Persistent Seizures Research Articles

Midazolam as an anticonvulsant antidote for organophosphate intoxication--A pharmacotherapeutic appraisal.

This review summarizes the therapeutic potential of midazolam as an anticonvulsant antidote for organophosphate (OP) intoxication. Benzodiazepines are widely used to treat acute seizures and status epilepticus (SE), a neurologic emergency of persistent seizures that can lead to severe neuronal damage or death. Midazolam is a benzodiazepine hypnotic with a rapid onset and short duration of action. Midazolam is considered the new drug of choice for persistent acute seizures and SE, including those caused by neurotoxic OPs and nerve agents. Midazolam is a positive allosteric modulator of synaptic γ-aminobutyric acid (GABA)A receptors in the brain. It potentiates GABAergic inhibition and thereby controls hyperexcitability and seizures. Midazolam is administered intravenously or intramuscularly to control acute seizures and SE. Due to its favorable pharmacokinetic features, midazolam is being considered as a replacement anticonvulsant for diazepam in the antidote kit for nerve agents. Clinical studies such as the recent Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) trial have confirmed the anticonvulsant efficacy of midazolam in SE in prehospital settings. In experimental models, midazolam is effective when given at the onset of seizures caused by nerve agents. However, benzodiazepines are less effective at terminating seizures when given 30 min or later after OP exposure or seizure onset, likely because of internalization or downregulation of synaptic, but not extrasynaptic, GABAA receptors, which can lead to diminished potency and seizure recurrence.

New-onset refractory status epilepticus (NORSE)--The potential role for immunotherapy.

New-onset refractory status epilepticus (NORSE) is defined as a state of persistent seizures with no identifiable etiology in patients without preexisting epilepsy that lasts longer than 24h despite optimal therapy. Management of NORSE is challenging, and the role of immunotherapy (IT) is unclear. We identified patients fulfilling the criteria for NORSE at a single institution. These patients were described, analyzed, and compared with NORSE cases available from the literature. Finally, a pooled analysis of available case series was conducted to compare the outcomes in patients who received IT with those not treated with IT during the course of NORSE in order to generate hypotheses for further research. In our case series, NORSE was diagnosed in 11 patients (9 females) with a mean age of 48 years and a mean duration of 54.4 days. Autoantibodies were identified in 7 patients, of which anti-GAD (glutamic acid decarboxylase) and anti-NMDAR (N-methyl-D-aspartate receptor) were most frequent. Of the 11 patients, 8 were treated with IT (intravenous steroids, immunoglobulins, plasmapheresis, or a combination), and 4 received chemotherapy. Of the 8 patients treated with IT, 6 had favorable outcomes (defined as any outcome other than death, vegetative state, or inability to take care of oneself) compared with 0 out of 3 patients who did not receive IT. Difference in outcomes was significant (p=0.026). Pooled analysis of all identified case series, including ours, showed a statistically significant effect (p=0.022), with favorable outcomes in 42% of the patients who received any IT compared with 20% in those who did not. In all patients with refractory SE and negative comprehensive investigations, a diagnosis of NORSE should be considered. This would aid planning for early immunotherapy. Currently, only Class IV evidence for the use of immunotherapy in NORSE is available. Prospective multicenter studies are necessary to assess the true efficacy of IT in NORSE.

P203 – 2949: Seizures persistence's prognosis in children with arterial ischemic stroke

