Anti-seizure Treatment Research Articles

Acute Symptomatic Seizures and Provoked Seizures: to Treat or Not to Treat?

Acute symptomatic and provoked seizures by definition occur in close proximity to an event and are considered to be situational. The treatment implications and likelihood of recurrence of acute symptomatic and provoked seizures differ from unprovoked seizures. In this article, the authors review the literature on acute symptomatic and provoked seizures with regard to therapeutic approach and risk of recurrence. In the acute period, patients who suffer from acute symptomatic and provoked seizures have higher rates of morbidity and mortality. Patients with acute symptomatic seizures in the setting of certain conditions including subdural hemorrhage, traumatic penetrating injuries, cortical strokes, neurocysticercosis, venous sinus thrombosis, and viral encephalitis have a higher rate of seizure recurrence although the rate of recurrence of seizures is less than that of patients with unprovoked seizures. In patients with acute symptomatic and provoked seizures, short-term treatment with anti-seizure medications is appropriate given the higher morbidity and mortality in the acute phase of illness. In patients with acute symptomatic seizures with persistent epileptiform activity on EEG and structural changes on imaging, longer-term treatment (i.e., a few months as opposed to 1week) with anti-seizure medications can be considered due to high risk of seizure recurrence. If a patient subsequently has an unprovoked seizure, there is yet a higher risk of recurrence of seizures and likelihood of the development of epilepsy. In these patients, long-term seizure treatment can be considered, keeping in mind that although anti-seizure treatment may reduce risk of seizure recurrence in the short-term, it does not appear to influence long-term seizure remission rates.

F126. Focal seizures detected with intracranial electrodes after traumatic hemorrhage may appear as focal slowing on scalp EEG and be missed

Traumatic intracranial hemorrhage (TIH) predisposes patients to clinical and subclinical seizures, which may contribute to worsened neurological outcomes. However, experimental data suggests that scalp EEG may be insensitive for detecting some nonconvulsive seizures, especially those originating from a deeper focus. We report the simultaneous scalp and intracranial EEG findings of a 32-year-old man following evacuation of a traumatic left epidural and subdural hematoma. The patient was enrolled in an exploratory study to obtain intracranial electroencephalography (IEEG) in adults undergoing emergent post-traumatic hemicraniectomy for TIH. Following hemicraniectomy and opening of the dura mater, a 4-contact depth electrode was placed in the subdural space overlying the ipsilateral frontal cortex adjacent to the evacuated hematoma. Intraparenchymal placement was avoided to prevent insertional damage in a friable brain. The leads were tunneled through the skin adjacent to the incision, and secured externally with a silk suture, under a single layer of oxidized regenerated cellulose sheet. Positioning of the electrodes was confirmed using routine postoperative noncontrast head CT. Scalp and intracranial EEG were recorded for 94 h. Scalp EEG demonstrated severe diffuse slowing (1–4 Hz) with overlying fast activity (12–20 Hz), consistent with anesthetic effect, and a left hemispheric breech rhythm. Focal slowing persisted over the left hemisphere despite anesthetic wean. Throughout the recording, IEEG showed intermittent rhythmic or sharp waves consistent with lateralized periodic discharges (1–2 Hz). At times these evolved sufficiently in frequency, morphology and amplitude to meet criteria for nonconvulsive seizures, and could be triggered consistently with stimulation. On scalp EEG however, these periodic discharges and seizures were not detected, although rhythmic or semi-rhythmic focal slowing (1–2 Hz) was concurrently seen on occasion. In response to the IEEG findings and given the persistence of clinical encephalopathy despite weaning of anesthesia, antiseizure treatment was increased until the seizures identified on IEEG resolved. The patient’s level of consciousness subsequently improved, suggesting that the nonconvulsive seizures may have contributed to a worsened encephalopathy. Following the recording, a rhythmicity spectrogram trends panel was developed for the intracranial electrode and consistently demonstrated low-frequency bands during seizure activity that could be used for rapid seizure identification. Following TIH, clinically relevant focal seizure activity may be entirely missed on scalp EEG or have subtle intermittent nonspecific correlate such as focal slowing. More research is needed to determine the frequency of this phenomenon and determine whether treatment of such seizures improves patient outcomes.

