Showing papers in "Epilepsia in 2005"

Epileptic seizures and epilepsy : Definitions proposed by the international league against epilepsy (ILAE) and the international bureau for epilepsy (IBE)

Abstract: The International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE) have come to consensus definitions for the terms epileptic seizure and epilepsy. An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiologic, cognitive, psychological, and social consequences of this condition. The definition of epilepsy requires the occurrence of at least one epileptic seizure.

Brain inflammation in epilepsy: experimental and clinical evidence.

Abstract: Inflammatory reactions occur in the brain in various CNS diseases, including autoimmune, neurodegenerative, and epileptic disorders. Proinflammatory and antiinflammatory cytokines and related molecules have been described in CNS and plasma, in experimental models of seizures and in clinical cases of epilepsy. Inflammation involves both the innate and the adaptive immune systems and shares molecules and pathways also activated by systemic infection. Experimental studies in rodents show that inflammatory reactions in the brain can enhance neuronal excitability, impair cell survival, and increase the permeability of the blood-brain barrier to blood-borne molecules and cells. Moreover, some antiinflammatory treatments reduce seizures in experimental models and, in some instances, in clinical cases of epilepsy. However, inflammatory reactions in brain also can be beneficial, depending on the tissue microenvironment, the inflammatory mediators produced in injured tissue, the functional status of the target cells, and the length of time the tissue is exposed to inflammation. We provide an overview of the current knowledge in this field and attempt to bridge experimental and clinical evidence to discuss critically the possibility that inflammation may be a common factor contributing, or predisposing, to the occurrence of seizures and cell death, in various forms of epilepsy of different etiologies. The elucidation of this aspect may open new perspectives for the pharmacologic treatment of seizures.

Drug resistance in epilepsy : Putative neurobiologic and clinical mechanisms

Abstract: Drug-resistant epilepsy with uncontrolled severe seizures despite state-of-the-art medical treatment continues to be a major clinical problem for up to one in three patients with epilepsy. Although drug resistance may emerge or remit in the course of epilepsy or its treatment, in most patients, drug resistance seems to be continuous and to occur de novo. Unfortunately, current antiepileptic drugs (AEDs) do not seem to prevent or to reverse drug resistance in most patients, but add-on therapy with novel AEDs is able to exert a modest seizure reduction in as many as 50% of patients in short-term clinical trials, and a few become seizure free during the trial. It is not known why and how epilepsy becomes drug resistant, while other patients with seemingly identical seizure types can achieve seizure control with medication. Several putative mechanisms underlying drug resistance in epilepsy have been identified in recent years. Based on experimental and clinical studies, two major neurobiologic theories have been put forward: (a) removal of AEDs from the epileptogenic tissue through excessive expression of multidrug transporters, and (b) reduced drug-target sensitivity in epileptogenic brain tissue. On the clinical side, genetic and clinical features and structural brain lesions have been associated with drug resistance in epilepsy. In this article, we review the laboratory and clinical evidence to date supporting the drug-transport and the drug-target hypotheses and provide directions for future research, to define more clearly the role of these hypotheses in the clinical spectrum of drug-resistant epilepsy.

Cellular and network mechanisms of spike-wave seizures

Abstract: Summary: Spike-wave seizures are often considered a relatively “pure” form of epilepsy, with a uniform defect present in all patients and involvement of the whole brain homogenously. Here, we present evidence against these common misconceptions. Rather than a uniform disorder, spike-wave rhythms arise from the normal inherent network properties of brain excitatory and inhibitory circuits, where they can be provoked by many different insults in several different brain networks. Here we discuss several different cellular and molecular mechanisms that may contribute to the generation of spike-wave seizures, particularly in idiopathic generalized epilepsy. In addition, we discuss growing evidence that electrical, neuroimaging, and molecular changes in spike-wave seizures do not involve the entire brain homogenously. Rather, spike-wave discharges occur selectively in some thalamocortical networks, while sparing others. It is hoped that improved understanding of the heterogeneous defects and selective brain regions involved will ultimately lead to more effective treatments for spike-wave seizures.

Photic- and pattern-induced seizures: a review for the Epilepsy Foundation of America Working Group.

Abstract: Summary: Purpose: This report summarizes background material presented to a consensus conference on visually provoked seizures, convened by the Epilepsy Foundation of America. Methods: A comprehensive review of literature was performed. Results: Photosensitivity, an abnormal EEG response to light or pattern stimulation, occurs in ∼0.3–3% of the population. The estimated prevalence of seizures from light stimuli is ∼1 per 10,000, or 1 per 4,000 individuals age 5–24 years. People with epilepsy have a 2–14% chance of having seizures precipitated by light or pattern. In the Pokemon cartoon incident in Japan, 685 children visited a hospital in reaction to red–blue flashes on broadcast television (TV). Only 24% who had a seizure during the cartoon had previously experienced a seizure. Photic or pattern stimulation can provoke seizures in predisposed individuals, but such stimulation is not known to increase the chance of subsequent epilepsy. Intensities of 0.2–1.5 million candlepower are in the range to trigger seizures. Frequencies of 15–25 Hz are most provocative, but the range is 1–65 Hz. Light–dark borders can induce pattern-sensitive seizures, and red color also is a factor. Seizures can be provoked by certain TV shows, movie screen images, video games, natural stimuli (e.g, sun on water), public displays, and many other sources. Conclusions: Recommendations on reducing risk of seizures have been developed by agencies in the United Kingdom, Japan, and the International Telecommunications Union, affiliated with the United Nations. The Epilepsy Foundation of America has developed a consensus of medical experts and scientists on this subject, reported in an accompanying work.

Intracranial EEG substrates of scalp EEG interictal spikes.

