Adequate Antiepileptic Drugs Research Articles

Drug-resistant epilepsy: Current concepts, pathogenesis, risk factors, outcomes of surgical treatment

Despite the wide choice of antiepileptic drugs (AEDs), a third of patients remain resistant to the effects of modern AEDs. Drug-resistant epilepsy (DRE) is characterized by the inability to control seizures in a patient when using at least two adequate AED regimens at an effective daily dose as monotherapy or in combination. In this case, the mechanisms responsible for drug resistance are mainly either increased excretion of AEDs by transporters from epileptogenic tissue (the multidrug transporter hypothesis) or a decrease in the sensitivity of drug receptors in epileptogenic brain tissue. It is assumed that there are other mechanisms, but they remain understudied. A number of factors are associated with the risk of DRE developing in patients with diagnosed epilepsy, including genetic, iatrogenic, brain malformations, and others. Patients with DRE have a higher probability of developing psychopathological disorders (depression, anxiety, psychosis), the proportion of which is significantly higher than in the general population. They have a 10-fold increased risk of death due to injury, cognitive decline, and sudden unexpected death in epilepsy (SUDEP). The priority treatment method for DRE is surgery. Early identification of DRE is critical for identifying potential treatment alternatives and determining whether a patient is a surgical candidate. Analysis of data from clinical and instrumental research of operated patients with DRE in the early and late postoperative period will allow us to identify factors of unfavorable outcome and to increase the effectiveness of treatment for this category of patients.The aim was to study and to summarize literature data on the pathogenesis and risk factors of drug resistance to antiepileptic drugs in patients with epilepsy, justifying the need for timely identification of drug resistance and referral of patients with drugresistant epilepsy to specialized centers for possible surgical treatment.

Sclérose hippocampique associée à l’épilepsie : conséquences cliniques, histopathologie et évolution avec l’âge

Hippocampal sclerosis is the most frequent etiology of patients with drug-resistant mesial temporal lobe epilepsy, which is the most frequent localization for focal epilepsy. Hippocampal sclerosis is the consequence of a cerebral aggression during early childhood, called the initial precipitating event, the most frequent of which are: febrile seizure, intracranial infection, hypoxia, or cranial trauma. The epilepsy onset usually occurs a few years after this event, with an association of focal temporal seizures and rarer secondarily generalized tonic-clonic seizures. Most patients have a drug-resistant focal epilepsy, with a failure of two different and adequate antiepileptic drugs to achieve seizure freedom. Patients also demonstrated with cognitive impairment, with a typical episodic memory impairment affecting both verbal and non-verbal episodic memory. Cognitive impairment is however more diffuse than the sole episodic memory impairment, and also affects language, visuo-spatial processing, and executive functions. With aging, subjects demonstrated a progressive cognitive decline, that appears to parallel the decline associated with normal aging, but starts earlier and from a lower global cognitive functioning with less cognitive reserve. Patients may therefore reach an impairment threshold sooner than healthy subjects, and are much more vulnerable to any other disease that impairs cognitive functioning. Patients exhibited cortical and subcortical atrophy patterns on volumetric brain MRI similar to normal aging in its distribution, but with an earlier pattern of atrophy (4.5 years sooner in patients than in healthy subjects). Hippocampal sclerosis is associated with amyloid and tau deposits inside the hippocampus, which increases with the subjects’ age. Those deposits pattern is close to the one observed in patients with tau / amyloïd neurodegenerative diseases, which demonstrates a bilateral relationship between epilepsy, hippocampal sclerosis, and neurodegenerative diseases. Clinical consequences of such a relationship are yet to be precisely determined.

Persistent treatment resistance in genetic generalized epilepsy: A long-term outcome study in a tertiary epilepsy center.

To assess prognostic patterns and investigate clinical and electroencephalography (EEG) variables associated with persistent treatment resistance in a population of genetic generalized epilepsy (GGE) patients with a long-term follow-up. Data from GGE patients followed from 1975 to 2019 were reviewed retrospectively. Subjects with a follow-up >10years, starting from epilepsy diagnosis, were included. Persistent treatment resistance was defined as the absence of any period of remission ≥1year despite treatment with two appropriate and adequate antiepileptic drugs (AEDs). One hundred ninety-nine patients were included. The median age was 39.5years (interquartile range [IQR] 30-49) and the median follow-up was 27years (IQR 18-35). The most common syndrome was juvenile myoclonic epilepsy (JME), diagnosed in 44.2% of patients. During follow-up, 163 subjects (81.9%) experienced 3-year remission from any seizure type, whereas 5- and 10-year remission occurred in 141 (70.8%) and 92 (46.2%) cases, respectively. The most common prognostic pattern was a relapsing-remitting course, observed in 80 patients (40.2%), whereas 29 (14.6%) displayed persistent treatment resistance. According to multivariable logistic regression analysis, febrile seizures (FS), specific EEG patterns (namely generalized paroxysmal fast activity, GPFA) and valproate (VPA) resistance were the only variables significantly associated with persistent treatment resistance. JME was the only epilepsy syndrome statistically associated with persistent treatment resistance in univariable logistic regression analysis. Persistent treatment resistance was observed in almost 15% of GGE patients followed in a tertiary epilepsy center. A worse outcome was associated with specific clinical variables (JME, FS) and EEG patterns (GPFA).