Benign Neonatal Sleep Myoclonus Evokes Somatosensory Responses.

Benign neonatal sleep myoclonus is a common nonepileptic condition occurring in neurologically normal full-term newborns. During jerks, EEG has always been described as normal. The aim of this study was to describe EEG changes associated with the myoclonic jerks. Polygraphic video-EEG recordings of four full-term neonates presenting benign neonatal sleep myoclonus were studied. Myoclonic jerks were analyzed regarding their topography, frequency, propagation pattern, and reflex component. EEG averaging time-locked to myoclonic jerks and to somatosensory stimuli (realized by tapping on palms and feet) was performed to study eventual EEG correlates of myoclonus and to asses somatosensory evoked responses-for the latter, two control newborns were added. Visual analysis of the EEG disclosed theta band slow waves on central and vertex electrodes concomitant to myoclonic jerks and jerk-locked back-averaging disclosed a sequence of deflections, not preceding, but following the myoclonus. This response predominated on the vertex electrode (CZ) and consisted of five components (N1, P1, N2, P2, and N3), with only the three later components being constantly present (at 110, 200, and 350-500 ms, respectively). Back-averaging locked to the tactile stimuli in four subjects and two control newborns showed similar components and were comparable to those described in the literature as late somatosensory evoked responses in full-term newborns. Myoclonic jerks in benign neonatal sleep myoclonus can evoke visually identifiable EEG potentials on vertex electrodes corresponding to somatosensory responses. This EEG aspect may be misleading and could give rise to an anti-seizure treatment that mostly worsens the condition.

Ganaxolone: A New Treatment for Neonatal Seizures.

Neonatal seizures are amongst the most common neurologic conditions managed by a neonatal care service. Seizures can exacerbate existing brain injury, induce “de novo” injury, and are associated with neurodevelopmental disabilities in post-neonatal life. In this mini-review, we present evidence in support of the use of ganaxolone, a GABAA agonist neurosteroid, as a novel neonatal therapy. We discuss evidence that ganaxolone can provide both seizure control and neuroprotection with a high safety profile when administered early following birth-related hypoxia, and show evidence that it is likely to prevent or reduce the incidence of the enduring disabilities associated with preterm birth, cerebral palsy, and epilepsy. We suggest that ganaxolone is an ideal anti-seizure treatment because it can be safely used prospectively, with minimal or no adverse effects on the neonatal brain.

Treatable Genetic Metabolic Epilepsies.

In the absence of a culprit epileptogenic lesion, pharmacoresistant seizures should prompt the physician to consider potentially treatable metabolic epilepsies, especially in the presence of developmental delays. Even though the anti-seizure treatment of the epilepsies remains symptomatic and usually tailored to an electroclinical phenotype rather than to an underlying etiology, a thorough metabolic workup might reveal a disease with an etiology-specific treatment. Early diagnosis is essential in the case of treatable metabolic epilepsies allowing timely intervention. Despite the advances in genetic testing, biochemical testing including cerebrospinal fluid studies are still needed to expedite the diagnostic workup and potential therapeutic trials. The diagnostician should have a high index of suspicion despite potential clinical digressions from seminal publications describing the initial cases, as these index patients may represent the most severe form of the condition rather than its most common presenting form. The often gratifying developmental outcome and seizure control with early treatment calls for a prompt diagnostic consideration of treatable metabolic diseases; even though relatively rare or potentially only seemingly so.

Febrile status epilepticus due to respiratory syncytial virus infection.