Abstract: Summary: Purpose: To determine the area of cortical generators of scalp EEG interictal spikes, such as those in the temporal lobe epilepsy. Methods: We recorded simultaneously 26 channels of scalp EEG with subtemporal supplementary electrodes and 46 to 98 channels of intracranial EEG in 16 surgery candidates with temporal lobe epilepsy. Cerebral discharges with and without scalp EEG correlates were identified, and the area of cortical sources was estimated from the number of electrode contacts demonstrating concurrent depolarization. Results: We reviewed ∼600 interictal spikes recorded with intracranial EEG. Only a very few of these cortical spikes were associated with scalp recognizable potentials; 90% of cortical spikes with a source area of >10 cm2 produced scalp EEG spikes, whereas only 10% of cortical spikes having <10 cm2 of source area produced scalp potentials. Intracranial spikes with <6 cm2 of area were never associated with scalp EEG spikes. Conclusions: Cerebral sources of scalp EEG spikes are larger than commonly thought. Synchronous or at least temporally overlapping activation of 10–20 cm2 of gyral cortex is common. The attenuating property of the skull may actually serve a useful role in filtering out all but the most significant interictal discharges that can recruit substantial surrounding cortex.

Sudden unexpected death in epilepsy: a review of incidence and risk factors.

Abstract: Sudden unexpected death in epilepsy (SUDEP) is the most important direct epilepsy-related cause of death. However, SUDEP is rare in patients with new onset epilepsy and in patients in remission. Incidence is about 0.35 cases/1,000 person-years in population-based incidence cohort of epilepsy. Incidence is considerably higher in patients with chronic epilepsy, 1-2/1,000 person-years, and highest with severe, refractory seizures, 3-9/1,000. The highest rates occur from 20 to 40 years. Most SUDEP appears seizure-related. When witnessed, the fatal event generally occurred in association with generalized tonic-clonic seizure. Two recent case-control studies suggest that seizure frequency is the strongest risk factor for SUDEP: relative risk = 23 (95% CI = 3.2-170) for persons with > or =1 seizure during the year of observation versus seizure-free patients. Onset of epilepsy at an early age and long duration of the disorder are other risk factors. Although SUDEP has not been associated with the use of any particular antiepileptic drugs (AEDs), some case-control studies have pointed to an association between SUDEP and polytherapy with AEDs and frequent dose changes independent of seizure frequency. Although recent epidemiological studies have been helpful in identifying patients at risk for SUDEP, providing clues to mechanisms behind SUDEP, no single risk factor is common to all SUDEP, suggesting multiple mechanisms or trigger factors. Seizure control seems of paramount importance to prevent SUDEP. Further large-scale case-control studies are needed to assess the role of AEDs in order to form a basis for treatment strategies aiming at seizure control and prevention of SUDEP.

Psychological distress, comorbidities, and health behaviors among U.S. adults with seizures: results from the 2002 National Health Interview Survey.

Abstract: Summary: Purpose: To examine the association of seizures with health-related quality of life (HRQOL), physical and psychiatric comorbidities, and health behaviors. Methods: We analyzed data obtained from adults aged 18 years or older (n = 30,445) who participated in the 2002 National Health Interview Survey, an ongoing, computer-assisted personal interview of the noninstitutionalized U.S. population. Results: An estimated 1.4% of adults 18 years or older reported being told by a health care professional that they had seizures. Persons with seizures were significantly more likely than those without seizures to report lower levels of education, higher levels of unemployment, pain, hypersomnia and insomnia, and psychological distress (e.g., feelings of sadness, nervousness, hopelessness, and worthlessness). In addition, they were significantly more likely to report insufficient leisure-time physical activity as well as physical comorbidities such as cancer, arthritis, heart disease, stroke, asthma, severe headaches, lower back pain, and neck pain. Conclusions: Our findings suggest that it is advisable for health care professionals to assess psychiatric and physical comorbidities among patients with a history of seizures potentially to improve patient health outcomes. Furthermore, public health surveillance systems should include questions on seizures, epilepsy, and mental health to better examine associations among these disorders and to better identify populations meriting further assessment and intervention.

Depression and Anxiety Disorders in Pediatric Epilepsy

Abstract: Summary: Purpose: This study examined affective disorders, anxiety disorders, and suicidality in children with epilepsy and their association with seizure-related, cognitive, linguistic, family history, social competence, and demographic variables. Methods: A structured psychiatric interview, mood self-report scales, as well as cognitive and language testing were administered to 100 children with complex partial seizures (CPSs), 71 children with childhood absence epilepsy (CAE), and 93 normal children, aged 5 to 16 years. Parents provided behavioral information on each child through a structured psychiatric interview and behavior checklist. Results: Significantly more patients had affective and anxiety disorder diagnoses (33%) as well as suicidal ideation (20%) than did the normal group, but none had made a suicide attempt. Anxiety disorder was the most frequent diagnosis among the patients with a diagnosis of affective or anxiety disorders, and combined affective/anxiety and disruptive disorder diagnoses, in those with suicidal ideation. Only 33% received some form of mental health service. Age, verbal IQ, school problems, and seizure type were related to the presence of a diagnosis of affective or anxiety disorder, and duration of illness, to suicidal ideation. Conclusions: These findings together with the high rate of unmet mental health underscore the importance of early detection and treatment of anxiety disorders and suicidal ideation children with CPSs and CAE. Ke yW ords: Depression—Anxiety—Suicide—Complex partial seizure disorder— Absence epilepsy—Child.