Sudden Unexpected Death in Epilepsy (SUDEP) — What Pediatricians Need to Know

Sudden unexpected death in epilepsy (SUDEP) is a devastating complication in children with epilepsy. Children with generalized tonic-clonic convulsions, nocturnal seizures, and co-morbid developmental delay/intellectual disability are at higher risk of SUDEP. The pathogenic mechanisms are incompletely understood and involve cardiac, respiratory, autonomic and cerebral dysfunction. Prone positioning is also significantly associated with SUDEP and may be a target for SUDEP prevention. Good epilepsy control also attenuates the risk; hence, it is important to provide adequate antiepileptic drug therapy with stress on drug compliance as well as early surgical referral for seizure control, wherever necessary. It is recommended that parents of children with epilepsy be counseled about the risk factors for SUDEP and potential measures of SUDEP prevention. We herein provide a pediatric perspective of the problem and guidance about parental counselling for its prevention.

Antiepileptic Drugs in Children : Current Concept.

An epileptic seizure is defined as the transient occurrence of signs and/or symptoms due to abnormally excessive or synchronous neuronal activity in the brain. The type of seizure is defined by the mode of onset and termination, clinical manifestation, and by the abnormal enhanced synchrony. If seizures recur, that state is defined as epilepsy. Antiepileptic drugs (AEDs) are the mainstay of treatment. Knowledge about initiating and maintaining adequate AEDs is beneficial for the clinician who treats children with epilepsy. This article will delineate the general principles for selecting, introducing, and discontinuing AEDs and outline guidelines for monitoring adverse effects. In general, AED therapy following a first unprovoked seizure in children is not recommended. However, treatment should be considered after a second seizure. In children and adolescents, if they are seizure-free for at least 2 years, attempts to withdraw medication/s should be made, taking into account the risks vs. benefits for the individual patient. The decision on when and what AED to use should be tailored according to the patient. For optimal treatment, the selection of adequate AEDs can be achieved by considering the precise definition of the patient’s seizure and epilepsy syndrome. Continuous monitoring of both therapeutic and adverse effects is critical for successful treatment with AEDs.

Epileptički napad kao prva manifestacija frontoparijetalne arteriovenske malformacije mozga

Abstract: Introduction: Arteriovenous malformations of the brain include a group of congenital disorders in the early development of arterial-venous blood vessels of the brain. Their clinical presentation is most common in the form of a brain hemorrhage, epileptic seizures, and headaches. Case report: We showed a man who at the age of 28 early in the morning after breakfast had the first generalized tonic-clonic seizure. After the second unprovoked epileptic seizure, antiepileptic therapy was introduced. The brain scanner showed the existence of arteriovenous malformations in the right frontoparietal region. As the size of the malformation was less than 30mm, it was decided that the patient should be treated with Gamma knife radiosurgery. After the successful radiosurgery together with the antiepileptic drugs treatment, the patient is in a stable 1.5 yearlong remission of epileptic seizures without neurological failures. Conclusion: Epileptic seizures can be the initial clinical manifestations of arteriovenous malformations of the brain. With an early diagnosis, adequate antiepileptic drugs therapy and neurosurgery, radiosurgery (Gamma Knife), which is often necessary, many symptomatic epilepsies enter a stable remission of epileptic seizures.

