial temporal lobe epilepsy. Behavioural responsiveness was determined based on blinded review of video during seizures and classified as impaired (complex-partial seizures) or unimpaired (simple-partial seizures). We observed significantly increased delta-range 1–2 Hz slow wave activity in the bilateral frontal and parietal neocortices during complex-partial compared with simple-partial seizures. In addition, we confirmed prior work suggesting that propagation of unilateral mesial temporal fast seizure activity to the bilateral temporal lobes was significantly greater in complex-partial than in simple-partial seizures. Interestingly, we found that the signal power of frontoparietal slow wave activity was significantly correlated with the temporal lobe fast seizure activity in each hemisphere. Finally, we observed that complex-partial seizures were somewhat more common with onset in the language-dominant temporal lobe. These findings provide direct evidence for cortical dysfunction in the form of bilateral frontoparietal slow waves associated with impaired consciousness in temporal lobe seizures. We hypothesize that bilateral temporal lobe seizures may exert a powerful inhibitory effect on subcortical arousal systems. Further investigations will be needed to fully determine the role of cortical-subcortical networks in ictal neocortical dysfunction and may reveal treatments to prevent this important negative consequence of temporal lobe epilepsy.
cortex; EEG; seizures; temporal lobe epilepsy; consciousness
Absence seizures cause transient impairment of consciousness. Typical absence seizures occur in children, and are accompanied by 3–4 Hz spike-wave discharges (SWD) on EEG. Prior EEG-fMRI studies of SWD have shown a network of cortical and subcortical changes during these electrical events. However, fMRI during typical childhood absence seizures with confirmed impaired consciousness has not been previously investigated.
We performed EEG-fMRI with simultaneous behavioral testing in 37 children with typical childhood absence epilepsy. Attentional vigilance was evaluated by a continuous performance task (CPT), and simpler motor performance was evaluated by a repetitive tapping task (RTT).
SWD episodes were obtained during fMRI scanning from 9 patients among the 37 studied. fMRI signal increases during SWD were observed in the thalamus, frontal cortex, primary visual, auditory, somatosensory, and motor cortex, and fMRI decreases were seen in the lateral and medial parietal cortex, cingulate gyrus, and basal ganglia. Omission error rate (missed targets) with SWD during fMRI was 81% on CPT and 39% on RTT. For those seizure epochs during which CPT performance was impaired, fMRI changes were seen in cortical and subcortical structures typically involved in SWD, while minimal changes were observed for the few epochs during which performance was spared.
These findings suggest that typical absence seizures involve a network of cortical-subcortical areas necessary for normal attention and primary information processing. Identification of this network may improve understanding of cognitive impairments in childhood absence epilepsy, and help guide development of new therapies for this disorder.
epilepsy; attention; consciousness; thalamus; BOLD; spike-wave
Absence seizures are caused by brief periods of abnormal synchronized oscillations in the thalamocortical loops, resulting in widespread spike-and-wave discharges (SWDs) in the electroencephalogram (EEG). SWDs are concomitant with a complete or partial impairment of consciousness, notably expressed by an interruption of ongoing behaviour together with a lack of conscious perception of external stimuli. It is largely considered that the paroxysmal synchronizations during the epileptic episode transiently render the thalamocortical system incapable of transmitting primary sensory information to the cortex. Here, we examined in young patients and in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a well-established genetic model of absence epilepsy, how sensory inputs are processed in the related cortical areas during SWDs. In epileptic patients, visual event-related potentials (ERPs) were still present in the occipital EEG when the stimuli were delivered during seizures, with a significant increase in amplitude compared to interictal periods and a decrease in latency compared to that measured from non-epileptic subjects. Using simultaneous in vivo EEG and intracellular recordings from the primary somatosensory cortex of GAERS and non-epileptic rats, we found that ERPs and firing responses of related pyramidal neurons to whisker deflection were not significantly modified during SWDs. However, the intracellular subthreshold synaptic responses in somatosensory cortical neurons during seizures had larger amplitude compared to quiescent situations. These convergent findings from human patients and a rodent genetic model show the persistence of cortical responses to sensory stimulations during SWDs, indicating that the brain can still process external stimuli during absence seizures. They also demonstrate that the disruption of conscious perception during absences is not due to an obliteration of information transfer in the thalamocortical system. The possible mechanisms rendering the cortical operation ineffective for conscious perception are discussed, but their definite elucidation will require further investigations.