Objective To investigate clinical and electroencephalographic features of seizures during acute and recovery periods of arterial ischemic stroke (AIS) in children. Methods Type of study: case series. Inclusion criteria Children 0–15 y.o. with seizures during AIS's debut. We identified the type of episodes and EEG features in acute and recovery periods after one year. Results 152 children with AIS were examined. Seizures occurred during the acute period of stroke in 39 (25.7%) cases and antiepileptic therapy was prescribed for all of them. Generalized seizures type was registered in 56.4% (n=22), focal type in 23% (n=9), focal type with secondary generalization – in 20.6% (n=8) children. Epileptiform activity was registered in 31% (n=9) patients. Disorganized changes on background EEG without signs of paroxysmal activity were predominant in most children – 75.9% (n=22) as well as background activity was normal only in 13.8% (n=4) of them. In the recovery period seizures persisted in 10.5% (n=16). Generalized seizures of acute period pass to recovery period in 27.2% (n=6, RR=0.56 95%CI 0.3–1.0), and focal seizures with secondary generalization – in 75% (n=6, RR=2.75 95%CI 1.2–6.0). Seizures accompanied by epileptiform activity on EEG during acute period persisted in the recovery period in 55.6% (n=5, RR=2.7 95%CI 1.1–6.1), without activity – in 30% (n=9, RR=0.5 95%CI 0.2–1.1). At the same time generalized seizures of acute period combined with epileptiform activity on EEG persist in recovery period in 50% (n=2, RR=2.2 95%CI 0.6–8.3), without it – in 22.2% (n=4, RR=0.6 95%CI 0.2–1.7). Conclusion The presence of epileptiform activity on EEG and the development of focal with secondary generalization seizures type in children with AIS and seizures in the acute period increase the risk of seizure persistence in the recovery period in spite of antiepileptic therapy have been prescribed.

The potential use of trigeminal nerve stimulation in the treatment of epilepsy.

Editorial For reprint orders, please contact reprints@future-science.com Therapeutic Delivery The potential use of trigeminal nerve stimulation in the treatment of epilepsy “ ...after billions of R&D dollars to develop new drugs, this needle has not budged. A new approach is needed. ” Keywords: adjunctive treatment • anti-convulsant • bilateral stimulation • brain stimulation • cranial nerve stimulation • drug resistance • epilepsy • neuromodulation • non-invasive • trigeminal nerve stimulation Among neurological disorders, epilepsy poses an enormous clinical and societal problem, affecting approximately 50,000,000 people worldwide [1] . For individual patients, the presence of a chronic brain disorder marked by episodic convulsions and loss of control of mental and physical actions can limit occupational and social achievement. From a macro perspective, epilepsy is associated with considerable societal economic burden, accounting for a substantial proportion of the ‘disability adjusted life years’ ascribed to neurological illnesses [2] . Critically, approxi- mately a third of patients with epilepsy have ‘drug resistant epilepsy (DRE),’ character- ized as having persistent seizures despite hav- ing tried at least two different antiepileptic drugs (AEDs) [3] . Of the roughly three dozen AEDs used in the USA, approximately half have been introduced over the past four decades, and while strides have been made in improving efficacy and tolerability, the clinical challenge of DRE persists at roughly a third of all patients with epilepsy: stated differently, after billions of R&D dollars to develop new drugs, this needle has not budged. A new approach is needed. Neuromodulation interventions offer an alternative to the administration of phar- maceutical products. These therapies are intended to alter brain function by applying electric or magnetic fields to the CNS, either directly to the CNS as in deep brain stimula- tion, or via peripheral or cranial nerves, as in vagus nerve stimulation. Some key theoretical advantages of neuromodulation over drug 10.4155/TDE.14.120 © 2015 Future Science Ltd therapy are the lack of systemic exposure to key organ systems, the absence of drug–drug interactions and a reduced risk of teratogenic- ity. In epilepsy, these approaches have offered new hope because they utilize very different mechanisms of action than the medications, by directly changing regional brain activity, and commercially successful neuromodula- tion products, such as deep brain stimulation for Parkinson’s Disease, have been implanted in approximately 8000 to 10,000 new patients per year worldwide [4] . Although many of these patients have benefited from their implants, the absolute numbers stand in stark contrast to the tens of millions of patients who are inad- equately treated with medications and clearly need new therapeutic options. Therapeutic delivery for the surgically implantable devices has been limited, with issues around risks and costs of implantation and explantation, the limited availability of requisite surgical exper- tise, an inability to screen preoperatively for who will benefit and patient acceptability of an implanted system. Noninvasive and minimally invasive neurmodulation approaches might offer the advantages of neuromodulation without the challenges of surgical implantation. Trigemi- nal nerve stimulation (TNS) is a new therapy for epilepsy that can offer ‘neuromodulation without implantation.’ Noninvasive external TNS (eTNS) offers the therapeutic benefits of neuromodulation with the convenience of a prescribed pharmaceutical and yet without the side effects of a typical AED. In studies to date, subjects have applied an ‘electric patch’ Ther. Deliv. (2015) 6(3), 273–275 Ian A Cook Author for correspondence University of California, Los Angeles, CA, USA and NeuroSigma, Inc, Los Angeles, CA, USA iancookmd@ gmail.com Colin P Kealey University of California, Los Angeles, CA, USA and NeuroSigma, Inc, Los Angeles, CA, USA Christopher M DeGiorgio University of California, Los Angeles, CA, USA and NeuroSigma, Inc, Los Angeles, CA, USA part of ISSN 2041-5990

Thalamotemporal alteration and postoperative seizures in temporal lobe epilepsy.

