Showing papers in "Epilepsia in 2003"

The epidemiology of traumatic brain injury: a review.

Abstract: Summary: Purpose: Traumatic brain injury (TBI) not only has considerable morbidity and mortality, but it is a major cause of epilepsy. We wish to determine the frequency of TBI, special groups at risk for TBI, and mortality from TBI. Methods: We reviewed studies of TBI that are either population based or derived from definable catchment areas that allow determination of incidence, identification of risk groups, and mortality. We review methodology used in epidemiologic studies of TBI and try to distinguish this data from that of head injury not necessarily affecting the brain. We report epidemiologic characteristics of TBI, including incidence, differences by age, gender, race and ethnic group, and geographic variation, and mortality. Results: Population-based studies in the United States suggest that the incidence of TBI is between 180 and 250 per 100,000 population per year. Incidence may be higher in Europe and South Africa. There are groups at high risk for TBI. This includes males and individuals living in regions characterized by socioeconomic deprivation. There are selective age groups at risk for TBI. This includes the very young, adolescents and young adults, and the elderly. Mortality varies by severity but is high in those with severe injury and in the elderly. Conclusions: TBI is a major public health problem as well as a major cause of epilepsy. If primary prevention is to be undertaken, we must understand the epidemiology of the condition. The primary causes of TBI vary by age, socioeconomic factors, and geographic region, so any planned interventions must be tailored accordingly.

Proposal for a New Classification of Outcome with Respect to Epileptic Seizures Following Epilepsy Surgery

Abstract: *Neurology Clinic, Epileptology & EEG, University Hospital, Zurich, Switzerland; †Department of Neurology, University Hospital, London, Ontario, Canada; ‡The National Hospital for Neurology and Neurosurgery, Queen Square, London, England; §Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, New York, U.S.A.; Department of Neurology, University of Essen, Essen, Germany; ¶Department of Neurology, Medical College of Georgia, Augusta, Georgia; **Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania; and ††Department of Neurology, The Cleveland Clinic Foundation, Cleveland, Ohio, U.S.A.

Epidemiology of Posttraumatic Epilepsy : A Critical Review

Abstract: Summary: Problem: Traumatic brain injury (TBI) is a major cause of epilepsy. We need to understand its frequency and its contribution to the total spectrum of the convulsive disorders. Methods: A review of selected articles dealing with epilepsy after brain trauma was undertaken. Results: The number of epidemiologic studies of posttraumatic seizures has increased substantially over the past 40–50 years, offering steadily increasing knowledge of the frequency, natural history, and risk factors of this well-recognized complication of TBI. In general, the incidence of posttraumatic seizures varies with the time period after injury and population age range under study, as well as the spectrum of severity of the inciting injuries, and has been reported to be anywhere from 4 to 53%. As high as 86% of patients with one seizure after TBI will have a second in the next 2 years. Longer-term remission rates of 25–40% have been reported. Significant risk factors for the development of seizures in the first week after injury include acute intracerebral hematoma (especially subdural hematoma), younger age, increased injury severity, and chronic alcoholism. Significant risk factors for the development of seizures >1 week after TBI include seizures within the first week, acute intra-cerebral hematoma (especially subdural hematoma), brain contusion, increased injury severity, and age >65 years at the time of injury. Conclusions: Epilepsy is a frequent consequence of brain injury in both civilian and military populations. We understand some factors associated with its development, but there remain many unanswered questions.

Epilepsies as Dynamical Diseases of Brain Systems : Basic Models of the Transition Between Normal and Epileptic Activity

Abstract: Summary: Purpose: The occurrence of abnormal dynamics in a physiological system can become manifest as a sudden qualitative change in the behavior of characteristic physiologic variables. We assume that this is what happens in the brain with regard to epilepsy. We consider that neuronal networks involved in epilepsy possess multistable dynamics (i.e., they may display several dynamic states). To illustrate this concept, we may assume, for simplicity, that at least two states are possible: an interictal one characterized by a normal, apparently random, steady -state of ongoing activity, and another one that is characterized by the paroxysmal occurrence of a synchronous oscillations (seizure). Methods: By using the terminology of the mathematics of nonlinear systems, we can say that such a bistable system has two attractors, to which the trajectories describing the system's output converge, depending on initial conditions and on the system's parameters. In phase-space, the basins of attraction corresponding to the two states are separated by what is called a “separatrix.” We propose, schematically, that the transition between the normal ongoing and the seizure activity can take place according to three basic models: Model I: In certain epileptic brains (e.g., in absence seizures of idiopathic primary generalized epilepsies), the distance between “normal steady -state” and “paroxysmal” attractors is very small in contrast to that of a normal brain (possibly due to genetic and/or developmental factors). In the former, discrete random fluctuations of some variables can be sufficient for the occurrence of a transition to the paroxysmal state. In this case, such seizures are not predictable. Model II and model III: In other kinds of epileptic brains (e.g., limbic cortex epilepsies), the distance between “normal steady-state” and “paroxysmal” attractors is, in general, rather large, such that random fluctuations, of themselves, are commonly not capable of triggering a seizure. However, in these brains, neuronal networks have abnormal features characterized by unstable parameters that are very vulnerable to the influence of endogenous (model II) and/or exogenous (model III) factors. In these cases, these critical parameters may gradually change with time, in such a way that the attractor can deform either gradually or suddenly, with the consequence that the distance between the basin of attraction of the normal state and the separatrix tends to zero. This can lead, eventually, to a transition to a seizure. Results: The changes of the system's dynamics preceding a seizure in these models either may be detectable in the EEG and thus the route to the seizure may be predictable, or may be unobservable by using only measurements of the dynamical state. It is thinkable, however, that in some cases, changes in the excitability state of the underlying networks may be uncovered by using appropriate stimuli configurations before changes in the dynamics of the ongoing EEG activity are evident. A typical example of model III that we discuss here is photosensitive epilepsy. Conclusions: We present an overview of these basic models, based on neurophysiologic recordings combined with signal analysis and on simulations performed by using computational models of neuronal networks. We pay especial attention to recent model studies and to novel experimental results obtained while analyzing EEG features preceding limbic seizures and during intermittent photic stimulation that precedes the transition to paroxysmal epileptic activity.