In a previous report of 900 patients with epileptic
seizures, 24 children had ictal vomiting. Twelve had a previously
unrecognised syndrome of early onset benign childhood occipital
seizures (EBOS) and three had symptomatic epilepsy. The other nine
children with extraoccipital EEG foci or normal EEG are described in
this paper based on a prospective follow up for a median of 9 years
after their first seizure. All had normal neurology, mental state, and development. All seizures of all but one patient occurred in sleep. Seizures manifested with ictal vomiting (nine), deviation of the eyes
(four), speech arrest (three), hemiconvulsions (five),
oropharyngolaryngeal symptoms, and hypersalivation (one) with or
without impairment of consciousness. Median age at onset was 5 years,
seizures were infrequent and remitted at a median age of 6. Four
children had a single fit, four had two to three, and only one child
had many seizures before the initiation of treatment. This study
certifies that idiopathic childhood partial seizures with ictal
vomiting may occur with EEG spike foci in other than the occipital
regions or EEG may be normal. Despite some clinico-EEG differences from the EBOS, childhood seizures with ictal vomiting, and extraoccipital EEG foci are of equally excellent prognosis. Their existence on the
border between rolandic and occipital seizures is consistent with a
unified concept of a benign childhood partial seizure susceptibility syndrome.
The default mode network has been hypothesized following the observation that specific regions of the brain are consistently activated during the resting state and deactivated during engagement with task. The primary nodes of this network, which typically include the precuneus / posterior cingulate, the medial frontal and lateral parietal cortices, are thought to be involved in introspective and social cognitive functions. Interestingly, this same network has been shown to be selectively impaired during epileptic seizures associated with loss of consciousness. Using a wide range of neuroimaging and electrophysiological modalities, decreased activity in the default state has been confirmed during complex partial, generalized tonic-clonic, and absence seizures. In this review we will discuss these three seizure types and will focus on possible mechanisms by which decreased default mode network activity occurs. Although the specific mechanisms of onset and propagation differ considerably across these seizure types, we propose that the resulting loss of consciousness in all three types of seizures is due to active inhibition of subcortical arousal systems that normally maintain default mode network activity in the awake state. Further, we suggest that these findings support a general “network inhibition hypothesis,” by which active inhibition of arousal systems leads to cortical deactivation resembling other states of reduced consciousness.
Epilepsy; Consciousness; Default Mode Network
Evaluating transient impairment of consciousness is critical to diagnose epileptic seizures, syncope, parasomnias, organic encephalopathies, and psychogenic nonepileptic seizures. Effective evaluation of episodic unconscious events demands interactive interviewing of the patient and witnesses of the events, with judgment as to historians' observational abilities. When generalized tonic-clonic seizures have been witnessed by medical staff or other reliable observers, a search for concomitant nonconvulsive events and for comorbid illnesses often elucidates diagnoses unsuspected by the referring physician. Consultation for stupor-coma should not miss a potentially reversible acute severe encephalopathy, particularly when reversibility requires timely therapy. Perspicacious analyses of complex cognitive-motor phenomena support judicious application of diagnostic procedures, including brief or prolonged EEG and video-EEG, EKG tilt-table testing, EKG loop monitoring, and brain imaging.