Analysis of fractional anisotropy and mean diffusivity in refractory and non-refractory idiopathic generalized epilepsies

PurposeTo compare white matter bundles and fiber tract changes in seizure-free and non-seizure-free idiopathic generalized epilepsy (IGE) patients. MethodForty adult patients with IGE underwent a 3 T brain MRI with DTI sequences. According to seizure control status, eighteen patients were classified as refractory (R) if they had presented at least one incapacitating seizure in the previous six months, while on appropriate antiepileptic drug treatment. Twenty two seizure-free patients with adequate seizure control were considered non-refractory (NR). We compared fractional anisotropy (FA) and mean diffusivity (MD) values in sixteen white matter tracts in the R and NR groups, and in twenty healthy subjects. ResultsR and NR groups did not differ in gender, age and education. We found decreased FA in two tracts in the R group (forceps major and right uncinate fasciculus) and approaching statistical significance in two tracts in the NR group (right cingulate gyrus and right uncinate fasciculus) group, as well as increased MD in six tracts in the R group (forceps minor, left thalamic anterior radiation, right inferior longitudinal fasciculus, right longitudinal superior parietal and temporal fasciculi, and right cingulate gyrus) and in five tracts in the NR group (forceps minor, left thalamic anterior radiation, right inferior longitudinal fasciculus, right longitudinal superior parietal and temporal fasciculi), compared to controls. No differences were noted comparing FA and MD values between R and NR groups. ConclusionsIn our patient population, refractory IGE patients on adequate antiepileptic drug treatment did not present more severe white matter tract involvement compared to non-refractory patients.

Treatment strategy for the patient with hippocampal sclerosis who failed to the first antiepileptic drug.

Despite many epilepsy patients respond to antiepileptic drugs (AED) successfully, more than 30% of patients continue to have seizures on multiple AEDs. The refractory epilepsy increases the risk of cognitive deterioration, psychosocial dysfunction, and sudden unexpected death of epilepsy patients (SUDEP). It is important to identify refractory epilepsy early and make the goal of epilepsy treatment as the prevention of decline in social, vocational, and cognitive performances and minimizing the risk of accident or SUDEP. The syndrome of medial temporal lobe epilepsy with hippocampal sclerosis (MTLE with HS) is often resistant to AEDs, and surgically remediable. Initially well-controlled seizures often become intractable to AEDs. There are progressive behavioral changes including increasing memory deficit. Surgical outcome is also worse with longer duration of epilepsy or increasing age at surgery, which suggests that MTLE is a progressive disorder. Some emphasized the ultimate intractability of MTLE in which intractability of MTLE could be evident only after some years following initial diagnosis. However, when patients considered to have intractable epilepsy were followed up for a long period of time, many of them experienced seizure-free state. Some studies clearly demonstrated the wax and wane courses of treatment response in epilepsy. Late remission could be achieved up to in a half of patients. Thus intractable state is not a static condition but a fluctuating one and initial refractoriness does not necessarily mean the final intractability. Even though the chance of seizure remission with AEDs is not high for MTLE, some of them do well respond to drugs. It is even possible to withdraw AEDs for a few patients. Though epilepsy surgery is very effective method to treat MTLE, considering the fluctuation courses of intractability and the possibility of delayed remission, at least two adequate AEDs could be applied to the patients before surgery. However, medical intractability becomes evident by definition, it is not reasonable to delay epilepsy surgery.

COGNITIVE IMPAIRMENT IN EPILEPSY

Epilepsy is the most common and serious diseases of the nervous system, the social aspects of the patients, quality of life become in recent years one of the most important medical problems. [1] Objective: to study the features of the higher mental and cognitive function in patients with idiopathic epilepsy. Work results of the study were 141 patients with idiopathic epilepsy aged 15 to 55 years who were under clinical observation in a dynamic period of 3 years. We observed patients were characterized by polymorphism displays, with a predominance of monomorphic attacks by 16.4% than the polymorphic (respectively 58.2% and 41.8%). Partial seizures were observed in 17 (12.0%), of whom 9 (6.3%) patients. In general, cognitive impairment occurred in 132 (93.6%) of the patients, dominated by moderately expressed and easy changes of memory, attention, thinking. Mild cognitive impairment were detected in 74 (56.0%), moderately expressed - 43 (32.5%) expressed human - 15 cases (11.4%). In pathologies are associated with the cognitive deficits prevailed impaired memory, attention and thinking, often accompanied by mood disorders. The growth of cognitive deficits is poor prognostic criteria. The severity of cognitive deficits depends on the frequency and nature of seizures, frequent, complex partial seizures and polymorphic accompanied by more severe cognitive impairment, which is confirmed by electroencephalographic monitoring. Assessment of the dynamics of cognitive function is an important component of a differentiated approach to the tactics of treatment of patients with epilepsy, the choice of adequate antiepileptic drugs, and should be taken into account in the outpatient care of health facilities.

Seizures in patients with high-grade glioma: a serious challenge in the end-of-life phase

BackgroundTo analyse the prevalence of seizures and use of antiepileptic drugs (AEDs) in the end-of-life (EOL) phase of patients with high-grade glioma (HGG) and to identify patient characteristics associated with...