Practice parameter: temporal lobe and localized neocortical resections for epilepsy.

Abstract: Summary: Purpose: To examine evidence for effectiveness of anteromesial temporal lobe and localized neocortical resections for disabling complex partial seizures. Methods: Systemic review and analysis of the literature since 1990. Results: One intention-to-treat Class I randomized controlled trial of surgery for mesial temporal lobe epilepsy found that 58% of patients randomized to be evaluated for surgical therapy (64% of those who received surgery) were free of disabling seizures and 10 to 15% were unimproved at the end of 1 year, compared with 8% free of disabling seizures in the group randomized to continued medical therapy. There was a significant improvement in quantitative quality-of-life scores and a trend toward better social function at the end of 1 year for patients in the surgical group, no surgical mortality, and infrequent morbidity. Twenty-four Class IV series of temporal lobe resections yielded essentially identical results. There are similar Class IV results for localized neocortical resections; no Class I or II studies are available. Conclusions: A single Class I study and 24 Class IV studies indicate that the benefits of anteromesial temporal lobe resection for disabling complex partial seizures is greater than continued treatment with antiepileptic drugs, and the risks are at least comparable. For patients who are compromised by such seizures, referral to an epilepsy surgery center should be strongly considered. Further studies are needed to determine if neocortical seizures benefit from surgery, and whether early surgical intervention should be the treatment of choice for certain surgically remediable epileptic syndromes.

The Spectrum of Long-term Epilepsy-associated Tumors : Long-term Seizure and Tumor Outcome and Neurosurgical Aspects

Abstract: Summary: Purpose: To describe the histologic spectrum and clinical characteristics of patients with neuroepithelial tumors and drug-resistant epilepsy and to analyze clinical data and treatment related to seizure outcome and survival Methods: Data were analyzed from 207 consecutive patients with intractable epilepsy (aged 2–54 years), who between 1988 and 1999 had ≥50% resection of supratentorial, neuroepithelial tumors Extent of resection was assessed on postoperative magnetic resonance imaging (MRI); seizure outcome was classified according to Engel's outcome scale; and follow-up data were prospectively updated Results: Median follow-up was eight years (range, 2–14 years) Histologic examination revealed 154 classic epilepsy-associated tumors (ganglioglioma, dysembryoplastic neuroepithelial tumor, pleomorphic xanthoastrocytoma, and pilocytic astrocytomas) and 53 others (astrocytomas and oligodendrogliomas) Four World Health Organization (WHO) grade III tumors were found (astrocytoma, n = 3; ganglioglioma, n = 1) After surgery, 82% of the patients were seizure free (class I) The following factors were associated with improved seizure outcome: Short duration of epilepsy before surgery, single EEG focus, absence of additional hippocampal sclerosis or cortical dysplasia, transsylvian approach, other than astrocytomas, and complete tumor resection After 5 years, only nine (4%) patients had tumor recurrence, four (2%) with malignant transformation and death None of the four patients with anaplastic tumors died Even patients with astrocytomas of WHO grade II or III showed 10-year recurrence of only 25% and 10-year survival of 90% Conclusions: Tumors associated with long-term epilepsy should be removed early for two different reasons: high rate of seizure freedom and rare but potential risk of malignant tumor progression The unexpected long survival of these astrocytomas should be investigated by using immunohistochemistry and molecular biology

A possible role for gap junctions in generation of very fast EEG oscillations preceding the onset of, and perhaps initiating, seizures

Abstract: Summary: Purpose: We propose an experimentally and clinically testable hypothesis, concerning the origin of very fast (>∼70 Hz) EEG oscillations that sometimes precede the onset of focal seizures. These oscillations are important, as they may play a causal role in the initiation of seizures. Methods: Subdural EEG recordings were obtained from children with focal cortical dysplasias and intractable seizures. Intra- and extracellular recordings were performed in rat hippocampal slices, with induction of population activity, as follows: (a) bath-applied tetramethylamine (an intracellular alkalinizing agent, that opens gap junctions); (b) bath-applied carbachol, a cholinergic agonist; and (c) focal pressure ejection of hypertonic K+ solution. Detailed network simulations were performed, the better to understand the cellular mechanisms underlying oscillations. A major feature of the simulations was inclusion of axon–axon gap junctions between principal neurons, as supported by recent experimental data. Results: Very fast oscillations were found in children before seizure onset, but also superimposed on bursts during the seizure, and on interictal bursts. In slice experiments, very fast oscillations had previously been seen on interictal-like bursts; we now show such oscillations before, between, and after epileptiform bursts. Very fast oscillations were also seen superimposed on gamma (30–70 Hz) oscillations induced by carbachol or hypertonic K+, and in the latter case, very fast oscillations became continuous when chemical synapses were blocked. Simulations replicate these data, when axonal gap junctions are included. Conclusions: Electrical coupling between principal neurons, perhaps via axonal gap junctions, could underlie very fast population oscillations, in seizure-prone brain, but possibly also in normal brain. The anticonvulsant potential of gap-junction blockers such as carbenoxolone, now in clinical use for treatment of ulcer disease, should be considered.