The analysis of the brain CT Scan results in patients with epilepsy referred to the neurology clinic of Kermanshah during 1996-2007. Epilepsy is a transient disorder of the nervous system due to sudden discharge of brain neurons. The sudden and abnormal neuronal discharge may lead to consciousness level reduction, changes in perception or mental dysfunction of seizure movements, sensorineural disorders or a combination of these symptoms.
This was a descriptive-cross sectional study. Patients with epilepsy referred to the neurology clinic in Kermanshah (Iran) who were studied by Brain CT scan during 1996-2007 were investigated. After confirming the epilepsy of patients by neurosurgery experts and removal of the seizure of consciousness loss due to other causes such as syncope, 931 patients were enrolled in our study.
Among 931 patients, only 905 patients had undergone Brain CT of which 464 were female and the rest were male. 325 patients suffered from focal motor epilepsy, patients referred with temporal epilepsy, 473 patients with Grand Mal epilepsy, 12 patients with absence epilepsy, 54 patients with myoclonic epilepsy, and 7 patients suffered from other types of epilepsy. The greatest Brain CT disorder was related to focal epilepsy. Among 125 patients with abnormal Brain CT, the greatest disorder was associated with cerebrovascular disorders (58 cases). In this study, the age range of samples was 1-89 years old. The lowest disorder was found in the age group of 10-19 and 20-39 years old (8.7% and 12.4%, respectively). The greatest disorder was observed in patients over 60 years old (38.3%). It should be noted that no Brain CT disorder was found in patients with youth myoclonic and absence epilepsy.
The results of the present study can be helpful for proper use of brain imaging in patients with epilepsy.
Epilepsy, Brain CT, Neurology Clinic, Mayoclonic epilepsy
Recently, several patients have been reported with various signs of encephalopathy and high thyroid antibody levels together with good responsiveness to glucocorticoid therapy. Despite the various clinical presentations, these cases have been termed “Hashimoto encephalopathy” (HE). Although all of the pathogenic components have not yet been clearly elucidated, it is believed that brain vasculitis and autoimmunity directed against common brain-thyroid antigens represent the most likely etiologic pathway. The most common clinical signs include unexplained or epilepsy-like seizures resistant to anti-convulsive treatment, confusion, headaches, hallucinations, stroke-like episodes, coma, impairment of cognitive function, behavioral and mood disturbance, focal neurological deficits, disturbance of consciousness, ataxia, and presenile dementia, together with the presence of high thyroid antibody levels, especially against thyroperoxidase (TPOab). In most cases, the thyroid function is normal or decreased; the thyroid function is rarely increased. The examination of the cerebrospinal fluid, EEG, MRI, SPECT, and neuropsychological examinations are primarily used as diagnostic tools. Most cases showed neural symptoms for months before the acute onset; in some cases, a dramatic acute onset was described. Once the diagnosis is made, corticosteroid treatment usually provides a dramatic recovery. The authors also present a short review of literary cases reported in last decade.
Hashimoto’s Encephalitis; Vasculitis; Glucocorticoids
Twenty-four out of 900 adult and children patients with epilepsy, were found to have vomiting during an ictus. All the 24 patients were children before puberty with a similar clinical pattern consisting of partial seizures which were mainly nocturnal. Ictal vomiting was always concurrent with other epileptic manifestations, more often deviation of the eyes and impairment of consciousness. The initial part of the ictus was short or prolonged for hours with frequent "marching" to hemi-convulsions and generalised seizures. Seventeen of the 24 children suffered from benign childhood epilepsies (BCE) with complete remission in long follow-up. A significantly higher association was found between ictal vomiting and the syndrome of BCE with occipital spikes (p less than 0.001) but not with centro-temporal spikes (p less than 0.2). The recognition of this association may have important theoretical implications. On clinical grounds, it may prevent unnecessary investigations and undue concern.