Modulation of Immunity and the Inflammatory Response: A New Target for Treating Drug-resistant Epilepsy

Until recently, epilepsy medical therapy is usually limited to anti-epileptic drugs (AEDs). However, approximately 1/3 of epilepsy patients, described as drug-resistant epilepsy (DRE) patients, still suffer from continuous frequent seizures despite receiving adequate AEDs treatment of sufficient duration. More recently, with the remarkable progress of immunology, immunity and inflammation are considered to be key elements of the pathobiology of epilepsy. Activation of inflammatory processes in brain tissue has been observed in both experimental seizure animal models and epilepsy patients. Anti-inflammatory and immunotherapies also showed significant anticonvulsant properties both in clinical and in experimental settings. The above emerging evidence indicates that modulation of immunity and inflammatory processes could serve as novel specific targets to achieve potential anticonvulsant effects for the patients with epilepsy, especially DRE. Herein we review the recent evidence supporting the role of inflammation in the development and perpetuation of seizures, and also discuss the recent achievements in modulation of inflammation and immunotherapy applied to the treatment of epilepsy. Apart from medical therapy, we also discuss the influences of surgery, ketogenic diet, and electroconvulsive therapy on immunity and inflammation in DRE patients. Taken together, a promising perspective is suggested for future immunomodulatory therapies in the treatment of patients with DRE.

Modulation of Immunity and the Inflammatory Response: A New Target for Treating Drug-resistant Epilepsy

Until recently, epilepsy medical therapy is usually limited to anti-epileptic drugs (AEDs). However, approximately 1/3 of epilepsy patients, described as drug-resistant epilepsy (DRE) patients, still suffer from continuous frequent seizures despite receiving adequate AEDs treatment of sufficient duration. More recently, with the remarkable progress of immunology, immunity and inflammation are considered to be key elements of the pathobiology of epilepsy. Activation of inflammatory processes in brain tissue has been observed in both experimental seizure animal models and epilepsy patients. Anti-inflammatory and immunotherapies also showed significant anticonvulsant properties both in clinical and in experimental settings. The above emerging evidence indicates that modulation of immunity and inflammatory processes could serve as novel specific targets to achieve potential anticonvulsant effects for the patients with epilepsy, especially DRE. Herein we review the recent evidence supporting the role of inflammation in the development and perpetuation of seizures, and also discuss the recent achievements in modulation of inflammation and immunotherapy applied to the treatment of epilepsy. Apart from medical therapy, we also discuss the influences of surgery, ketogenic diet, and electroconvulsive therapy on immunity and inflammation in DRE patients. Taken together, a promising perspective is suggested for future immunomodulatory therapies in the treatment of patients with DRE. Keywords: Immunity, Inflammation, Drug-Resistant Epilepsy, Auto-antibodies, Cytokines

Associated factors with adherence to antiepileptic drug in the capital city of Lao PDR

Available medical care for epilepsy and antiepileptic drugs (AED) are provided in Vientiane Municipality by district hospitals supported by a non-governmental organization, which is referred to as a community-based intervention (CB), and reference hospital which is referred to as hospital-based interventions (HB). Identifying underlying factors of AED adherence is of public health interest. A community-based cross-sectional survey among randomly selected patients with epilepsy (PWE) who were being cared in Vientiane Municipality was undertaken in 2010. The Morisky scale was used to assess the level of adherence. Univariate and multivariate logistic regression analyses were performed to address predictive factors. Overall, 99 PWE were included in the study. Overall adherence was estimated at 57.6%, 57.1% and 58.0% for the HB and CB group, respectively. High level of adherence was related to illiteracy, being on monotherapy and experiencing fewer seizures. Implementing closer medical care at primary level to PWE improves the likelihood of reducing primary and secondary treatment gap which is related to PWEs' adherence. An active intervention through a downstream channel of training of medical health staff from reference level to community level enhances the prescription of adequate AED, the improvement of the quality of relation between PWE and medical staff.