Electrocardiographic Changes at the Onset of Epileptic Seizures

Abstract: Summary: Purpose: We studied heart-rate (HR) changes at the transition from the preictal to the ictal state in patients with focal epilepsies to gain some insight into the mechanisms involved in the neuronal regulation of cardiovascular function. Methods: We assessed ECG changes during 145 seizures recorded with scalp EEG in 58 patients who underwent video-EEG monitoring. Consecutive RR intervals were analyzed with a newly developed mathematical method for a total of 90 s. Results: Ictal-onset tachycardia occurred in 86.9% of all seizures, whereas bradycardia was documented only in 1.4%. The incidence as well as the amount of ictal HR increase was significantly more pronounced in patients with mesial temporal lobe epilepsy (TLE) as compared with those with non-lesional TLE or extratemporal epilepsy. Moreover, right hemispheric seizures were associated with ictal-onset tachycardia. On average, ictal HR increase preceded EEG seizure onset by 13.7 s in TLE patients and 8.2 s in patients with extratemporal epilepsy. This difference was significant. Ictal HR changes could be classified according to their temporal evolution into two different patterns. These two patterns differed significantly between the temporal lobe and the extratemporal epilepsy patient group. Conclusions: Epileptic discharges directly influence areas of the central autonomic network, thus regulating HR and rhythm. Such changes occur before ictal discharges appear on surface electrodes. Our newly developed method may be of potential use for clinical applications such as automatic seizure-detection systems. Moreover, our method might help to clarify further the basic mechanisms of interactions between heart and brain.

Epidemiology of Neural Tube Defects

Abstract: Neural tube defects (NTDs)-malformations secondary to abnormal neural tube closure between the third and fourth weeks of gestational age-have a complex and imperfectly understood etiology in which both genetic and environmental factors appear to be involved. A number of specific chromosomal or single-gene disorders, presumably not affected by environmental influences, are associated with the development of NTDs, but such syndromal cases account for a small proportion of NTDs in live-born infants. Analysis of recurrence patterns within families and of twin-concordance data provides evidence of a genetic influence in nonsyndromal cases, but factors such as socioeconomic status and geographic area (independent of race or ethnicity) are also associated with variations in the incidence of NTDs. The prevalence at birth of both anencephaly and spina bifida has decreased, but the advent of antenatal diagnosis and elective termination of affected pregnancies has undermined the reliability of birth prevalence rate as an estimate of incidence. Some occupational and other exposures, including maternal use of antiepileptic drugs (AEDs), are associated with increased risk for NTDs. Among women who have had an NTD-affected pregnancy, recurrence risk is markedly higher than the risk for a first NTD-affected pregnancy in the general population. There is strong evidence, overall, for a protective effect of adequate folate consumption. In some high-risk groups, however, such as women taking AEDs, folate supplementation has not been proven to reduce NTD risk.

Behavioral disorders in pediatric epilepsy: unmet psychiatric need.

Abstract: Summary: Purpose: This study examined the relation between psychiatric diagnosis and mental health services in children with epilepsy and the associated demographic, cognitive, linguistic, behavioral, and seizure-related variables. Methods: The Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS), the Child Behavior Checklist, the Test of Language Development, and the Wechsler Intelligence Scale for Children–Revised (WISC-R) were administered to 114 children, aged 5 to 16 years, with either complex partial seizures (CPS) or primary generalized with absence (PGE, petit mal). A Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) diagnosis and information regarding mental health services were derived from the K-SADS. Results: Although ∼60% of the subjects had a DSM-IV psychiatric diagnosis, >60% received no mental health treatment. Absence of mental health care was associated with younger age, less parental education, limited number of antiepileptic drugs (AEDs; i.e., one or none), and higher verbal IQ. In addition, children with PGE and a single psychiatric diagnosis were less likely to have a history of mental health treatment. Conclusions: This is the first study to demonstrate unmet mental health need in a large sample of children with CPS and PGE. The study's findings suggest that parents and clinicians should be aware of the mental health needs of children with epilepsy, particularly if they have one or more of the identified risk factors.

Cardiac asystole in epilepsy: clinical and neurophysiologic features.

Abstract: Summary: Purpose: Cardiac asystole provoked by epileptic seizures is a rare but important complication in epilepsy and is supposed to be relevant to the pathogenesis of sudden unexplained death in epilepsy (SUDEP). We sought to determine the frequency of this complication in a population of patients with medically intractable epilepsy and to analyze the correlation between EEG, electrocardiogram (ECG), and clinical features obtained from long-term video-EEG monitoring. Methods: Retrospective analysis of the clinical records of hospitalized patients from May 1992 to June 2001 who underwent long-term video-/EEG monitoring. Results: Of a total of 1,244 patients, five patients had cardiac asystole in the course of ictal events. In these patients, 11 asystolic events, between 4 and 60 s long in a total of 19 seizures, were registered. All seizures had a focal origin with simple partial seizures (n = 13), complex partial seizures (n = 4), and secondarily generalized seizures (n = 2). One patient showed the longest asystole ever reported (60 s) because of a seizure. Cardiac asystole occurred in two patients with left-sided temporal lobe epilepsy (TLE) and in three patients with frontal lobe epilepsy (FLE; two left-sided, one bifrontal). Two patients reported previous cardiac disease, but only one had a pathologic ECG by the time of admission. Two patients had a simultaneous central ictal apnea during the asystole. None of the patients had ongoing deficits due to the asystole. Conclusions: These findings confirm that seizure-induced asystole is a rare complication. The event appeared only in focal epilepsies (frontal and temporal) with a lateralization to the left side. A newly diagnosed or known cardiac disorder could be a risk factor for ictal asystole. Abnormally long postictal periods with altered consciousness might point to reduced cerebral perfusion during the event because of ictal asystole. Central ictal apnea could be a frequent associated phenomenon.

Newer antiepileptic drugs and cognitive issues.

