Concept: Status epilepticus
Neural stimulation can reduce the frequency of seizures in persons with epilepsy, but rates of seizure-free outcome are low. Vagus nerve stimulation prevents seizures by continuously activating noradrenergic projections from the brainstem to the cortex. Cortical norepinephrine then increases GABAergic transmission and increases seizure threshold. Another approach, responsive nervous stimulation, prevents seizures by reactively shocking the seizure onset zone in precise synchrony with seizure onset. The electrical shocks abort seizures before they can spread and manifest clinically. The goal of this study was to determine whether a hybrid platform in which brainstem activation triggered in response to impending seizure activity could prevent seizures. We chose the zebrafish as a model organism for this study because of its ability to recapitulate human disease, in conjunction with its innate capacity for tightly controlled high-throughput experimentation. We first set out to determine whether electrical stimulation of the zebrafish hindbrain could have an anticonvulsant effect. We found that pulse train electrical stimulation of the hindbrain significantly increased the latency to onset of pentylenetetrazole-induced seizures, and that this apparent anticonvulsant effect was blocked by noradrenergic antagonists, as is also the case with rodents and humans. We also found that the anticonvulsant effect of hindbrain stimulation could be potentiated by reactive triggering of single pulse electrical stimulations in response to impending seizure activity. Finally, we found that the rate of stimulation triggering was directly proportional to pentylenetetrazole concentration and that the stimulation rate was reduced by the anticonvulsant valproic acid and by larger stimulation currents. Taken as a whole, these results show that that the anticonvulsant effect of brainstem activation can be efficiently utilized by reactive triggering, which suggests that alternative stimulation paradigms for vagus nerve stimulation might be useful. Moreover, our results show that the zebrafish epilepsy model can be used to advance our understanding of neural stimulation in the treatment of epilepsy.
Background Convulsive status epilepticus often results in permanent neurologic impairment. We evaluated the effect of induced hypothermia on neurologic outcomes in patients with convulsive status epilepticus. Methods In a multicenter trial, we randomly assigned 270 critically ill patients with convulsive status epilepticus who were receiving mechanical ventilation to hypothermia (32 to 34°C for 24 hours) in addition to standard care or to standard care alone; 268 patients were included in the analysis. The primary outcome was a good functional outcome at 90 days, defined as a Glasgow Outcome Scale (GOS) score of 5 (range, 1 to 5, with 1 representing death and 5 representing no or minimal neurologic deficit). The main secondary outcomes were mortality at 90 days, progression to electroencephalographically (EEG) confirmed status epilepticus, refractory status epilepticus on day 1, “super-refractory” status epilepticus (resistant to general anesthesia), and functional sequelae on day 90. Results A GOS score of 5 occurred in 67 of 138 patients (49%) in the hypothermia group and in 56 of 130 (43%) in the control group (adjusted common odds ratio, 1.22; 95% confidence interval [CI], 0.75 to 1.99; P=0.43). The rate of progression to EEG-confirmed status epilepticus on the first day was lower in the hypothermia group than in the control group (11% vs. 22%; odds ratio, 0.40; 95% CI, 0.20 to 0.79; P=0.009), but there were no significant differences between groups in the other secondary outcomes. Adverse events were more frequent in the hypothermia group than in the control group. Conclusions In this trial, induced hypothermia added to standard care was not associated with significantly better 90-day outcomes than standard care alone in patients with convulsive status epilepticus. (Funded by the French Ministry of Health; HYBERNATUS ClinicalTrials.gov number, NCT01359332 .).
Individual variability has clear effects upon the outcome of therapies and treatment approaches. The customization of healthcare options to the individual patient should accordingly improve treatment results. We propose a novel approach to brain interventions based on personalized brain network models derived from non-invasive structural data of individual patients. Along the example of a patient with bitemporal epilepsy, we show step by step how to develop a Virtual Epileptic Patient (VEP) brain model and integrate patient-specific information such as brain connectivity, epileptogenic zone and MRI lesions. Using high-performance computing, we systematically carry out parameter space explorations, fit and validate the brain model against the patient’s empirical stereotactic EEG (SEEG) data and demonstrate how to develop novel personalized strategies towards therapy and intervention.