Febrile status epilepticus can have neurological sequelae. The type of sequelae, however, depend on the etiology, including infection due to viral agents such as the influenza virus. Respiratory syncytial virus (RSV) infection in childhood may also contribute to this. The aim of this study was therefore to characterize febrile status epilepticus associated with RSV infection, and to determine whether this type of infection is a risk factor for neurological sequelae in febrile status epilepticus. We reviewed the medical records of children aged ≤3years with febrile status epilepticus who were admitted to a tertiary hospital between January 2007 and December 2011. The differences between the RSV-positive and RSV-negative groups were evaluated according to the demographic and clinical data. A total of 99 patients with febrile status epilepticus who had been tested for RSV infection were identified. Three patients in the RSV-positive group (n=19) and four in the RSV-negative group (n=80) presented with bronchiolitis. The incidence of intubation and anti-seizure drug treatment in the RSV-positive group was significantly higher than in the -negative group. While all of the patients in the RSV-negative group recovered completely, six patients in the RSV-positive group developed encephalopathy and profound neurological sequelae. In five of the six patients, diffusion-weighted magnetic resonance imaging showed subcortical white matter lesions. RSV infection in the absence of bronchiolitis can initially present as febrile status epilepticus and subsequently develop into acute encephalopathy with profound neurological sequelae.

Outcomes following electrographic seizures and electrographic status epilepticus in the pediatric and neonatal ICUs.

Increasing recognition of electrographic seizures and electrographic status epilepticus in critically ill neonates and children has highlighted the importance of identifying their potential contributions to neurological outcomes to guide optimal management. Recent studies in children and neonates have found an independent association between increasing seizure burden and worse short-term and long-term outcomes, even after adjusting for other important contributors to outcome such as seizure cause and illness severity. The risk of worse neurological outcome has been shown to increase above a seizure burden threshold of 12-13 min/h, which is considerably lower than the conventional definition of status epilepticus of 30 min/h. Randomized controlled trials in neonates have demonstrated that electroencephalography-targeted therapy can successfully reduce seizure burden, but due to their small size these trials have not been able to demonstrate that more aggressive electroencephalography-targeted treatment of both subclinical and clinical seizures results in improved outcome. Despite mounting evidence for an independent association between increasing seizure burden and worse outcome, further study is needed to determine whether early seizure identification and aggressive antiseizure treatment can improve neurodevelopmental outcomes.

Treatment of Established Status Epilepticus.

Status epilepticus is the most severe form of epilepsy, with a high mortality rate and high health care costs. Status epilepticus is divided into four stages: early, established, refractory, and super-refractory. While initial treatment with benzodiazepines has become standard of care for early status epilepticus, treatment after benzodiazepine failure (established status epilepticus (ESE)) is incompletely studied. Effective treatment of ESE is critical as morbidity and mortality increases dramatically the longer convulsive status epilepticus persists. Phenytoin/fosphenytoin, valproic acid, levetiracetam, phenobarbital, and lacosamide are the most frequently prescribed antiseizure medications for treatment of ESE. To date there are no class 1 data to support pharmacologic recommendations of one agent over another. We review each of these medications, their pharmacology, the scientific evidence in support and against each in the available literature, adverse effects and safety profiles, dosing recommendations, and limitations of the available evidence. We also discuss future directions including the established status epilepticus treatment trial (ESETT). Substantial further research is urgently needed to identify these patients (particularly those with non-convulsive status epilepticus), elucidate the most efficacious antiseizure treatment with head-to-head randomized prospective trials, and determine whether this differs for convulsive vs. non-convulsive ESE.

Management of Status Epilepticus in Children.

Status epilepticus is a common pediatric neurological emergency. Management includes prompt administration of appropriately selected anti-seizure medications, identification and treatment of seizure precipitant(s), as well as identification and management of associated systemic complications. This review discusses the definitions, classification, epidemiology and management of status epilepticus and refractory status epilepticus in children.

Monotherapy or Polytherapy for First-Line Treatment of SE?