Abstract: Although the causes of cognitive impairment in patients with epilepsy have not been completely elucidated, three factors are clearly involved: the underlying etiology of epilepsy, the effects of seizures themselves, and the central nervous system effects of antiepileptic drugs (AEDs). All commonly used AEDS have some effect on cognitive function, and the effect may be substantial when crucial functions are involved, such as learning in children or driving ability in adults, or when already-vulnerable functions are involved, such as memory in elderly patients. The available evidence is insufficient to support definite conclusions about the cognitive effects of three of the newer AEDs, tiagabine, gabapentin, and levetiracetam. Better evidence is available for lamotrigine (LTG), topiramate (TPM), and, to a lesser degree, oxcarbazepine (OXC). OXC appears not to affect cognitive function in healthy volunteers or adults with newly diagnosed epilepsy, but its cognitive effects in children and adolescents have not been systematically studied. A relatively large number of studies are available for LTG, which has demonstrated a favorable cognitive profile overall, both in volunteers and in patients with epilepsy. Although dose and titration speed may be confounding factors in some of the studies of TPM, there is clear evidence that this agent does affect cognitive function, with specific effects on attention and verbal function. For LTG, attempts have been made to correlate cognitive effects with what is known of the drug's mechanism of action; this is an area of research that deserves further exploration with regard to other AEDs as well, especially TPM.

A retrospective analysis of hippocampal pathology in human temporal lobe epilepsy: evidence for distinctive patient subcategories.

Abstract: Summary: Purpose: This study is a retrospective analysis of the pathology of the hippocampus from patients with medically intractable temporal lobe epilepsy. We attempted to relate neuronal density, immunohistochemistry, electrophysiologic data, and surgical outcome. Methods: Immunostaining patterns for neuropeptide Y, somatostatin, substance P, and dynorphin defined the immunohistochemical characteristics of the hippocampi. Neuronal densities were determined by microscopic cell counts. Sharp electrode recordings from dentate granule cells determined measures of inhibition and excitation. Results: Patient hippocampi without evidence of sclerosis generally resembled autopsy controls on the basis of neuronal densities of hippocampal subfields and patterns of immunostaining. The nonsclerotic hippocampi were divisible into two subgroups on the basis of neuronal density correlations between hippocampal subfields, the excitability of dentate granule cells, etiology, and surgical outcome. Hippocampi with sclerosis were divisible into those with significant neuronal loss confined to area CA1 and those with neuronal loss throughout the hippocampus and dentate gyrus. In the former, the dentate gyrus resembled in morphology the nonsclerotic hippocampi but with slightly increased excitability of the dentate granule cells. The hippocampi with more extensive neuronal loss had changes in immunostaining patterns associated with the dentate gyrus, correlated with significant hyperexcitability of dentate granule cells. The surgical outcome, with the exception of one group, was good in ∼70–90%. Conclusions: Hippocampi from patients with intractable temporal lobe epilepsy can be assigned to several groups on the basis of pathophysiology. Different pathologies may represent differing causative mechanisms of intractable temporal lobe epilepsy and be predictive of surgical outcome.

Incidence and short-term prognosis of status epilepticus in adults in Bologna, Italy.

Abstract: Summary: Purpose: To determine the incidence and the 30-day case fatality of status epilepticus (SE) in the adult resident population of the city of Bologna, Italy. Methods: Over a 1-year period (March 1, 1999 to February 29, 2000), all patients older than 20 years with SE were included. The case-finding method was based on (a) a prospective surveillance of all public general hospitals in the city by neurologic units, and (b) a review of all discharge codes concerning epilepsy. Results: The crude and standardized annual incidence rate of SE was 13.1 per 100,000 [95% confidence interval (CI), 9.5‐ 17.5] and 10.7 (95% CI, 7.5‐13.8). It was higher in the elderly (older than 60 years) than in young adults (26.2 vs. 5.2) and in women than in men (14.9 vs. 11.0). Acute symptomatic SE accounted for 48%, and a cerebrovascular pathology was the most frequently associated etiologic condition (41%). A history of seizures was reported in 39% of patients. The 30-day case fatality was 39% (33% excluding postanoxic patients). Conclusions: This study reports the first data on the epidemiology of SE in Italy. The incidence rate found in the population of Bologna is in the same range as that of the other European countries. The 30-day case fatality is higher than all the other population studies (both European and American), despite the broadly similar clinical features of patients. Indirect evidence suggests that some inaccurate patient management could have negatively influenced the outcome of SE. Key Words: Status epilepticus—Incidence—Prognosis.

Preclinical development of antiepileptic drugs: past, present, and future directions.

Abstract: Summary: Since 1993, nine new antiepileptic drugs (AEDs) have been introduced into the U.S. market for the symptomatic treatment of partial epilepsy. Their antiepileptic activity was, for the most part, defined by acute seizure models such as the maximal electroshock (MES) and subcutaneous pentylenetetrazol (scPTZ) seizure tests and the kindled rat. Unfortunately, the clinical evidence to date would suggest that none of these models, albeit useful, are likely to identify those therapeutics that will effectively manage the patient with refractory seizures. In recent years, a number of in vivo and in vitro models have been developed that display varying degrees of pharmacoresistance. As such, they may provide a unique opportunity for identifying the truly novel AED. Through a greater understanding of the pathophysiology of acquired epilepsy at the molecular and genetic level, it may be possible to identify a new therapeutic approach that reaches beyond the symptomatic treatment of epilepsy to modify the progression, or, dare we suggest, prevent the development of epilepsy in the susceptible patient. The realization of such a possibility will necessitate a change in our current AED discovery approach. The present review describes the current approach used in the search for new AEDs and offers some insight into future directions incorporating new and emerging models of therapy resistance and epileptogenesis.

fMRI activation in continuous and spike-triggered EEG-fMRI studies of epileptic spikes.

Abstract: Summary: Purpose: To evaluate functional magnetic resonance imaging (fMRI) with simultaneous EEG for finding metabolic sources of epileptic spikes To find the localizing value of activated regions and factors influencing fMRI responses Methods: Patients with focal epilepsy and frequent spikes were subjected to spike-triggered or continuous fMRI with simultaneous EEG Results were analyzed in terms of fMRI activation, concordance with the location of EEG spiking and anatomic MRI abnormalities, and other EEG and clinical variables In four patients, results also were compared with those of intracerebral EEG Results: Forty-eight studies were performed on 38 patients Seventeen studies were not analyzed, primarily because no spikes occurred during scanning Activation was obtained in 39% of 31 studies, with an activation volume of 255 ± 484 cc Activated regions were concordant with EEG localization in almost all studies and confirmed by intracerebral EEG in four patients Forty percent of patients without an MRI lesion showed activation; 375% of patients with a lesion had an activation; the activation was near or inside the lesion Bursts of spikes were more likely to generate an fMRI response than were isolated spikes (76 vs 11%; p < 005) Conclusions: Combining EEG and fMRI in focal epilepsy yields regions of activation that are presumably the source of spiking activity These regions are highly linked with epileptic foci and epileptogenic lesions in a significant number of patients Activation also is found in patients with no visible MRI lesion Intracerebral recordings largely confirm that these activation regions represent epileptogenic areas It is still unclear why many patients show no activation Key Words: Functional magnetic resonance imaging—Activation—Spikes

Induced oscillations in the alpha band: functional meaning.