Neonatal seizures are the most common manifestation of neurological dysfunction in the neonate. The prognosis of neonatal seizures is highly variable, and the controversy remains whether the severity, duration, or frequency of seizures may contribute to brain damage independently of its etiology. Animal data indicates that seizures during development are associated with a high probability of long-term adverse effects such as learning and memory impairment, behavioral changes and even epilepsy, which is strongly age dependent, as well as the severity, duration, and frequency of seizures. In preliminary studies, we demonstrated that adolescent male rats exposed to one-single neonatal status epilepticus (SE) episode showed social behavior impairment, and we proposed the model as relevant for studies of developmental disorders. Based on these facts, the goal of this study was to verify the existence of a persistent deficit and if the anxiety-related behavior could be associated with that impairment. To do so, male Wistar rats at 9 days postnatal were submitted to a single episode of SE by pilocarpine injection (380 mg/kg, i.p.) and control animals received saline (0.9%, 0.1 mL/10 g). It was possible to demonstrate that in adulthood, animals exposed to neonatal SE displayed low preference for social novelty, anxiety-related behavior, and increased stereotyped behavior in anxiogenic environment with no locomotor activity changes. On the balance, these data suggests that neonatal SE in rodents leads to altered anxiety-related and abnormal social behaviors.
neonatal status epilepticus; pilocarpine; social anxiety; general anxiety; social behavior
Absence seizures are 5–10 second episodes of impaired consciousness accompanied by 3–4Hz generalized spike-and-wave discharge on electroencephalography (EEG). The timecourse of functional magnetic resonance imaging (fMRI) changes in absence seizures in relation to EEG and behavior is not known. We acquired simultaneous EEG-fMRI in 88 typical childhood absence seizures from 9 pediatric patients. We investigated behavior concurrently using a continuous performance task (CPT) or simpler repetitive tapping task (RTT). EEG time-frequency analysis revealed abrupt onset and end of 3–4 Hz spike-wave discharges with a mean duration of 6.6 s. Behavioral analysis also showed rapid onset and end of deficits associated with electrographic seizure start and end. In contrast, we observed small early fMRI increases in the orbital/medial frontal and medial/lateral parietal cortex >5s before seizure onset, followed by profound fMRI decreases continuing >20s after seizure end. This timecourse differed markedly from the hemodynamic response function (HRF) model used in conventional fMRI analysis, consisting of large increases beginning after electrical event onset, followed by small fMRI decreases. Other regions, such as the lateral frontal cortex, showed more balanced fMRI increases followed by approximately equal decreases. The thalamus showed delayed increases after seizure onset followed by small decreases, most closely resembling the HRF model. These findings reveal a complex and long lasting sequence of fMRI changes in absence seizures, which are not detectible by conventional HRF modeling in many regions. These results may be important mechanistically for seizure initiation and termination and may also contribute to changes in EEG and behavior.
EEG-fMRI; Thalamus; Absence epilepsy; HRF; Attention; Orbitofrontal cortex
Generalised spike wave (GSW) discharges are the electroencephalographic (EEG) hallmark of absence seizures, clinically characterised by a transitory interruption of ongoing activities and impaired consciousness, occurring during states of reduced awareness. Several theories have been proposed to explain the pathophysiology of GSW discharges and the role of thalamus and cortex as generators. In this work we extend the existing theories by hypothesizing a role for the precuneus, a brain region neglected in previous works on GSW generation but already known to be linked to consciousness and awareness. We analysed fMRI data using dynamic causal modelling (DCM) to investigate the effective connectivity between precuneus, thalamus and prefrontal cortex in patients with GSW discharges.
Methodology and Principal Findings
We analysed fMRI data from seven patients affected by Idiopathic Generalized Epilepsy (IGE) with frequent GSW discharges and significant GSW-correlated haemodynamic signal changes in the thalamus, the prefrontal cortex and the precuneus. Using DCM we assessed their effective connectivity, i.e. which region drives another region. Three dynamic causal models were constructed: GSW was modelled as autonomous input to the thalamus (model A), ventromedial prefrontal cortex (model B), and precuneus (model C). Bayesian model comparison revealed Model C (GSW as autonomous input to precuneus), to be the best in 5 patients while model A prevailed in two cases. At the group level model C dominated and at the population-level the p value of model C was ∼1.