Effect of dosage failed of first antiepileptic drug on subsequent outcome

The recent definition of drug-resistant epilepsy proposed by the International League Against Epilepsy (ILAE) stipulated failure of an adequate trial of two tolerated, appropriately chosen and used antiepileptic drug (AED) schedules to achieve seizure freedom. Doses failed were not specifically discussed. We explored the effect of the doses at which the first and second AED regimens failed on subsequent outcomes in a population of adults with newly diagnosed epilepsy followed for up to 20 years. Patients in whom epilepsy was diagnosed and the first AED prescribed between July 1, 1982 and April 1, 2006, were followed until March 31, 2008. Dosage at which an AED failed was categorized according to the World Health Organization's defined daily dose (DDD) for each drug. Cumulative incidence curves for time to final seizure freedom (no seizure for at least 1 year on unchanged dosage at last follow up) were stratified by whether the first regimen was failed at doses above or below the 25%, 50%, or 75% cutoffs for the DDD of each AED. Among patients who had taken a second regimen (n = 327), those in whom the first AED failed at doses above the various cutoffs (particularly 50% and 75% DDD) had lower probability of becoming seizure-free at last follow-up (p = 0.06 for 25% DDD, p < 0.001 for both 50% and 75% DDD). The same difference was observed for patients who had taken a third regimen (n = 141; p = 0.23 for 25% DDD, p < 0.01 for 50% DDD; and p = 0.002 for 75% DDD). A trend to higher seizure-free rate was observed in patients who had taken the third regimen when both the first and second regimens failed at <75% DDD. The difference remained significant after adjusting for covariates when using 50% DDD as the cutoff for patients who took a second regimen (hazard ratio 1.60, 95% confidence interval 1.08-2.37). Higher failure dosage of the first AED predicts poorer subsequent outcome. This methodology could be used to refine further the ILAE definition of drug-resistant epilepsy by exploring the doses need to fail to provide an adequate AED trial.

Epilepsy surgery: Recommendations for India

The following article recommends guidelines for epilepsy surgery for India. This article reviews the indications, the various surgical options available and the outcome of surgery for drug resistant epilepsy based on current evidence. Epilepsy surgery is a well-established option for patients who have been diagnosed to have drug resistant epilepsy (DRE) (on at least two appropriate, adequate anti-epileptic drugs (AEDs) (either in monotherapy or in combination) with continuing seizures), where the presurgical work-up has shown concordance of structural imaging (magnetic resonance imaging) and electrical mapping data (electroencephalography (EEG), video EEG). There may be a requirement of functional imaging techniques in a certain number of DRE like positron emission tomography (PET), single photon emission tomography, (SPECT)). Invasive monitoring should be restricted to a few when all noninvasive investigations are inconclusive, there is a dual pathology or there is a discordance of noninvasive data. The types of surgery could be curative (resective surgeries: amygdalo hippocampectomy, lesionectomy and multilobar resections; functional surgeries: hemispherotomy) and palliative (multiple subpial transaction, corpus callosotomy, vagal nerve stimulation). Epilepsy surgery in indicated cases has a success range from 50 to 86% in achieving seizure freedom as compared with <5% success rate with AEDs only in persons with DRE. Centers performing surgery should be categorized into Level I and Level II.

Dementia associated with epilepsy

In this review, we explore the relationship between epilepsy and cognition and between epilepsy and dementia. Chronic epilepsy, particularly mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis, may be associated with impaired cognition, which can be secondary to uncontrolled seizures, to adverse effects of antiepileptic drugs (AEDs) or to the underlying biological abnormality. The choice of an adequate AED with an appropriate dose regimen may lead to a favorable outcome. This feature is especially relevant in elderly patients with dementia and associated epilepsy, a vulnerable population in which the diagnosis of seizures can be difficult and for whom treatment guidelines are not yet available. Based on available information and on data derived from studies with other populations, recommendations for the management of these patients are presented.

Prognosis for total control of complex partial and secondarily generalized tonic clonic seizures. Department of Veterans Affairs Epilepsy Cooperative Studies No. 118 and No. 264 Group.

Two prospective observations of adults with symptomatic, localization-related (partial) epilepsy included 1,102 patients in VA multicenter studies (VA-118 and VA-264). Analyses assessed the likelihood of remaining seizure free for 12 and 24 months after initiating adequate antiepileptic drug therapy. Patients were grouped as having only secondarily generalized tonic-clonic seizures (GTC), only complex partial seizures (CPS), or both types (MIXED) at entry. The cumulative proportion of patients remaining seizure free with standard antiepileptic drug therapy was determined by actuarial life table methods. At 12 months, 70% and 61% of GTC patients (VA-118 and VA-264, respectively) had no further GTC; 53% and 50% of MIXED, predominantly GTC patients had no further GTC, 21% and 28% of CPS patients had no further CPS and 98% and 91% were seizure free for GTC; 32% and 35% of MIXED, predominantly CPS patients had no further CPS, and 62% and 51% of patients with MIXED seizure types remained seizure free for CPS for 12 months after enrollment. The overall prognosis for control of seizures of any type for 12 months was best for those who had only GTC at entry (55% and 48%), worst for those who had only CPS at entry (23% and 26%), and intermediate for those with MIXED seizures at entry (32% and 25%) (all p < 0.0001). Prognosis can be based on the predominant seizure type in patients with multiple types.