Abstract: The phenomena of event-related desynchronization (ERD) and synchronization (ERS) reflect the dynamics of neural networks and can be observed on different scalp locations at the same moment of time. Whereas on one cortical area a focal 10-Hz ERD can be found, other areas can display a 10-Hz ERS. This phenomenon is called focal ERD/surround ERS and is interpreted as a correlate of an activated cortical area (ERD) and simultaneously deactivated or inhibited other areas. The induced oscillations (ERS) are dominant in the 10- to 13-Hz band and very likely mediated by thalamic gating.

Risk factors for posttraumatic seizures in adults.

Abstract: Summary: Purpose: Traumatic brain injury has long been known to be a cause of epilepsy. Most information on risk factors for developing posttraumatic seizures is from before computed tomography (CT) scanning became universal. This article looks at factors about the injury or individual that put people at especially high risk of developing posttraumatic seizures. Methods: We considered 783 cases at high risk of developing seizures, followed up for 2 years as part of seizure prophylaxis studies. Cumulative incidence of seizures in subgroups and standardized incidence ratios were used to identify factors related to unprovoked seizure risk. Results: Subgroups with significantly elevated risk include those with evacuation of a subdural hematoma; surgery for an intracerebral hematoma; Glasgow Coma Scale in the severe range of 3 to 8; early seizures, especially delayed early seizures; time to following commands of a week or more; depressed skull fracture that was not surgically elevated; dural penetration by injury; at least one nonreactive pupil; and parietal lesions on CT scan. Conclusions: Both the risk factors and the time course of the risk are important for designing seizure-prophylaxis studies and, if an effective prophylactic regimen is identified, for deciding on appropriate candidates for prophylaxis.

Health‐related Quality of Life in Children with Epilepsy: Development and Validation of Self‐report and Parent Proxy Measures

Abstract: Purpose To answer a need to include and measure accurately the impact and burden of epilepsy as outcomes of interventions with affected children, we developed and validated self-report and parent-proxy respondent health-related quality of life (HRQL) instruments for preadolescent children with epilepsy. Methods We combined qualitative and quantitative research methods. Items were extracted from focus group discussions involving children with epilepsy and their parents. We created scales formatted with alternative paired options of forced responses and used factor analysis to generate relevant subscales and reduce the number of items. We checked internal consistency, assessed test-retest reliability 10-14 days apart, and documented construct validity. Results A sample of 381 children with epilepsy, age 6-15 years, and their parents independently completed a 67-item questionnaire, from which we chose five items for each subscale. The measures share four subscales, but each measure has an additional distinct subscale. The children and parents could discern differences and report differentially between the various aspects of the HRQL. Internal consistency measured with Cronbach's alpha was acceptable for all subscales; construct validity has been demonstrated from the testing of several hypotheses. Test-retest reliability examined with the intraclass correlation coefficient was satisfactory for the parents and for children age 8 years and older. The correlations between the mothers' and children's responses was poor to moderate. Conclusions The data demonstrate sound psychometric properties for both related measures, which are easy to administer for children with epilepsy who are 8 years and older and their parents. The subscales encompass HRQL dimensions judged most important by children with epilepsy for the self-report measure and by parents for the proxy response measure. The parent-proxy measure should be useful as a complement to the child self-report measure in evaluating the validity of parental assessment of the child's health status; in longitudinal outcome research; and in HRQL assessment of children who are unable to respond independently.

Topiramate and psychiatric adverse events in patients with epilepsy.

Abstract: Summary: Purpose: The aim of this study was to determine the prevalence of psychiatric adverse events (PAEs) in patients with epilepsy treated with topiramate (TPM). Classification, relation to TPM dosing, and outcome were evaluated to identify a patient profile at risk of developing PAEs. Methods: We evaluated the data of the first consecutive and prospectively collected patients in therapy with TPM. Results: Follow-up information was available for 431 patients. PAEs occurred in 103 (23.9%) patients; M/F ratio, 55:48; mean age (±SD), 36.5 ± 11.2. In 46 (10.7%) patients, an affective disorder developed; in 16 (3.7%), a psychotic disorder; in 24 (5.6%), aggressive behavior with or without irritability; in 17 (3.9%), other behavior abnormalities such as agitated behavior, anger/hostility behavior, or anxiety. High starting dose and rapid titration schedule were relevant for the development of PAEs. Family psychiatric history and family history of epilepsy, personal history of febrile convulsions, psychiatric history, and presence of tonic–atonic seizures were found to be significant risk factors. Low seizure frequency before starting TPM and TPM/lamotrigine coadministration had a protective effect for PAEs. Conclusions: We found that PAEs associated with TPM were related to the titration schedule of the drug and that a unique patient profile is suggested by the clinical history.