Epidemiology of Idiopathic Generalized Epilepsies

Abstract: Idiopathic generalized epilepsies (IGEs) are a relatively new category of disorders defined by strict clinical and electroencephalogram (EEG) features proposed by the International League Against Epilepsy (ILAE) classification of epileptic syndromes. IGEs are usually easy to diagnose when clinical and EEG data are collected, but epilepsy is not synonymous with epileptic syndrome. So far, IGEs are studied in the large group of epilepsies of undetermined or unknown etiology although the genetic origin is now largely accepted. ILAE-proposed criteria are helpful in the clinical and therapeutic management of IGEs, but many epidemiologic studies still confuse the cryptogenic and idiopathic groups. Some syndromes in childhood, which are completely described by strict electroclinical criteria such as the absence epilepsies, juvenile myoclonic epilepsies, are usually included and analyzed in epidemiologic studies; however, other epileptic syndromes observed in infancy, such as benign familial neonatal seizures and benign myoclonic epilepsy in infancy, are quite rare and are usually excluded from epidemiologic surveys because they are difficult to describe completely in electro-clinical terms. Another strong limitation in the study of epidemiology of IGEs is the lack of EEG data, either because EEG is not available or the routine EEG is normal. This is particularly relevant in the inclusion of patients with only tonic-clonic seizures. IGEs encompass several different syndromes, and a few patients shift from one phenotype to another. The overlapping of some syndromes during infancy and adolescence increased the difficulty to individualize strictly the correct syndrome. Many discrepancies can be observed in the distribution of the different syndromes included in the group of IGEs, because the strict criteria for classifying these syndromes proposed by the ILAE are often not respected. With this understanding, the general frequency of IGEs can be assessed at 15-20% of all epilepsies. The frequency and the distribution of incidence and prevalence of the different syndromes are tentatively reported and discussed. When the term idiopathic is used following the restrictive ILAE criteria, the mortality data concerning patients with idiopathic epilepsies do not show an increased standardized mortality ratio.

Potential role of drug transporters in the pathogenesis of medically intractable epilepsy.

Abstract: The pathogenesis underlying pharmacoresistance in epilepsy is unclear. One of the candidate mechanisms that has attracted growing interest is the limitation of antiepileptic drug (AED) access to the seizure focus by a range of efflux transporters, the prototype of which is P-glycoprotein (P-gp). P-gp is encoded by the multidrug resistance (MDR1 or ABCB1) gene. Predominantly expressed in organs with excretory functions and at blood-tissue barriers, P-gp is thought to act as a physiologic defense by extruding xenobiotics from mammalian cells and affording protection of sensitive organs. The high level of P-gp in the cerebrovascular endothelium is believed to contribute to the functionality of the blood-brain barrier. Overexpression of P-gp causes multidrug resistance in certain cancers. It has been hypothesized that overexpression of P-gp and other efflux transporters in the cerebrovascular endothelium, in the region of the epileptic focus, also may lead to drug resistance in epilepsy. This hypothesis is supported by the findings of elevated expression of efflux transporters in epileptic foci in patients with drug-resistant epilepsy, induction of expression by seizures in animal models, and experimental evidence that some commonly used AEDs are substrates. Conflicting reports suggest a possible association between variants of the MDR1 gene and medical intractability in epilepsy. Further studies to delineate the exact role, if any, of P-gp and other efflux transporters in drug-resistant epilepsy are warranted.

Cognitive Function in Preschool Children after Epilepsy Surgery: Rationale for Early Intervention

Abstract: Summary: Purpose: The detrimental effect of frequent early seizures on the cognitive potential of children is a significant clinical issue. Epilepsy surgery in childhood offers a good prognosis for seizure control and improved developmental outcome. We studied the postoperative outcome and the developmental velocity after surgery and analyzed risk factors for developmental delay in 50 consecutive preschool children treated surgically for severe epilepsy at ages 3 to 7 years. Methods: Pre- and postoperative developmental quotients (DQs) were analyzed with analysis of variance; stepwise linear regressions were performed on preoperative DQs and on a difference score between post- and preoperative DQs to determine risk factors for preoperative development and factors influencing postoperative development. Results: Of the 50 patients, 70% were retarded, with IQ < 70; 16% were of average intelligence, with IQ ranging from 85 to 115. Age at seizure onset and extent of lesion were predictive variables for preoperative cognitive development. Six to 12 months after surgery (early postoperative phase), 66% were seizure free (Engel outcome class I), 26% had substantial to worthwhile seizure reduction (classes II and III), and 8% were unchanged (class IV). Forty-one (82%) children showed stable velocity of development; three children showed gains of ≥15 IQ points; three had developmental decline (loss of ≥10 IQ points), which was transient in two children; and three children moved from not assessable to assessable. At last follow-up (6 months to 10 years after surgery), 11 children showed IQ/DQ gains of ≥15 IQ points. Gains in IQ were observed only in seizure-free children and were stable over time. Shorter duration of epilepsy was significantly associated with a postoperative increase in DQ. Conclusions: (a) Substantial global mental delay is common in young children treated for epilepsy with surgery; (b) In most patients, postoperative development proceeded at a stable velocity; (c) Catch-up development may occur but only in seizure-free patients; (d) Substantial cognitive losses were noted in only one child. and (e) Early seizure control stabilized developmental velocity in this patient cohort. Ke yW ords: Cognitive function— Early childhood epilepsy—Surgical treatment.

Epilepsy in Young Adults with Autism : A Prospective Population-based Follow-up Study of 120 Individuals Diagnosed in Childhood

Abstract: Summary: Purpose: Little is known about the long-term outcome of epilepsy in autism and the epilepsy characteristics of adults with autism. This prospective population-based study was conducted in an attempt to point out differences on a group basis between adults with autism with or without epilepsy, and to describe the occurrence, the seizure characteristics, and the outcome of epilepsy in autism. Methods: One hundred eight of 120 individuals with autism diagnosed in childhood and followed up prospectively for a period of 13–22 years were reevaluated at ages 17–40 years. As adults, the majority had mental retardation and autistic disorder or autistic-like condition. Interviews were performed with the caretakers of 42 of 43 individuals with a history of epilepsy, and their medical records were reviewed. Results: Adults with autism and mental retardation constituted a severely disabled group. On a group basis, both the cognitive level and the adaptive behavior level were lower in the epilepsy group than in the nonepilepsy group (p < 0.05). In all, 38% had epilepsy. One third had epilepsy onset before age 2 years. Remission of epilepsy was seen in 16%. Partial seizures with or without secondarily generalized seizures were the dominating seizure type. Conclusions: In a community sample of individuals with autism followed up from childhood through to adult age, one of three had epilepsy since childhood/adolescence. Severe mental retardation and autism are significantly associated with epilepsy, especially in female patients. Seizure frequency has a great impact on the individuals' lives. Specialist medical care is needed in this severely communication-disabled population.