The syndrome of malignant migrating partial seizures of infancy (MMPSI) is characterized by early onset of multiple seizure types and overall poor prognosis. Seizures are markedly drug resistant and few reports have suggested the efficacy of some antiepileptic drugs. We report one case of MMPSI in which prolonged seizure control is obtained with an association of clonazepam, levetiracetam and stiripentol, confirming thus the possibility of complete sustained seizure control in this epileptic syndrome. Of more than 60 cases reported to date, ours is the forth in which sustained complete control of seizures was obtained.
PURPOSE: Although differences in illness perceptions between neurologists and patients with epilepsy or psychogenic nonepileptic seizures (PNES) are likely to be clinically relevant, this is the first study to attempt a direct comparison. In addition, this study compares the illness perceptions of patients with epilepsy with those of patients with PNES. METHODS: Thirty-four patients with epilepsy, 40 patients with PNES, and 45 neurologists were recruited. All patient participants completed versions of the illness perception questionnaire revised (IPQ-R) adapted for epileptic or nonepileptic seizure disorders, single-item symptom attribution question (SAQ), Hospital Anxiety and Depression Scale (HADS), Quality of Life in Epilepsy-31 (QOLIE-31), and Liverpool Seizure Severity Scale (LSSS). Participating neurologists completed two versions of the IPQ-R and two SAQs for epileptic and nonepileptic seizure disorders. KEY FINDINGS: Differences in illness perceptions between patients with epilepsy and patients with PNES were minor compared to those between patients with either seizure disorder and neurologists. Neurologists considered both seizure disorders more treatable and more amenable to personal control than did the patients themselves. Neurologists had much more polarized views of the etiology of both conditions; whereas patients mostly considered the causes of their seizure disorders as partially “physical” and partially “psychological,” neurologists perceived epilepsy as an essentially “physical” and PNES as a clearly “psychological” problem. SIGNIFICANCE: There are considerable differences between the illness perceptions of patients with seizure disorders and their doctors, which could represent barriers to successful clinical management. In particular, a discrepancy between neurologists' and patients' beliefs about the personal control that patients may be able to exert over PNES could contribute to the confusion or anger some patients report after the diagnosis has been explained to them. Furthermore, patients' endorsement of “physical” causes for PNES may reflect an unrealistic faith in the effectiveness of “physical” treatments and could be a cause of tension in patients' relationship with their doctor, for instance when the neurologist attempts to withdraw antiepileptic drug treatment or refers patients for psychological interventions.
To evaluate the clinical efficacy and safety of the newer antiepileptic drugs (AEDs), namely, Eslicarbazepine (ESL), Retigabine/Ezogabine (RTG), Carisbamate (CAR), Lacosamide (LAC), Brivaracetam (BRI) or Perampanel (PER) as adjunctive therapy for adults with partial-onset seizures (POS).
Anticonvulsant treatment of asphyxiated newborns under hypothermia with lidocaine: efficacy, safety and dosing
- Archives of disease in childhood. Fetal and neonatal edition
- Published about 7 years ago
BACKGROUND: Lidocaine is an antiarrythmicum used as an anticonvulsant for neonatal seizures, also during therpeutic hypothermia following (perinatal) asphyxia. Hypothermia may affect the efficacy, safety and dosing of lidocaine in these patients. OBJECTIVE: To study the efficacy and safety of lidocaine in newborns with perinatal asphyxia during moderate hypothermia, and to develop an effective and safe dosing regimen. METHODS: Hypothermic newborns with perinatal asphyxia and lidocaine for seizure control were included. Efficacy was studied using continuous amplitude-integrated electroencephalography. Safety was assessed using continuous cardiac monitoring. An optimal dosing regimen was developed with simulations using data from a pharmacokinetic model. Plasma samples were collected during hypothermia on consecutive mornings. RESULTS: A total of 22 hypothermic and 26 historical normothermic asphyxiated newborns with lidocaine were included. A response of 91% on epileptiform activity on the amplitude-integrated EEG was observed for lidocaine add-on therapy. No relationship between lidocaine or MEGX plasma concentrations and heart frequency could be identified. None of the newborns experienced cardiac arrythmias. Hypothermia reduced lidocaine clearance by 24% compared with normothermia. A novel dosing regimen was developed an initial bolus loading dose of 2 mg/kg, for patients with body weight 2.0-2.5 kg followed by consecutive continuous infusions of 6 mg/kg/h (for 3.5 h), 3 mg/kg/h (for 12 h), 1.5 mg/kg/h (for 12 h), or for patients with bodyweights 2.5-4.5 kg 7 mg/kg/h (for 3.5 h), 3.5 mg/kg/h (for 12 h), 1.75 mg/kg/h (for 12 h), before stopping. CONCLUSIONS: Lidocaine can be assumed to be an effective antiepileptic drug during hypothermia in asphyxiated neonates.