Seizure Suppression by Adenosine A1 Receptor Activation in a Mouse Model of Pharmacoresistant Epilepsy

Abstract: Summary: Purpose: Because of the high incidence of pharmacoresistance in the treatment of epilepsy (20–30%), alternative treatment strategies are needed. Recently a proof-of-principle for a new therapeutic approach was established by the intraventricular delivery of adenosine released from implants of engineered cells. Adenosine-releasing implants were found to be effective in seizure suppression in a rat model of temporal lobe epilepsy. In the present study, activation of the adenosine system was applied as a possible treatment for pharmacoresistant epilepsy. Methods: A mouse model for drug-resistant mesial temporal lobe epilepsy was used, in which recurrent spontaneous seizure activity was induced by a single intrahippocampal injection of kainic acid (KA; 200 ng in 50 nl). Results: After injection of the selective adenosine A1-receptor agonist, 2-chloro-N6-cyclopentyladenosine (CCPA; either 1.5 or 3 mg/kg, i.p.), epileptic discharges determined in EEG recordings were completely suppressed for a period of ≤3.5 h after the injections. Seizure suppression was maintained when 8-sulfophenyltheophylline (8-SPT), a non–brain-permeable adenosine-receptor antagonist, was coinjected systemically with CCPA. In contrast, systemic injection of carbamazepine or vehicle alone did not alter the seizure pattern. Conclusions: This study demonstrates that activation of central adenosine A1 receptors leads to the suppression of seizure activity in a mouse model of drug-resistant epilepsy. We conclude that the local delivery of adenosine into the brain is likely to be effective in the control of intractable seizures.

The multicenter study of epilepsy surgery: Recruitment and selection for surgery

Abstract: Summary: Purpose: Multiple studies have examined predictors of seizure outcomes after epilepsy surgery. Most are single-center series with limited sample size. Little information is available about the selection process for surgery and, in particular, the proportion of patients who ultimately have surgery and the characteristics that identify those who do versus those who do not. Such information is necessary for providing the epidemiologic and clinical context in which epilepsy surgery is currently performed in the United States and in other developed countries. Methods: An observational cohort of 565 surgical candidates was prospectively recruited from June 1996 through January 2001 at six Northeastern and one Midwestern surgical centers. Standardized eligibility criteria and protocol for presurgical evaluations were used at all seven sites. Results: Three hundred ninety-six (70%) study subjects had resective surgery. Clinical factors such as a well-localized magnetic resonance imaging (MRI) abnormality and consistently localized EEG findings were most strongly associated with having surgery. Of those who underwent intracranial monitoring (189, 34%), 85% went on to have surgery. Race/ethnicity and marital status were marginally associated with having surgery. Age, education, and employment status were not. Demographic factors had little influence over the surgical decision. More than half of the patients had intractable epilepsy for ≥10 years and five or more drugs had failed by the time they initiated their surgical evaluation. During the recruitment period, eight new antiepileptic drugs were approved by the Food and Drug Administration for use in the United States and came into increasing use in this study's surgical candidates. Despite the increased availability of new therapeutic options, the proportion that had surgery each year did not fluctuate significantly from year to year. This suggests that, in this group of patients, the new drugs did not provide a substantial therapeutic benefit. Conclusions: Up to 30% of patients who undergo presurgical evaluations for resective epilepsy surgery ultimately do not have this form of surgery. This is a group whose needs are not currently met by available therapies and procedures. Lack of clear localizing evidence appears to be the main reason for not having surgery. To the extent that these data can address the question, they suggest that repeated attempts to control intractable epilepsy with new drugs will not result in sustained seizure control, and eligible patients will proceed to surgery eventually. This is consistent with recent arguments to consider surgery earlier rather than later in the course of epilepsy. Postsurgical follow-up of this group will permit a detailed analysis of presurgical factors that predict the best and worst seizure outcomes.

From molecules to networks: cortical/subcortical interactions in the pathophysiology of idiopathic generalized epilepsy.

Abstract: Generalized epilepsy involves abnormally synchronized activity in large-scale neuronal networks. Burst firing of action potentials is a potent mechanism for increasing neural synchrony and is thought to enhance cortical and thalamic rhythmic network activity. Absence seizures, a form of generalized epilepsy, occur in children as brief 5- to 10-s periods of behavioral arrest associated with massive 3- to 4-Hz spike-wave discharges in cortical and thalamic networks. Prior research has shown that enhanced burst firing may be crucial for the transition from normal to epileptic activity. Can enhanced burst firing in one region of the nervous system, such as the cortex, transform the entire thalamocortical network from normal activity to spike-and-wave seizures? Enhanced burst firing in corticothalamic neurons may increase gamma-aminobutyric acid-B (GABAB) receptor activation in the thalamus, leading to the slower, more synchronous oscillations seen in spike-and-wave seizures. Does "generalized" spike-wave activity homogeneously involve the entire brain, or are there crucial nodes that are more important than others for the generation and behavioral manifestations of generalized seizures? Animal and human data suggest that so-called generalized seizures involve selective thalamocortical networks while sparing others. A greater understanding of these molecular and network mechanisms will ultimately lead to improved targeted therapies for generalized epilepsy.

Epileptogenicity of Focal Malformations Due to Abnormal Cortical Development: Direct Electrocorticographic–Histopathologic Correlations

Abstract: Summary: Purpose: Malformations due to abnormal cortical development (MCDs) are common pathologic substrates of medically intractable epilepsy. The in situ epileptogenicity of these lesions as well as its relation to histopathologic changes remains unknown. The purpose of this study was to correlate the cellular patterns of MCDs with the expression of focal cortical epileptogenicity as assessed by direct extraoperative electrocorticographic (ECoG) recordings by using subdural grids. Methods: Fifteen patients with drug-resistant focal epilepsy due to pathologically confirmed MCD who underwent subdural electrode placement for extraoperative seizure localization and cortical mapping between 1997 and 2000 were included in the study. Areas of interictal spiking and ictal-onset patterns were identified and separated during surgery for further pathologic characterization (cellular and architectural). Three pathologic groups were identified: type I; architectural disorganization with/without giant neurons, type IIA; architectural disorganization with dysmorphic neurons, and type IIB; architectural disorganization, dysmorphic neurons, and balloon cells (BCs). The focal histopathologic subtypes of MCDs in cortical tissue resected were then retrospectively correlated with in situ extraoperative ECoG patterns. Results: Cortical areas with histopathologic subtype IIA showed significantly higher numbers of slow repetitive spike pattern in comparison with histopathologic type I (p = 0.007) and normal pathology (p = 0.002). The ictal onset came mainly from cortical areas with histopathologic type IIA (nine of 15 patients). None of the seizures originated from neocortical areas that showed BC-containing MCD (type IIB). Conclusions: This study shows that areas containing BCs are less epileptogenic than are closely located dysplastic regions. These results suggest a possible protective effect of BCs or a severe disruption in the neuronal networks in BCs containing dysplastic lesions. Further studies are needed to elucidate the nature and the potential role(s) of balloon cells in MCD-induced epileptogenicity.