Mortality of epilepsy in developed countries: a review.

Abstract: Mortality in people with epilepsy has been studied in many different populations. In population-based incidence cohorts of epilepsy with 7-29 years follow-up, there was up to a threefold increase in mortality, compared to the general population (standardized mortality ratios [SMR] ranged from 1.6 to 3.0). When studies include selected epilepsy populations where patients with frequent and severe seizures are more common, the mortality is even greater. Relative survivorship (RS) following the diagnosis of epilepsy was 91%, 85%, and 83% after 5, 10, and 15 years, respectively. In a population with childhood-onset epilepsy, RS was 94% and 88% after 10 and 20 years. The level of increased mortality is affected by several factors. In idiopathic epilepsy where the causes of seizures are unknown, the results are conflicting. There was no significant increase in mortality in studies from Iceland, France, and Sweden, a barely increased risk in a study from the United Kingdom, and a significantly increased risk in a study from the United States. In contrast, all studies report a significant increased mortality in remote symptomatic epilepsy (standardized mortality ratios [SMRs] ranging from 2.2 to 6.5). The highest mortality is found in patients with epilepsy and neurodeficits present since birth, including mental retardation or cerebral palsy (SMRs ranging from 7 to 50). Mortality is also affected by age, with the highest SMRs in children, the combined effect of low mortality in the reference population, and high mortality in children with neurodeficits and epilepsy. The highest excess mortality is found in the elderly, > or =75 years. A pronounced increase in mortality is found during the first year following the onset of seizures due to underlying severe diseases. The increased mortality remains in different studies 2-14 years following diagnosis. Most of the factors responsible for the increased mortality are related to the underlying disorder causing epilepsy with pneumonia, cerebrovascular disease, and neoplastic disorders (risk remains elevated when primary brain tumors are excluded), as the most frequently recorded causes. The most common direct seizure-related cause of death in adolescents and young adults is sudden unexpected death, which is 24 times more common than in the general population.

Somatic comorbidity of epilepsy in the general population in Canada.

Abstract: Summary: Purpose: There is a notion that people with epilepsy have substantial and often unrecognized comorbidity of chronic conditions. However, most studies focus on selected patient groups; population-based studies are scarce. We compared the prevalence of chronic somatic conditions in people with epilepsy with that in the general population using Canadian, nationwide, population-based health data. Method: We examined epilepsy-specific and general population health data obtained through two previously validated, independently performed, door-to-door Canadian health surveys, the National Population Health Survey (NPHS, N = 49,000) and the Community Health Survey (CHS, N = 130882), which represent 98% of the Canadian population. The prevalence of epilepsy and 19 other chronic conditions was ascertained through direct inquiry from respondents about physician-diagnosed illnesses. Weighted prevalence, prevalence ratios (PR), and 95% confidence intervals were obtained for the entire population and for males and females separately. Multivariate analyses assessed the strength of association of comorbid conditions with epilepsy as compared with the general population. Results: People with epilepsy had a statistically significant higher prevalence of most chronic conditions than the general population. Conditions with particularly high prevalence in epilepsy (prevalence ratio ≥ 2.0) include stomach/intestinal ulcers (PR, CHS 2.5, NPHS 2.7), stroke (PR, CHS 3.9, NPHS 4.7), urinary incontinence (PR, CHS 3.2, NPHS 4.4), bowel disorders (PR, CHS 2.0, NPHS 3.3), migraine (PR, CHS 2.0, NPHS 2.6), Alzheimer's disease (PR, NPHS 4.3), and chronic fatigue (PR, CHS 4.1). There were no gender-specific differences in prevalence of chronic conditions among people with epilepsy. Conclusions: People with epilepsy in the general population, not only those actively seeking medical care, have a high prevalence of chronic somatic comorbid conditions. The findings are consistent across two independent surveys, which show that people with epilepsy in the general population have a two- to five-fold risk of somatic comorbid conditions, as compared with people without epilepsy. This patient-centered comorbidity profile reflects health aspects that are important to people with epilepsy, and indicate the need for a more integrated approach to people with epilepsy. The impact of epilepsy relative to other comorbid conditions requires further analysis, as does the contribution of comorbidity to epilepsy intractability and to differential health care needs. Similarly, it remains to be determined whether the observed comorbidity patterns are specific to epilepsy or simply reflect a pattern that is common to chronic illnesses in general.

Fasting versus gradual initiation of the ketogenic diet: a prospective, randomized clinical trial of efficacy.