Status epilepticus (SE) is one of the most frequent neurologic emergencies, and a rapid and effective treatment is warranted. Current guidelines recommend a stepwise approach using a sequence of different antiepileptic drugs with benzodiazepines (BZD) being the first treatment proposed. To provide the more effective treatment as soon as possible, some authors have suggested using a combined polytherapy as first-line treatment. Strong evidence supports the use of benzodiazepines, mostly lorazepam and midazolam as initial monotherapy treatment for SE. Insufficient data are available to support the use of nonsedating antiepileptic drugs as phenytoin, valproic acid, or levetiracetam without a previous benzodiazepine administration. Studies assessing the role of a combined initial therapy are rare, if not missing. Moreover, owing the wide range of SE etiologies, a "one fits all" initial polytherapy seems difficult to achieve. After reviewing the available evidence, guidelines, and current practices regarding monotherapy and polytherapy as first-line treatment in SE in adults, the authors propose a rational algorithm for early antiseizure treatment in SE.

Disease Course, Outcome Measures, and Prognostic Predictors in Epilepsy: Opportunities for Improving Outcome of Drug Trials.

A major concern over the development of new antiepileptic drugs (AEDs) is that the new AEDs have not added substantial clinical benefit over available antiseizure treatment. Additionally, current AEDs have neither improved the health of epilepsy patients nor been shown to prevent epilepsy or to improve the disease. This chapter reviews new data on patterns of epilepsy with remission and relapse, prognostic factors for seizure outcome, and innovative patient-related outcome measures. Applying this knowledge presents opportunities to improve the drug treatment of epilepsy. Patient-relevant outcome measures and trial designs may be optimized to provide both evidence for efficacy and safety of AEDs and, in addition, for added clinical benefit over existing treatment. Added benefit of a new AED may be shown by evidence of higher antiseizure efficacy, better health, shorter disease duration, fewer side effects, and improved quality of life compared to available standard treatment. Moving from largely patient-irrelevant outcome measures such as 50% seizure reduction or use of placebo controls to innovative comparison of new AEDs versus standard treatment will revitalize the clinical development of new antiseizure treatments. Hopefully this will usher in a new era of much-needed antiepileptogenic agents that prevent or improve the patterns of epilepsy.

Children with status epilepticus can face considerable delays before receiving effective antiseizure treatment

Children with status epilepticus can face considerable delays before receiving effective antiseizure treatment

Evaluating an etiologically relevant platform for therapy development for temporal lobe epilepsy: effects of carbamazepine and valproic acid on acute seizures and chronic behavioral comorbidities in the Theiler's murine encephalomyelitis virus mouse model.

Central nervous system infections can underlie the development of epilepsy, and Theiler's murine encephalomyelitis virus (TMEV) infection in C57BL/6J mice provides a novel model of infection-induced epilepsy. Approximately 50-65% of infected mice develop acute, handling-induced seizures during the infection. Brains display acute neuropathology, and a high number of mice develop spontaneous, recurrent seizures and behavioral comorbidities weeks later. This study characterized the utility of this model for drug testing by assessing whether antiseizure drug treatment during the acute infection period attenuates handling-induced seizures, and whether such treatment modifies associated comorbidities. Male C57BL/6J mice infected with TMEV received twice-daily valproic acid (VPA; 200 mg/kg), carbamazepine (CBZ; 20 mg/kg), or vehicle during the infection (days 0-7). Mice were assessed twice daily during the infection period for handling-induced seizures. Relative to vehicle-treated mice, more CBZ-treated mice presented with acute seizures; VPA conferred no change. In mice displaying seizures, VPA, but not CBZ, reduced seizure burden. Animals were then randomly assigned to acute and long-term follow-up. VPA was associated with significant elevations in acute (day 8) glial fibrillary acidic protein (astrocytes) immunoreactivity, but did not affect NeuN (neurons) immunoreactivity. Additionally, VPA-treated mice showed improved motor performance 15 days postinfection (DPI). At 36 DPI, CBZ-treated mice traveled significantly less distance through the center of an open field, indicative of anxiety-like behavior. CBZ-treated mice also presented with significant astrogliosis 36 DPI. Neither CBZ nor VPA prevented long-term reductions in NeuN immunoreactivity. The TMEV model thus provides an etiologically relevant platform to evaluate potential treatments for acute seizures and disease modification.