Mental Retardation in Pediatric Candidates for Epilepsy Surgery: The Role of Early Seizure Onset

Abstract: Summary: Purpose: We sought to determine whether early age at seizure onset is a risk factor for mental retardation, independent of etiology. Assessment of risk for mental retardation with continued uncontrolled seizures plays a role in considerations of timing for epilepsy surgery. Previous studies have indicated that onset of seizures in the first years of life may be a risk factor for mental retardation, but the etiologies of the epilepsies were not included in the analyses. Methods: Intellectual function was assessed at ages 2–20 years during presurgical evaluation in 100 patients with intractable epilepsy due to focal lesions limited to part of one lobe of the brain. Mental retardation (MR) was defined as Full-Scale Intelligence Quotient (FSIQ) ≤70. The age at seizure onset and the seizure frequency were obtained retrospectively. Results: Younger ages at seizure onset were associated with lower FSIQ scores, and mean FSIQ was also significantly lower for patients with onset of epilepsy at ≤24 months of age (74.0 ± 21.5) versus that in patients with onset of epilepsy later in life (87.8 ± 18.8; p = 0.005). The frequency of patients with MR was significantly higher for patients with seizure onset at ≤24 months of age (15 of 33, 46%) than for patients with seizure onset later in life (eight of 67, 12%; p 24 months (p 24 months (p = 0.003); and for patients with hippocampal sclerosis, MR was seen in two (28%) of seven patients with seizure onset at ≤24 months versus none of 30 patients with seizure onset at >24 months (NS). Within the subgroup with daily seizures, MR was present in 13 (65%) of 20 patients with seizure onset at ≤24 months versus five (17%) of 29 patients with seizure onset later in life (p = 0.001). Conclusions: These results indicate that onset of intractable epilepsy within the first 24 months of life is a significant risk factor for MR, especially if seizures occur daily. The risk based on early age at seizure onset appeared independent of etiology and persisted within subgroups of patients with focal malformation of cortical development, tumor, or hippocampal sclerosis. Prospective studies will be important to clarify whether early surgical intervention may reduce the risk for subsequent MR in carefully selected infants.

The Effects of Adjunctive Topiramate on Cognitive Function in Patients with Epilepsy

Abstract: Summary: Purpose: We investigated possible cognitive effects of topiramate (TPM) in polypharmacy on patients with intractable epilepsy. Methods: Study 1 evaluated 22 consecutively admitted patients whose antiepileptic drugs (AEDs) on admission to the Montreal Neurological Hospital included TPM. Performance on neuropsychological tests administered on and subsequently off TPM was analyzed. Four patients also were tested before taking TPM, allowing comparisons off, then on, and then off the drug again. Measures included intellectual function, verbal and nonverbal memory, language, word and design fluency, somatosensory sensitivity, and motor skills. In Study 2, 16 patients at the Minnesota Epilepsy Group were tested first off, then on TPM with nine cognitive tasks that measured concentration, verbal fluency, language, and psychomotor speed. Results: In Study 1, significant (p ≤ 0.01) improvements were observed off TPM on 13 measures including verbal and nonverbal fluency and certain verbal and perceptual tasks. Notably, verbal learning and memory were unaffected; a limited effect was observed on nonverbal memory. Patients tested 3 times scored better in both tests off TPM compared with on this drug. In Study 2, declines on TPM were observed on all measures, significantly (p ≤ 0.05) for tests of fluency, sustained concentration, and visual motor processing speed. Conclusions: TPM was associated with declines in fluency, attention/concentration, processing speed, language skills, and perception; working memory but not retention was affected. As the two studies used an opposite order of testing on versus off TPM, our results clearly show a performance decrement while patients are taking TPM, without respect to which condition is tested first.

Therapy discovery for pharmacoresistant epilepsy and for disease-modifying therapeutics: summary of the NIH/NINDS/AES models II workshop.