Abstract: Summary: Purpose: The ketogenic diet (KD) is a 90% fat diet that is an effective treatment for intractable epilepsy. Rapid initiation of the KD requires hospital admission because of the complexity of the protocol and frequent mild and moderate adverse events. The purpose of the study was to compare the efficacy of a gradual KD initiation with the standard KD initiation preceded by a 24- to 48-h fast. Methods: Children ages 1 to 14 years with intractable epilepsy were randomized to a fasting initiation (FAST-KD) or gradual initiation (GRAD-KD). Baseline seizure activity was recorded daily for 28 days before admission and continued for the 3-month duration of the study. Effectiveness was measured in two ways: (a) the proportion of subjects with >50% reduction in target seizure type from baseline to 3-month evaluation, and (b) percentage reduction in the frequency of the target seizure type from baseline to 3-month evaluation. Blood glucose was assessed q4 to 6h, and weights, electrolytes, hydration status, vomiting, acid balance, need for interventions (citric acid and sodium citrates (Bicitra) and IV fluids) were assessed daily. Fisher’s exact tests were used to examine the association between protocol and occurrence of adverse events, and longitudinal mixed-effects models were used to look for trends in tolerability data over time. Results: Forty-eight subjects, 24 in each arm, were randomized. In the FAST-KD protocol, 58% of the children had >50% reduction in the target seizure type at 3 months, and 21% were seizure free. In the GRAD-KD protocol, 67% had a >50% reduction at 3 months, and 21% were seizure free. The two protocols were equivalent in efficacy (p = 0.033). At 3 months, the FASTKD median percentage seizure reduction rate was 78% (ranging from 100% reduction to 73% increase in seizures per week) and was 94% (ranging from 100% reduction to 161% increase in seizures per week) for the GRAD-KD protocol. By using a logarithmic transformed percentage reduction rate and an equivalence limit difference of 20%, the efficacy of the two protocols was equivalent (p = 0.0002). Children in the GRAD protocol lost significantly less weight (p = 0.006), and had fewer and lesssevere episodes of hypoglycemia (p < 0.001), fewer treatments for acidosis (citric acid and sodium citrates) (p < 0.04) and dehydration (IV fluids) (p < 0.04), but no difference in vomiting was noted. Conclusions: These data suggest that in children with intractable epilepsy, a gradual initiation results in fewer adverse events and is tolerated better overall while maintaining the efficacy of the KD. Ke yW ords: Ketogenic diet—Fasting— Ketones—Children—Intractable epilepsy.

Double-blind, randomized controlled pilot study of bilateral cerebellar stimulation for treatment of intractable motor seizures.

Abstract: Summary: Purpose: The efficacy and safety of cerebellar stimulation (CS) was reevaluated in a double-blind, randomized controlled pilot study on five patients with medically refractory motor seizures, and especially generalized tonic–clonic seizures. Methods: Bilateral modified four-contact plate electrodes were placed on the cerebellar superomedial surface through two suboccipital burr holes. The implanted programmable, battery-operated stimulator was adjusted to 2.0 μC/cm2/phase with the stimulator case as the anode; at this level, no patient experienced the stimulation. Patients served as their own controls, comparing their seizure frequency in preimplant basal phase (BL) of 3 months with the postimplant phases from 10 months to 4 years (average, eight epochs of 3 months each). During the month after implantation, the stimulators were not activated. The patient and the evaluator were blinded as to the next 3-month epoch, as to whether stimulation was used. The patients were randomized into two groups: three with the stimulator ON and two with the stimulator OFF. After a 4-month postimplantation period, all patients had their stimulator ON until the end of the study and beyond. Medication was maintained unchanged throughout the study. EEG paroxysmal discharges also were measured. Results: Generalized tonic–clonic seizures: in the initial 3-month double-blind phase, two patients were monitored with the stimulation OFF; no change was found in the mean seizure rate (patient 1, 100%, and patient 5, 85%; mean, 93%), whereas the three patients with the stimulation initially ON had a reduction of seizures to 33% (patient 2, 21%; patient 3, 46%; patient 4, 32%) with a statistically significant difference between OFF and ON phase of p = 0.023. All five patients then were stimulated and monitored. At the end of the next 6 months of stimulation, the five patients had a mean seizure rate of 41% (14–75%) of the BL. The second patient developed an infection in the implanted system, which had to be removed after 11 months of stimulation; the seizures were being reduced with stimulation to a mean of one per month from a mean of 4.7 per month (BL level) before stimulation. At the end of 24 months, three patients were monitored with stimulation, resulting in a further reduction of seizures to 24% (11–38%). Tonic seizures: four patients had these seizures, which at 24 months were reduced to 43% (10–76%). Follow-up surgery was necessary in four patients because of infection in one patient and lead/electrode displacement needing repositioning in three patients. The statistical analysis showed a significant reduction in tonic–clonic seizures (p < 0.001) and tonic seizures (p < 0.05). Conclusions: The superomedial cerebellar cortex appears to be a significantly effective and safe target for electrical stimulation for decreasing motor seizures over the long term. The effect shows generalized tonic–clonic seizure reduction after 1–2 months and continues to decrease over the first 6 months and then maintains this effectiveness over the study period of 2 years and beyond.

Causal links between brain cytokines and experimental febrile convulsions in the rat.

Abstract: Summary: Purpose: Despite the prevalence of febrile convulsions (FCs), their pathophysiology has remained elusive. We tested the hypothesis that components of the immune response, particularly the proinflammatory cytokine interleukin-1β (IL-1β) and its naturally occurring antagonist interleukin-1 receptor antagonist (IL-1ra) may play a role in the genesis of FC. Methods: Postnatal day 14 rats were treated with lipopolysaccharide (LPS; 200 μg/kg, i.p.) followed by a subconvulsant dose of kainic acid (1.75 mg/kg, i.p.). Brains were harvested at and 2 h after onset of FCs to measure brain levels of IL-1β and IL-1ra. Separate groups of animals were given intracerebroventricular (ICV) injections of IL-1β, or IL-1ra in an attempt to establish a causal relation between the IL-1β/IL-1ra system and FCs. Results: Animals with FCs showed increased IL-1β in the hypothalamus and hippocampus but not in the cortex compared with noFC animals that also received LPS and kainic acid. This increase was first detected in the hippocampus at onset of FCs. No detectable difference in IL-1ra was found in brain regions examined in either group. When animals were treated with IL-1β ICV, a dose-dependant increase was noted in the proportion of animals that experienced FCs, whereas increasing doses of IL-1ra, given to separate groups of animals, were anticonvulsant. Conclusions: Our results suggest that excessive amounts of IL-1β may influence the genesis of FCs. This may occur by overproduction of IL-1β, or by alteration in the IL-1β/IL-1ra ratio in the brain after an immune challenge.