Our results provide strong evidence that activity in the precuneus gates GSW discharges in the thalamo-(fronto) cortical network. This study is the first demonstration of a causal link between haemodynamic changes in the precuneus - an index of awareness - and the occurrence of pathological discharges in epilepsy.
Epilepsy is characterized by intermittent, paroxysmal, hypersynchronous electrical activity, that may remain localized and/or spread and severely disrupt the brain’s normal multi-task and multi-processing function. Epileptic seizures are the hallmarks of such activity and had been considered unpredictable. It is only recently that research on the dynamics of seizure generation by analysis of the brain’s electrographic activity (EEG) has shed ample light on the predictability of seizures, and illuminated the way to automatic, prospective, long-term prediction of seizures. The ability to issue warnings in real time of impending seizures (e.g., tens of minutes prior to seizure occurrence in the case of focal epilepsy), may lead to novel diagnostic tools and treatments for epilepsy. Applications may range from a simple warning to the patient, in order to avert seizure-associated injuries, to intervention by automatic timely administration of an appropriate stimulus, for example of a chemical nature like an anti-epileptic drug (AED), electromagnetic nature like vagus nerve stimulation (VNS), deep brain stimulation (DBS), transcranial direct current (TDC) or transcranial magnetic stimulation (TMS), and/or of another nature (e.g., ultrasonic, cryogenic, biofeedback operant conditioning). It is thus expected that seizure prediction could readily become an integral part of the treatment of epilepsy through neuromodulation, especially in the new generation of closed-loop seizure control systems.
Spatio-Temporal Dynamical Analysis of EEG; Ictogenesis; Seizure Prediction; Closed-Loop Seizure Control
Although epilepsy is defined by the occurrence of spontaneous epileptic seizures, a large body of evidence indicates that epilepsy is linked to a spectrum behavioral, psychiatric, and cognitive disorders as well as to sudden death. Explanations for these associations include: (1) The effects of structural lesions which may impair the functions subserved by the regions of the brain involved in the lesion. (2) The effects of seizure activity which may begin well before a clinical seizure occurs and may persist long after it is over raising questions about what truly constitutes “interictal.” In addition, encephalopathic effects of epilepsy in infancy during critical periods in development may be particularly severe and potentially irreversible. (3) Shared mechanisms underlying seizures as well as these other disorders in the absence of structural lesions or separate diseases of the CNS. Epidemiological and clinical studies demonstrate the elevated risk of cognitive, psychiatric, and behavioral disorders not just during but also prior to the onset of epilepsy (seizures) itself. These may outlast the active phase of epilepsy as well. The mounting evidence argues strongly for the recognition of epilepsy as part of a spectrum of disorders and against the notion that even uncomplicated epilepsy can a priori be considered benign.
brain lesions; development; co-morbidity; encephalopathy; interictal discharge; progressive effects; seizures
Impaired consciousness in epilepsy has a major negative impact on quality of life. Prior work suggests that complex partial seizures (CPS) and generalized tonic-clonic seizures (GTCS), which both cause loss of consciousness, affect similar fronto-parietal networks. Milder involvement in CPS than in GTCS may spare some simple behavioral responses, resembling the minimally conscious state. However, this difference in responses has not been rigorously tested previously. During video/EEG monitoring, we administered a standardized prospective testing battery including responses to questions and commands, as well as tests for reaching/grasping a ball and visual tracking in 27 CPS (14 patients) and 7 GTCS (6 patients). Behavioral results were analyzed in the ictal and post-ictal periods based on video review. During both CPS and GTCS, patients were unable to respond to questions or commands. However, during CPS patients often retain minimally conscious ball grasping and visual tracking responses. Patients were able to successfully grasp a ball in 60% or to visually track in 58% of CPS, and could carry out both activities in 52% of CPS. In contrast, during GTCS preserved ball grasp (10%), visual tracking (11%) or both (7%) were all significantly less than in CPS. Post-ictal ball grasping and visual tracking were also somewhat better following CPS than GTCS. These findings suggest that impaired consciousness in CPS is more similar to minimally conscious state than to coma. Further work may elucidate the specific brain networks underlying relatively spared functions in CPS, ultimately leading to improved treatments aimed at preventing impaired consciousness.