Epilepsy is characterized by recurrent spontaneous seizures due to hyperexcitability and hypersynchrony of brain neurons. Current theories of pathophysiology stress neuronal dysfunction and damage, and aberrant connections as relevant factors. Most antiepileptic drugs target neuronal mechanisms. However, nearly one-third of patients have seizures that are refractory to available medications; a deeper understanding of mechanisms may be required to conceive more effective therapies. Recent studies point to a significant contribution by non-neuronal cells, the glia - especially astrocytes and microglia - in the pathophysiology of epilepsy. This review critically evaluates the role of glia-induced hyperexcitability and inflammation in epilepsy.
Purpose: Studies of seizure outcome in patients undergoing serial antiepileptic drug trials have all been uncontrolled, with no account made for the spontaneous changes in disease state that could confound the elucidation of drug effects. In addition, no study has ever looked at outcome following antiepileptic drug switch in seizure-free patients, despite the fact that this is done routinely in clinical practice. We aimed to address both of these issues using a matched case-cohort design. Methods: We followed patients taking phenytoin or carbamazepine in monotherapy for focal epilepsy who were being crossed over to a newer agent as part of studies on the metabolic effects of anticonvulsant therapy. Many had been seizure-free but were being switched nonetheless due to side effects or concerns about long-term adverse consequences. Each patient was matched with two controls of the same seizure status who were taking anticonvulsant monotherapy and whose drug was not switched. Seizure freedom over the ensuing 6 months was the primary end point. Key Findings: There were 43 cases and 86 matched controls. Twenty-three patients (cases) had been seizure-free on their old drug; 5 (21.7%) had seizure recurrence after drug switch compared to 2 (4.3%) of 46 matched controls. Twenty patients (cases) were having seizures on their old drug; 6 (30%) entered remission after drug switch, compared to 8 of 40 matched controls (20%). The two groups differed at baseline in number of anticonvulsants previously failed, which was the most important factor for prognosis. After statistical adjustment to account for this, seizure-free patients had 6.53 times higher odds of seizure recurrence if switched to a new drug (95% confidence interval [CI] 1.02-61.19; p = 0.06). Non-seizure-free patients had 1.66 times higher odds of remission if they remained on the same drug compared to switching, although this was not significant (95% CI 0.36-8.42; p = 0.532). Neither dose changes, nor drug mechanism, nor duration of seizure freedom had any bearing upon the results. Significance: Although the large majority of seizure-free patients remain so when switched to another agent, about one sixth have a recurrence attributable to the change. Conversely, our study design provides the first evidence to suggest that most improvements in drug-resistant patients are likely due to spontaneous remissions, not new drug introductions. These findings have conflicting implications for two competing models of comparative antiepileptic drug efficacy, which will require further study to elaborate.
The aim of epilepsy treatment is to achieve complete seizure freedom. Nonetheless, numerous side effects and seizure resistance to antiepileptic drugs (AEDs) affecting about 30-40% of all patients are main unmet needs in today’s epileptology. For this reason, novel approaches to treat epilepsy are highly needed. Herein, we highlight recent progress in stem-cell-based and gene transfer-based therapies in epilepsy according to findings in animal models and address their potential clinical application. Multiple therapeutic targets are described, including neuropeptides, neurotrophic factors, and inhibitory neurotransmitters. We also address new molecular-genetic approaches utilizing optogenetic technology. The therapeutic strategies presented herein are predominately aimed toward treatment of partial/focal epilepsies, but could also be envisaged for targeting key seizure propagation areas in the brain. These novel strategies provide proof-of-principle for developing effective treatments for refractory epilepsy in the foreseeable future.