ObjectiveThere are competing explanations for persistent postoperative seizures after temporal lobe surgery. One is that 1 or more particular subtypes of mesial temporal lobe epilepsy (mTLE) exist that are particularly resistant to surgery. We sought to identify a common brain structural and connectivity alteration in patients with persistent postoperative seizures using preoperative quantitative magnetic resonance imaging and diffusion tensor imaging (DTI).MethodsWe performed a series of studies in 87 patients with mTLE (47 subsequently rendered seizure free, 40 who continued to experience postoperative seizures) and 80 healthy controls. We investigated the relationship between imaging variables and postoperative seizure outcome. All patients had unilateral temporal lobe seizure onset, had ipsilateral hippocampal sclerosis as the only brain lesion, and underwent amygdalohippocampectomy.ResultsQuantitative imaging factors found not to be significantly associated with persistent seizures were volumes of ipsilateral and contralateral mesial temporal lobe structures, generalized brain atrophy, and extent of resection. There were nonsignificant trends for larger amygdala and entorhinal resections to be associated with improved outcome. However, patients with persistent seizures had significant atrophy of bilateral dorsomedial and pulvinar thalamic regions, and significant alterations of DTI‐derived thalamotemporal probabilistic paths bilaterally relative to those patients rendered seizure free and controls, even when corrected for extent of mesial temporal lobe resection.InterpretationPatients with bihemispheric alterations of thalamotemporal structural networks may represent a subtype of mTLE that is resistant to temporal lobe surgery. Increasingly sensitive multimodal imaging techniques should endeavor to transform these group‐based findings to individualize prediction of patient outcomes. Ann Neurol 2015;77:760–774

Morphometric MRI alterations and postoperative seizure control in refractory temporal lobe epilepsy.

Refractory mesial temporal lobe epilepsy (mTLE) is a debilitating condition potentially amenable to resective surgery. However, between 40 and 50% patients continue to experience postoperative seizures. The development of imaging prognostic markers of postoperative seizure outcome is a crucial objective for epilepsy research. In the present study, we performed analyses of preoperative cortical thickness and subcortical surface shape on MRI in 115 of patients with mTLE and radiologically defined hippocampal sclerosis being considered for surgery, and 80 healthy controls. Patients with excellent (International League Against Epilepsy outcome (ILAE) I) and suboptimal (ILAE II–VI) postoperative outcomes had a comparable distribution of preoperative atrophy across the cortex, basal ganglia, and amygdala. Conventional volumetry of whole hippocampal and extrahippocampal subcortical structures, and of global gray and white matter, could not differentiate between patient outcome groups. However, surface shape analysis revealed localized atrophy of the thalamus bilaterally and of the posterior/lateral hippocampus contralateral to intended resection in patients with persistent postoperative seizures relative to those rendered seizure free. Data uncorrected for multiple comparisons also revealed focal atrophy of the ipsilateral hippocampus posterior to the margins of resection in patients with persistent seizures. This data indicates that persistent postoperative seizures after temporal lobe surgery are related to localized preoperative shape alterations of the thalamus bilaterally and the hippocampus contralateral to intended resection. Imaging techniques that have the potential to unlock prognostic markers of postoperative outcome in individual patients should focus assessment on a bihemispheric thalamohippocampal network in prospective patients with refractory mTLE being considered for temporal lobe surgery. Hum Brain Mapp 36:1637–1647, 2015. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Presurgical entorhinal cortex volume and postoperative seizure outcome in temporal lobe epilepsy