Consciousness; Epilepsy; Complex Partial Seizures; Generalized Tonic-Clonic Seizures; Visual Tracking; Minimally Conscious State; Vegetative State
Epilepsy is a disorder of recurrent seizures that affects 1% of the population. To understand why some areas of cerebral cortex produce seizures and others do not, we identified differentially expressed genes in human epileptic neocortex compared to nearby regions that did not produce seizures. The transcriptome that emerged strongly implicates MAP kinase signaling and CREB-dependent transcription, with 74% of differentially expressed genes containing a cyclic AMP response element (CRE) in their proximal promoter, more than half of which are conserved. Despite the absence of recent seizures in these patients, epileptic brain regions prone to seizures showed persistent activation of ERK and CREB. Persistent CREB activation was directly linked to CREB-dependent gene transcription by chromatin immunoprecipitation that showed phosphorylated CREB constitutively associated with the proximal promoters of many of the induced target genes involved in neuronal signaling, excitability and synaptic plasticity. A distinct spatial pattern of ERK activation was seen in superficial axodendritic processes of epileptic neocortex that co-localized with both CREB phosphorylation and CREB target gene induction in well-demarcated populations of layer 2/3 neurons. These same neuronal lamina showed a marked increase in synaptic density. The findings generated in this study generate a robust and spatially-restricted pattern of epileptic biomarkers and associated synaptic changes that could lead to new mechanistic insights and potential therapeutic targets for human epilepsy.
There are various causes to a low level of consciousness in patients in the intensive care unit. Neurological injury, infection, and metabolic disarray are considered as some of the causes. A 39 year-old female patient was transferred to our hospital with septic shock due to ascending colon perforation. The patient had previously received ovarian cancer surgery and a cycle of chemotherapy at another hospital. Emergent operation for colon perforation was successful. After the operation, she was treated in the intensive care unit for infectious and pulmonary complications. She suddenly showed deterioration in her level of consciousness and had a generalized seizure. At the time of her seizure, she had severe hyperammonemia. Brain CT showed severe cerebral edema that was absent in the CT scan taken 2 days before. Continuous renal replacement therapy was conducted but was ineffective in lowering the level of serum ammonia and the patient subsequently died.
Hyperammonemia; Seizures; Status epilepticus
Focal seizures appear to start abruptly and unpredictably when recorded from volumes of brain probed by clinical intracranial electroencephalograms. To investigate the spatiotemporal scale of focal epilepsy, wide-bandwidth electrophysiological recordings were obtained using clinical macro- and research microelectrodes in patients with epilepsy and control subjects with intractable facial pain. Seizure-like events not detectable on clinical macroelectrodes were observed on isolated microelectrodes. These ‘microseizures’ were sparsely distributed, more frequent in brain regions that generated seizures, and sporadically evolved into large-scale clinical seizures. Rare microseizures observed in control patients suggest that this phenomenon is ubiquitous, but their density distinguishes normal from epileptic brain. Epileptogenesis may involve the creation of these topographically fractured microdomains and ictogenesis (seizure generation), the dynamics of their interaction and spread.