Abstract: The National Institutes of Health (NIH), through the Antiepileptic Screening Project (formerly known as the Antiepileptic Drug Development Program), has been a key element in the discovery and introduction of new pharmacologic therapies since the institution of the program more than 25 years ago. The program was established with the goals of facilitating the identification of new drugs that were safer and more efficacious epilepsy treatments. Through these efforts and leadership, the program has been highly successful, with the introduction of many new antiepileptic compounds, providing new and welcomed treatment options to epilepsy patients worldwide. In spite of these successes, these new drugs have yet to make a significant impact in the most difficult to treat conditions, or for those patients who are incompletely responsive to available pharmacologic treatments. It is estimated that more than one third of patients with epilepsy (∼750,000 Americans) belong in this pharmacoresistant category. Because of this large number of pharmacoresistant patients with epilepsy, a developing consensus mandates that the current process of therapy discovery and development must be reevaluated and enhanced in light of the evolution of available models and our understanding of epilepsy. Several large meetings (notably the White House–initiated conference, “Curing Epilepsy: Focus on the Future,” which was held in March 2000, and the NIH Workshop for Models for Epilepsy and Epileptogenesis, held in March 2001) started the process. One of the primary recommendations of these conferences was that the existing process of therapy discovery and development should be enhanced with a focus on developing preclinical models that would be more predictive of clinical success in stopping the seizures of patients currently incompletely controlled with existing therapies. In addition, strong recommendations were made to develop mechanisms to identify treatments that will prevent the development of epilepsy (epileptogenesis). A key element in this latter recommendation is the identification of appropriate models for epileptogenesis and the creation of a process that will use these models for antiepileptogenic therapy discovery. In response to these recommendations, a workshop was held in September 2002 to identify useful models for therapy discovery for treatment of resistant epilepsy and the actual prevention of the disease. The first goal of this conference focused on recommendations of models to identify potential new therapies and to predict the clinical efficacy of these therapies. The second was the development of a process that can be used to evaluate and add new and promising models as they come along. The following paragraphs are a summary of the meeting with an emphasis on the recommendations that were made regarding therapy resistance and epileptogenesis. Two working groups were created for the meeting: one to concentrate on issues of therapy-resistant epilepsy, and the other to focus on disease-modifying therapeutics (DzM). The two focus groups were asked to consider the potential of candidate models in predicting clinical success of any particular treatment. Other major considerations required in the evaluations were the relative ease of use and the potential parallels among the different human epilepsies. An important point of emphasis was that the evaluation and eventual recommendations must be focused on the potential for the models to be predictive for clinical success, not for the relative value of the models for basic epilepsy research, while acknowledging the critical need for the latter. This process of evaluation should at no time be considered a general ranking system of epilepsy models. The many models, in vitro and in vivo, possess important scientific value for our understanding of the mechanisms of epilepsy. Therefore the overall goal of this workshop was to apply these criteria toward model evaluation to identify the most scientifically feasible screening

Obstructive sleep apnea in a clinical series of adult epilepsy patients: frequency and features of the comorbidity.

Abstract: Summary: Purpose: The aim of this study was to evaluate the rate and features of obstructive sleep apnea (OSA) in adult epilepsy patients. Methods: Two hundred eighty-three adult epilepsy patients (137 men; mean age, 33 years; range, 18‐70 years) were prospectively screened for OSA by means of a structured interview. Those in whom OSA was clinically suspected were monitored for a full night by using a portable device (Polymesam), and OSA was diagnosed when they had an Apnea/Hypopnea Index greater than five. Results: Coexistence of OSA with epilepsy was found in 10.2% (15.4% of the male and 5.4% of the female) epilepsy patients investigated. The OSA was mild in 66.6%, moderate in 22.2%, and severe in 11.1% of the cases. The “epilepsy + OSA” patients were older, heavier, more frequently male, and sleepier (p < 0.05) than those with “epilepsy only.” Furthermore, they experienced their first seizure at an older age (p < 0.05). Conclusions: Systematic investigation reveals that OSA is frequent in epilepsy patients. The major risk factors for OSA in our epilepsy patients were the same as those typically found in the general population. Of the epilepsy-related factors, older age at onset of seizures appears to be significantly related to comorbidity with OSA (p < 0.05). The presence in epilepsy patients of these features should alert the clinician to the possibility of an underlying OSA. Key Words: Epilepsy—Obstructive sleep apnea.

Increased Frequency of Rolandic Spikes in ADHD Children

Abstract: Summary: Purpose: Some children with rolandic epilepsy have associated neuropsychiatric deficits resembling symptoms of attention deficit‐hyperactivity disorder (ADHD), the most common neurobehavioral disorder of childhood. The clinical overlap between both syndromes has received relatively little attention. The study examines the frequency of rolandic spikes in nonepileptic children with ADHD and compares it with a historic control group of 3,726 normal school-aged children. ADHD patients with and without discharges are compared regarding age at admission, sex, global functioning, and distribution of ADHD subtypes. Methods: The EEGs of 483 ADHD outpatients between 2 and 16 years meeting diagnostic criteria for ADHD according to Diagnostic and Statistical Manual of Mental Disorders (DSMIV) were evaluated prospectively. If rolandic spikes were present, separate sleep EEGs were performed to exclude a bioelectrical status epilepticus during slow-wave sleep. Results: Rolandic spikes were detected in the EEGs of 27 children (5.6%; 22 boys and five girls). Seizure rate during follow-up tended to be larger in children with rolandic spikes. No significant differences were found between ADHD patients with and without spikes regarding sex and global functioning. ADHD children with rolandic spikes came to our attention significantly earlier than did children without discharges and tended to exhibit more hyperactive‐impulsive symptoms, evidenced in a larger proportion of the diagnosis of ADHD combined type than ADHD inattentive type. Conclusions: The frequency of rolandic spikes in children with ADHD is significantly higher than expected from epidemiologic studies. The question arises how ADHD symptoms are related to rolandic spikes in this ADHD subgroup. Possibly rolandic discharges or underlying, not fully understood mechanisms of epileptogenesis decrease the vulnerability threshold, advance the onset, or aggravate the course of ADHD. Key Words: BECTS—Rolandic spikes—ADHD— Brain maturation—Transient cognitive impairment.

Hypothalamic hamartoma and seizures: a treatable epileptic encephalopathy.

Abstract: Hypothalamic hamartomas may be associated with gelastic seizures, focal seizures, and a generalized epileptic encephalopathy, with severe seizures and cognitive and behavior decline. Despite earlier views to the contrary, good evidence now exists that all these clinical features are caused, directly or indirectly, by the hamartoma. Resection of these lesions was long regarded as too hazardous and unlikely to benefit seizure control. It is now clear that hypothalamic hamartomas can be effectively treated with a variety of surgical approaches with sustained seizure control and often seizure freedom. Qualitative observations suggest that behavior and cognition also improve with treatment, but quantitative validation is required. The specific approach should be tailored according to the surgical anatomy of the lesion and the experience of the surgeon. Choices include a transcallosal approach (good for intraventricular lesions), a pterional approach (useful for interpeduncular lesions), a transventricular endoscopic approach, or destruction of the lesion with radiofrequency probes or gamma knife radiosurgery. The previously dismal outlook for children with severe seizures associated with this lesion has now dramatically changed. These insights may have implications for other epileptic encephalopathies of childhood.