Optimized methods for epilepsy therapy development using an etiologically realistic model of focal epilepsy in the rat

Conventionally developed antiseizure drugs fail to control epileptic seizures in about 30% of patients, and no treatment prevents epilepsy. New etiologically realistic, syndrome-specific epilepsy models are expected to identify better treatments by capturing currently unknown ictogenic and epileptogenic mechanisms that operate in the corresponding patient populations. Additionally, the use of electrocorticography permits better monitoring of epileptogenesis and the full spectrum of acquired seizures, including focal nonconvulsive seizures that are typically difficult to treat in humans. Thus, the combined use of etiologically realistic models and electrocorticography may improve our understanding of the genesis and progression of epilepsy, and facilitate discovery and translation of novel treatments. However, this approach is labor intensive and must be optimized. To this end, we used an etiologically realistic rat model of posttraumatic epilepsy, in which the initiating fluid percussion injury closely replicates contusive closed-head injury in humans, and has been adapted to maximize epileptogenesis and focal non-convulsive seizures. We obtained week-long 5-electrode electrocorticography 1month post-injury, and used a Monte-Carlo-based non-parametric bootstrap strategy to test the impact of electrode montage design, duration-based seizure definitions, group size and duration of recordings on the assessment of posttraumatic epilepsy, and on statistical power to detect antiseizure and antiepileptogenic treatment effects. We found that use of seizure definition based on clinical criteria rather than event duration, and of recording montages closely sampling the activity of epileptic foci, maximize the power to detect treatment effects. Detection of treatment effects was marginally improved by prolonged recording, and 24h recording epochs were sufficient to provide 80% power to detect clinically interesting seizure control or prevention of seizures with small groups of animals. We conclude that appropriate electrode montage and clinically relevant seizure definition permit convenient deployment of fluid percussion injury and electrocorticography for epilepsy therapy development.

In Rasmussen encephalitis, hemichannels associated with microglial activation are linked to cortical pyramidal neuron coupling: a possible mechanism for cellular hyperexcitability.

Rasmussen encephalitis (RE) is a rare but devastating condition, mainly in children, characterized by sustained brain inflammation, atrophy of one cerebral hemisphere, epilepsy, and progressive cognitive deterioration. The etiology of RE-induced seizures associated with the inflammatory process remains unknown. Cortical tissue samples from children undergoing surgical resections for the treatment of RE (n = 16) and non-RE (n = 12) were compared using electrophysiological, morphological, and immunohistochemical techniques to examine neuronal properties and the relationship with microglial activation using the specific microglia/macrophage calcium-binding protein, IBA1 in conjunction with connexins and pannexin expression. Compared with non-RE cases, pyramidal neurons from RE cases displayed increased cell capacitance and reduced input resistance. However, neuronal somatic areas were not increased in size. Instead, intracellular injection of biocytin led to increased dye coupling between neurons from RE cases. By Western blot, expression of IBA1 and pannexin was increased while connexin 32 was decreased in RE cases compared with non-RE cases. IBA1 immunostaining overlapped with pannexin and connexin 36 in RE cases. In RE, these results support the notion that a possible mechanism for cellular hyperexcitability may be related to increased intercellular coupling from pannexin linked to increased microglial activation. Such findings suggest that a possible antiseizure treatment for RE may involve the use of gap junction blockers.

Psychosis after vagus nerve stimulation therapy

A 24-year-old man developed psychosis after improvement of epilepsy with vagus nerve stimulation treatment. He had a similar response when seizures were controlled by anticonvulsion agents. Psychosis was relieved with withdrawal of antiseizure treatment, but seizures then recurred.

Issues related to development of new antiseizure treatments.