Best Practice Guidelines for the Management of Women with Epilepsy

Abstract: Being a woman with epilepsy is not the same as being a man with epilepsy. Epilepsy affects sexual development, menstrual cycle, aspects of contraception, fertility, and reproduction. MENSTRUAL CYCLE, EPILEPSY, AND FERTILITY: The diagnosis of epilepsy and the use of antiepileptic drugs (AEDs) present women of childbearing age with many problems; both the disease and its treatment can alter the menstrual cycle and fertility. CONTRACEPTION IN EPILEPSY: There are no contraindications to the use of nonhormonal methods of contraception in women with epilepsy (see Table 3). Nonenzyme-inducing AEDs (valproate sodium, benzodiazepines, ethosuximide, and levetiracetam) do not show any interactions with the combined oral contraceptive pill. There are interactions between the COCP and hepatic microsomal-inducing AEDs (phenytoin, barbiturates, carbamazepine, topiramate [doses above 200 mg/day], and oxcarbazepine) and also lamotrigine. SEXUALITY: The majority of women with epilepsy appear to have normal sex lives, although in some women with epilepsy, both the desire and arousal phases may be inhibited. PRECONCEPTION COUNSELING: Preconception counseling should be available to all women with epilepsy who are considering pregnancy. Women with epilepsy should be aware of a number of issues relating to future pregnancy, including methods and consequences of prenatal screening, genetics of their seizure disorder, teratogenicity of AEDs, folic acid and vitamin K supplements, labor, breast feeding, and childcare. PREGNANCY: The lowest effective dose of the most appropriate AED should be used, aiming for monotherapy where possible. Recent pregnancy databases have suggested that valproate is significantly more teratogenic than carbamazepine, and the combination of valproate sodium and lamotrigine is particularly teratogenic. Most pregnancies are uneventful in women with epilepsy, and most babies are delivered healthy with no increased risk of obstetric complications in women. BREAST FEEDING: All women with epilepsy should be encouraged to breastfeed their babies. The AED concentration profiled in breast milk follows the plasma concentration curve. The total amount of drug transferred to infants via breast milk is usually much smaller than the amount transferred via the placenta during pregnancy. However, as drug elimination mechanisms are not fully developed in early infancy, repeated administration of a drug such as lamotrigine via breast milk may lead to accumulation in the infant. THE CARE OF CHILDREN OF MOTHERS WITH EPILEPSY: Although there is much anxiety about the possible risks to a child from the mother's epilepsy, there is little published evidence. The risk of the child being harmed depends on the type of seizure and its severity and frequency, and this risk is probably small if time is taken to train mothers and caregivers in safety precautions. MENOPAUSE: During menopause, about 40% of women report worsening of their seizure disorder, 27% improve, and a third had no change. Hormone replacement therapy is significantly associated with an increase in seizure frequency during menopause, and this is more likely in women with a history of catamenial epilepsy. BONE HEALTH: Women with epilepsy are at increased risk of fractures, osteoporosis, and osteomalacia.

Incidence of Fractures among Epilepsy Patients: A Population-based Retrospective Cohort Study in the General Practice Research Database

Abstract: dence rate in the epilepsy cohort was 241.9 per 10,000 personyears. This rate was about twice as high as that in reference cohort: age- and sex-adjusted IDR, 1.89 (95% CI, 1.81‐1.98). When comparing IDRs among the different groups of fractures, the highest relative-risk estimate was found for hip and femur fractures (adjusted IDR, 2.79; 95% CI, 2.41‐3.24). IDRs were consistently elevated across age and sex groups and across fracture subtypes. Conclusions: The overall risk of fractures was nearly twice as high among patients with epilepsy compared with the general population. The relative fracture risk was highest for hip and femur. Further study is necessary to elucidate whether this elevated risk is due to the disease, the use of antiepileptic drugs, or both. Ke yW ords: Epilepsy—Incidence—Fracture— Population-based study—Cohort study—Epidemiology.

Screening for Major Depression in Epilepsy with Common Self-report Depression Inventories

Abstract: Summary: Purpose: Major depression is a common psychiatric comorbidity in chronic epilepsy that is frequently unrecognized and untreated. A variety of self-report mood inventories are available, but their validity as well as ability to detect major depression in epilepsy remains uncertain. The purpose of this study was to determine the ability of two common depressive symptom inventories to identify major depression in people with epilepsy. Methods: In total, 174 adult patients with epilepsy underwent standardized psychiatric interview techniques [Mini International Neuropsychiatric Interview (MINI) and Mood Disorders module of the Structured Clinical Interview for DSM-IV Axis I Disorders–Research Version (SCID-I)] to determine the presence of current major depression. Subjects completed two self-report depression inventories [Beck Depression Inventory-II (BDI-II), Center for Epidemiological Study of Depression (CES-D)]. The ability of these self-report measures to identify major depression as identified by the gold standard structured interviews was examined by using diagnostic efficiency statistics. Results: Both the BDI-II and the CES-D exhibited significant ability to identify major depression in epilepsy. All ROC analyses were highly significant (mean area under the curve, 0.92). Mean sensitivity (0.93) and specificity (0.81) were strong, with excellent negative predictive value (0.98) but lower positive predictive value (0.47). Conclusions: Common self-report depression measures can be used to screen for major depression in clinical settings. Use of these measures will assist in the clinical identification of patients with major depression so that treatment can be initiated.