epilepsy; seizure; intracranial EEG; microseizure; microcircuit; seizure generation; ictogenesis; epileptogenesis
This study aimed to investigate the clinical characteristics and the treatment principles and methods of recurrent epileptic seizures in patients with neurological disorders. A retrospective analysis was performed of the clinical data, treatment methods and results in 13 patients with recurrent epileptic seizures attending the neurosurgery department. Of the 13 patients, 10 had a history of epilepsy, 9 had organic frontal lobe brain lesions and 11 exhibited frontal lobe epilepsy. The causes of the epileptic seizure aggravation included drug withdrawal, dose reduction and dressing change (5 cases). The epileptic seizure types included partial and secondary full seizures and the seizure frequency ranged from 1 seizure/3 min to 1 seizure/several h. Following combined therapy with multiple anti-epileptic drugs (AEDs), including oral administration and injection, the epilepsy was controlled. The addition of orally administered levetiracetam improved the treatment efficiency. In cases of recurrent epileptic seizures in patients with neurological disorders, the combined administration of AEDs should be conducted with doses higher than the conventional initial dose to control the epileptic seizures as rapidly as possible.
epileptic seizure; treatment; levetiracetam
There are few data available on the causes and mechanistic basis, outcome and treatment of seizures and epilepsy in people with systemic cancer. Seizures and epilepsy in people with cancers other than primary brain tumours are reviewed here. Articles published in English, which discussed the neurological manifestations and complications of cancer and its treatment, were searched and information on the frequency, aetiology, and course of seizures and epilepsy was extracted. The frequency, aetiology and outcome of seizure disorders in patients with cancer differ from those in the general population. Intracranial metastasis, cancer drugs and metabolic disturbances are the most common causes. Infections, cerebrovascular complications of systemic cancer and paraneoplastic disorders are among the rarer causes of seizures in patients with neoplasms. Several drugs used in the treatment of cancer, or complications arising from their use, can trigger seizures through varied mechanisms. Most drug‐induced seizures are provoked and do not require long‐term treatment with antiepileptic drugs.
During a 10-year period 45 children were identified as having had neurological complications associated with severe arterial hypertension. Convulsions were the most common complication, occurring in 42 (82%) children. Two (4%) children each presented with a facial palsy and 2 (4%) with alterations in the level of consciousness. Nineteen (42%) presented with epileptic seizures as the first sign of arterial hypertension. The prognosis for children having had a single episode of hypertensive encephalopathy was good. Long-term follow-up showed no permanent neurological deficit on physical examination, and no focal abnormality on brain scan by computerised tomography. Psychometric analysis similarly failed to show any significant difference in cognitive assessment between children having had an episode of hypertensive encephalopathy and a control group with chronic renal disease, although reading skills were generally behind for chronological age and the average IQ was about 90 in both groups.
Status epilepticus (SE) is a medical emergency associated with significant morbidity and mortality. SE is defined as a continuous seizure lasting more than 30 min, or two or more seizures without full recovery of consciousness between any of them. Based on recent understanding of the pathophysiology, it is now considered that any seizure that lasts more than 5 min probably needs to be treated as SE. GABAergic mechanisms play a crucial role in terminating seizures. When the seizure persists, GABA-mediated mechanisms become ineffective and several other putative mechanisms of seizure suppression have been recognized. Early treatment of SE with benzodiazepines, followed if necessary by fosphenytoin administration, is the most widely followed strategy. About a third of patients with SE may have persistent seizures refractory to the first-line medications. They require aggressive management with second-line medications such as barbiturates, propofol, or other agents. In developing countries where facilities for assisted ventilation are not readily available, it may be helpful to use nonsedating antiepileptic drugs (such as sodium valproate, levetiracetam, or topiramate) at this stage. It is important to recognize SE and institute treatment as early as possible in order to avoid a refractory state. It is equally important to attend to the general condition of the patient and to ensure that the patient is hemodynamically stable. This article reviews current knowledge regarding the management of convulsive SE in adults.
Anticonvulsants; barbiturates; lorazepam; midazolam; phenytoin; propofol; refractory status epilepticus; status epilepticus