This report represents a summary of the discussions led by the antiseizure treatment working group of the International League Against Epilepsy (ILAE)/American Epilepsy Society (AES) Working Groups joint meeting in London (London Meeting). We review here what is currently known about the pharmacologic characteristics of current models of refractory seizures, both for adult and pediatric epilepsy. In addition, we address how the National Institute of Neurological Disorders and Stroke (NINDS)-funded Anticonvulsant Screening Program (ASP) is evolving to incorporate appropriate animal models in the search for molecules that might be sufficiently novel to warrant further pharmacologic development. We also briefly address what we believe is necessary, going forward, to achieve the goal of stopping seizures in all patients, with a call to arms for funding agencies, the pharmaceutical industry, and basic researchers.

EFFECT OF STIMULUS PARAMETERS IN THE TREATMENT OF SEIZURES BY ELECTRICAL STIMULATION IN THE KAINATE ANIMAL MODEL

Preliminary results from animal and clinical studies demonstrate that electrical stimulation of brain structures can reduce seizure frequency in patients with refractory epilepsy. Since most researchers derive stimulation parameters by trial and error, it is unclear what stimulation frequency, amplitude and duration constitutes a set of optimal stimulation parameters for aborting seizure activity in a given patient. In this investigation, we begin to quantify the independent effects of stimulation parameters on electrographic seizures, such that they could be used to develop an efficient closed-loop prosthesis that intervenes before the clinical onset of a seizure and seizure generalization. Biphasic stimulation is manually delivered to the hippocampus in response to a visually detected electrographic seizure. Such focal, responsive stimulation allows for anti-seizure treatment delivery with improved temporal and spatial specificity over conventional open-loop stimulation paradigms, with the possibility of avoiding tissue damage stemming from excessive exposure to electrical stimulation. We retrospectively examine the effects of stimulation frequency (low, medium and high), pulse-width (low and high) and amplitude (low and high) in seizures recorded from 23 kainic acid treated rats. We also consider the effects of total charge delivered and the rate of charge delivery, and identify stimulation parameter sets that induce after-discharges or more seizures. Among the stimulation parameters evaluated, we note 2 major findings. First, stimulation frequency is a key parameter for inhibiting seizure activity; the anti-seizure effect cannot be attributed to only the charge delivered per phase. Second, an after-discharge curve shows that as the frequency and pulse-width of stimulation increases, smaller pulse amplitudes are capable of eliciting an after-discharge. It is expected that stimulation parameter optimization will lead to devices with enhanced treatment efficacies and reduced side-effect profiles, especially when used in conjunction with seizure prediction or detection algorithms in a closed-loop control application.

Counterpoint: Emergency (“Stat”) EEG in the Era of Nonconvulsive Status Epilepticus

ABSTRACTThe most widely accepted indication for a stat EEG (stEEG) is the suspicion of nonconvulsive status epilepticus (NCSE). NCSE has been reported with surprising frequency in a wide variety of acute structural and metabolic brain injuries and significantly increases the risk of permanent brain damage and death. This risk rises and the effectiveness of treatment decreases with delays in diagnosis and increased duration of NCSE. Recent evidence confirms that more than half of NCSE patients improve with anti-seizure treatment. The emergence of NCSE as a common, dangerous, time-urgent, and treatable problem has positioned it as a target for emergency therapeutic intervention. NCSE can only be diagnosed by EEG testing, and stEEG has demonstrated value in improving NCSE management. As a result, in the near future, EEG laboratories will see increasing demands for stEEG related to NCSE. The two main obstacles to an effective stEEG program are EEG technologist coverage and electroencephalographer availability after work hours. We recommend three simple but fundamental changes in the traditional approach to stEEGs in order to overcome these obstacles: the use of EEG set-up templates by onsite personnel, easy access to EEG instruments after hours, and remote stEEG connectivity for real-time, off-site electroencephalographer interpretation.

Anti-seizure treatment longer in the Midwest

Anti-seizure treatment longer in the Midwest