Cognitive Decline in Severe Intractable Epilepsy

Abstract: Purpose: To explore the relation between seizure-related variables and cognitive change in patients with severe intractable epilepsy.Methods: A retrospective analysis of data from 136 patients who had undergone a cognitive assessment on two occasions at an interval of >= 10 years. Cognitive measures included tests of memory and executive skills in addition to intelligence quotients (IQ). Details were available regarding seizure type and frequency in the intertest interval.Results: Cognitive decline was severe and occurred across a wide range of cognitive functions. The frequency of generalised tonic-clonic seizures was the strongest predictor of decline. Complex partial seizure frequency was associated with a decline in memory and executive skills but not in IQ. Seizure-related head injuries and advancing age carried a poor cognitive prognosis, whereas periods of remission were associated with a better cognitive outcome. Early age at onset was not implicated, and duration of epilepsy was a much less potent predictor of cognitive decline than has been reported in cross-sectional studies. No evidence indicated that a higher level of cognitive function protected against cognitive decline.Conclusions: Our findings, together with those from animal studies and surgically treated patients, suggest that seizures can have a direct adverse effect on cognition and that good seizure control even after years of intractability can have a beneficial impact on cognitive prognosis. This study was based on individuals who merited two cognitive assessments >= 10 years apart and hence is biased in favor of those with the most severe forms of refractory epilepsy and those with decline.

Analysis of chronic seizure onsets after intrahippocampal kainic acid injection in freely moving rats.

Abstract: Summary: Purpose: The goal of this study was to analyze the transition period between interictal and ictal activity in freely moving rats with recurrent spontaneous seizures after unilateral intrahippocampal kainic acid (KA) injection. Methods: Pairs of tungsten electrodes (50 μm O/D) were implanted bilaterally under anesthesia at symmetrical points in the dentate gyrus (DG) and CA1 regions of anterior and posterior hippocampi and entorhinal cortex of adult Wistar rats. Stimulating electrodes were placed in the right angular bundle and KA was injected into the right posterior CA3 area of hippocampus after 1 week of baseline EEG recording. Beginning 24 h after injection, electrographic activity was recorded with video monitoring for seizures every day for 8 h/day for 60 days. Results: Seventy percent of seizures started locally in the DG ipsilateral to injection, with an increase in frequency of interictal EEG spikes (hypersynchronous type, HYP), and 26% of seizures started with a decrease of EEG amplitude with parallel increase in frequency (low-voltage fast type, LVF). During HYP seizures, a significant increase was observed in amplitude of beta-gamma range frequencies, ripple frequency, and fast ripple (FR) frequency, whereas during LVF seizure, an increase was noted only in the beta-gamma range. In all cases but one, an EEG wave preceded ripple and FR oscillations. Before seizure onset, the amplitude of DG-evoked responses to single pulses decreased, whereas the amplitude of the response to the second pulse delivered at 30-ms interval increased. Conclusions: If ripple and FR oscillations indicate the seizure-generating neuronal substrate, these areas must be small and widespread, so that the probability of recording from them directly is very low. The decreased response to electrical stimulation before seizures could indicate a protective inhibitory mechanism that contains or prevents seizure occurrence. The presence of decreased paired-pulse suppression could indicate a network predisposition to follow an external input with a certain frequency.

Entorhinal Cortex Involvement in Human Mesial Temporal Lobe Epilepsy: An Electrophysiologic and Volumetric Study

Abstract: Summary: Purpose: Several studies have demonstrated diminution in the volume of entorhinal cortex (EC) ipsilateral to the pathologic side in patients with temporal lobe epilepsy (TLE). The relation between the degree of EC atrophy and the epileptogenicity of this structure has never been directly studied. The purpose of the study was to determine whether atrophy of the EC evaluated by the quantitative magnetic resonance imaging (MRI) method is correlated with the epileptogenicity of this structure in TLE. Methods: Intracerebral recordings (SEEG method) of seizures from 11 patients with mesial TLE were analyzed. Seizures were classified according to patterns of onset: pattern 1 was the emergence of a low-frequency, high-amplitude rhythmic spiking followed by a tonic discharge, and pattern 2 was the emergence of a tonic discharge in the mesial structures. A nonlinear measure of SEEG signal interdependencies was used to evaluate the functional couplings occurring between hippocampus (Hip) and EC at seizure onset. MRI volumetric analysis was performed by using a T1-weighted three-dimensional gradient-echo sequence in TLE patients and 12 healthy subjects. Results: Significant interactions between Hip and Ec were quantified at seizure onset. The EC was found to be the leader structure in most of the pattern 2 seizures. Volumetric measurements of EC demonstrated an atrophy in 63% of patients ipsilateral to the epileptic side. A significant correlation between the strength of EC–Hip coupling and the degree of atrophy was found. In addition, in those patients that had a normal EC volume, the EC was never the leader structure in Ec–Hip coupling. Conclusions: These results validate the potential role of volumetry to predict the epileptogenesis of the EC in patients with hippocampal sclerosis and MTLE.

Epilepsy and neurocysticercosis in Atahualpa: a door-to-door survey in rural coastal Ecuador

Abstract: Summary: Purpose: To determine the prevalence of epilepsy and the role of neurocysticercosis in the occurrence of epilepsy in Atahualpa. Methods: We used a door-to-door survey to detect subjects with epileptic seizures, to collect a blood sample for determination of anticysticercal antibodies, and to evaluate social characteristics of the population, including household pig ownership. Neurologists examined suspected cases and a sample of negative individuals. Then patients with epilepsy, as well as age- and sex-matched controls, underwent a head computed tomography (CT) and a scalp EEG. Results: The questionnaire was answered by 2,415 of 2,548 residents of Atahualpa, and cysticercosis serology was performed in 1,687 consenting individuals. Cysticercosis seroprevalence was 145 (8.6%) per 1,686). Neurologic examination confirmed 24 patients with epilepsy (crude prevalence, 9.9 per 1,000

Preemptive Low‐frequency Stimulation Decreases the Incidence of Amygdala‐kindled Seizures

Abstract: Summary: Purpose: The use of electrical stimulation as a therapy for epilepsy is currently being studied in experimental animals and in patients with epilepsy. This study examined the effect of preemptive, low-frequency, 1-Hz sine wave stimulation (LFS) on the incidence of amygdala-kindled seizures in the rat. Methods: Electrodes were implanted into the basolateral amygdalae of adult male rats. All animals received a kindling stimulus of 60-Hz, 400-μA, sine wave for 1 s twice a day. Experimental animals received an additional LFS consisting of 1 Hz, 50 μA for 30 s immediately before the kindling stimulus. Afterdischarge (AD) duration, behavioral seizure score, the number of stimulations required to elicit the first stage five seizure and to become fully kindled were measured. After 20 stimulations, a crossover procedure was performed. Fully kindled rats from each group were switched, so that the original controls received LFS plus the kindling stimulus, and the original experimental rats received only the kindling stimulus. Results: During kindling acquisition, LFS induced a significant decrease in AD duration. A significant increase in the number of times the kindling stimulus failed to elicit an AD was noted. Control rats exhibited an AD 99% of the time compared with 70% in experimental rats (p < 0.0001; Fisher's Exact test). In fully kindled animals, the incidence of stage five seizures in the original controls significantly decreased from 98% to 42% (p < 0.0001) when the LFS was added to the kindling paradigm. Conclusions: The dramatic decrease in the incidence of stage 5 seizures in fully kindled animals after preemptive LFS strongly suggests that LFS may be an effective therapy for the prevention of seizures in patients with epilepsy.

An Introduction to Antiepileptic Drugs

Abstract: In recent years, the number of commercially available antiepileptic drugs (AEDs) has increased steadily. Although this may complicate management choices, it also offers welcome new options to individualize treatment more effectively. Because each of the available AEDs differs from others in many clinically relevant properties, opportunities to tailor drug treatment to the characteristics of the individual patient have never been greater. Properties that are especially important in drug selection in patients with epilepsy include spectrum of efficacy in different seizure types, adverse effects profile, pharmacokinetic properties, susceptibility to cause or be a target of clinically important drug-drug interactions, ease of use, and cost. Other factors that need to be considered in tailoring drug choice include availability of user-friendly pediatric formulations, and potentially favorable effects on co-morbid conditions. In fact, a number of AEDs are efficacious and widely prescribed in additional indications, particularly psychiatric disorders, migraine prophylaxis, and neuropathic pain. Recently, advances have been made in understanding the mechanisms of actions of AEDs at the molecular level. While a fully mechanistic approach to the clinical use of these agents is not yet feasible, knowledge of mechanisms of action offers useful clues in predicting their efficacy profile and spectrum of potential adverse effects.

Epidemiology of bipolar disorders

Abstract: Bipolar, or manic-depressive, disorders are frequent and severe mental illnesses associated with considerable morbidity and mortality. Epilepsy and bipolar disorder could probably share some aspects of pathophysiology because manic as well as depressive symptoms are seen in patients with seizures, and a number of antiepileptic drugs are effectively used in the acute and prophylactic treatment of bipolar disorder. Epidemiologic research suggests a dimensional composition of bipolar illness at the population level. Apart from the DSM-IV diagnostic features of bipolar I (mania and depression) and bipolar II (hypomania and depression), the concept of bipolar spectrum disorders comprises a range of bipolar conditions with less obvious manifestations with estimated lifetime prevalence rates ranging from 2.8 to 6.5%. Expanding the definition of bipolar II disorders shows that half of the patients currently diagnosed with a unipolar depressive episode could suffer from unrecognized bipolar II disorder, and about the same number of mild depressive patients could be minor bipolars. Research efforts to refine the diagnostic criteria of bipolar disorder aim at an earlier and complete recognition of the disease to provide appropriate pharmacological and nonpharmacological treatment early in the course of the illness to anticipate individual suffering, suicidal behavior, and increased socioeconomic costs for society. This article also discusses risk factors, comorbid conditions, course of illness, as well as the individual and socioeconomic impact of bipolar disorders. CONCLUSIONS: The findings suggest reconceptualizing bipolar illnesses as highly recurrent, malignant disorders that occur far more frequently than previously thought. Interdisciplinary knowledge transfer could help to increase our understanding of the pathophysiology of these disorders as well as provide grounds for better recognition and treatment of patients with manic and/or depressive symptoms. Language: en

Mortality after a first episode of status epilepticus in the United States and Europe.

Abstract: Summary: Objective: In the last decade several studies have been published on incidence, etiology, and prognosis of status epilepticus (SE) with population-based data from the United States and Europe. The aim of this review is to summarize the available information on the epidemiology of SE and to outline the sources of the variability in reported mortality after SE. Methods: Comparison of mortality studies in SE from the United States and Europe. Results: The incidence of SE is lower in Europe (9.9‐ 15.8/10,000) than in the United States (18.3‐41/100,000). The overall mortality after SE is similar in the two U.S. studies: the case fatality is 21% in Rochester, and 22% in Richmond. All European studies excluded SE after anoxic encephalopathy following cardiac arrest. This exclusion may partly explain the lower case fatality (around 10%) found in two of the European studies. The study from Bologna showed the highest case fatality (33%) even after exclusion of anoxic encephalopathy. The mortality in acute symptomatic SE was higher than for other forms of SE across all studies. Conclusions: Short-term mortality after SE occurs mainly in the acute symptomatic group. Based on published data, it is not clear if differences in early management and medical treatment have any impact on prognosis or whether the differences can be attributed only to differences in distribution of the underlying causes in acute symptomatic SE. Future studies should address this issue. Ke yW ords: Status epilepticus—Mortality— Prognosis. Status epilepticus (SE), usually defined as a seizure lasting at least 30 min, is considered a medical emergency. It occurs most frequently in the context of an acute systemic or neurological insult and less frequently in patients with epilepsy. There have been many published studies regarding mortality after SE, most of which are based on clinical series from tertiary care centers. The reported mortality varies from 7% to 46% (1‐15).