BackgroundAlthough temporal lobe surgery is an effective treatment for patients with intractable mesial temporal lobe epilepsy (mTLE), a third of patients will continue to experience seizures at 2 years after surgery. The reasons are unknown. One suggestion is that patients with abnormalities of the entorhinal cortex might have a subtype of mTLE that is resistant to surgery. We investigated the association between presurgical entorhinal cortex volume and postoperative outcome in patients with mTLE. Methods78 patients with intractable mTLE and unilateral hippocampal sclerosis underwent comprehensive presurgical evaluation at the Department of Epileptology, University Hospital Bonn, Germany. Patients and 76 age-matched healthy controls received an MP-RAGE T1-weighted MRI. We determined left and right entorhinal cortex volume, masked to participant identity, using rigorous manual techniques. All patients had complex partial seizures, underwent amygdalohippocampectomy, and received postoperative outcome assessment. FindingsThere was a significant effect of group (controls, left mTLE, right mTLE) on the volume of the left (univariate ANOVA F=29·6, p<0·001) and right (F=8·3, p<0·001) entorhinal cortex, and entorhinal asymmetry (F=92·6, p<0·001). Post-hoc analysis with Bonferroni correction revealed that patients with left (p<0·001) and right (p=0·01) mTLE had significantly reduced volume of the ipsilateral entorhinal cortex relative to controls, and patients with right mTLE also had volume reduction of the contralateral entorhinal cortex (p=0·01). We found no significant differences in entorhinal cortex volumes and clinical data between patients (n=48, 62%) surgically rendered seizure free (ILAE I-II) and patients (n=30, 38%) with persistent seizures (ILAE III-VI). InterpretationThese data indicate that gross atrophy of the entorhinal cortex is not a predictor of postoperative outcome in patients with intractable mTLE. We are evaluating whether alterations in entorhinal cortex connectivity and extent of resection are related to postoperative outcome in our series of patients. FundingThis work was supported by a UK Medical Research Council grant awarded to SSK.

Quantitative MRI in refractory temporal lobe epilepsy: relationship with surgical outcomes.

Medically intractable temporal lobe epilepsy (TLE) remains a serious health problem. Across treatment centers, up to 40% of patients with TLE will continue to experience persistent postoperative seizures at 2-year follow-up. It is unknown why such a large number of patients continue to experience seizures despite being suitable candidates for resective surgery. Preoperative quantitative MRI techniques may provide useful information on why some patients continue to experience disabling seizures, and may have the potential to develop prognostic markers of surgical outcome. In this article, we provide an overview of how quantitative MRI morphometric and diffusion tensor imaging (DTI) data have improved the understanding of brain structural alterations in patients with refractory TLE. We subsequently review the studies that have applied quantitative structural imaging techniques to identify the neuroanatomical factors that are most strongly related to a poor postoperative prognosis. In summary, quantitative imaging studies strongly suggest that TLE is a disorder affecting a network of neurobiological systems, characterized by multiple and inter-related limbic and extra-limbic network abnormalities. The relationship between brain alterations and postoperative outcome are less consistent, but there is emerging evidence suggesting that seizures are less likely to remit with surgery when presurgical abnormalities are observed in the connectivity supporting brain regions serving as network nodes located outside the resected temporal lobe. Future work, possibly harnessing the potential from multimodal imaging approaches, may further elucidate the etiology of persistent postoperative seizures in patients with refractory TLE. Furthermore, quantitative imaging techniques may be explored to provide individualized measures of postoperative seizure freedom outcome.

Comparative efficacy of phenobarbital, phenytoin and lorazepam for the treatment of neonatal seizures: A randomized Trial

Aims: To compare efficacy of phenobarbital (PB), phenytoin (PHT) and lorazepam (LZP) for neonatal seizures. Settings: Medical College Hospital. Design: Prospective block design randomized trial (registration-CTRI/2012/12/003255). Subjects and Methods: Of 121 neonates with convulsions, 106 were grouped to receive PB (20 mg/kg), PHT (20 mg/kg) or LZP (0.05 mg/kg) intravenously over 5 min. The primary end point was clinical control of seizures within 2.5 min of starting single dose anti-epileptic drug (AED). Treatment was considered to have failed if the seizures lasted longer than 5 min, or a total of 2.5 min of seizure activity within 5 min period after a single dose. Statistical Analysis: Chi-square, Fisher's exact test, t-test, ANOVA. Results: Seizures subsided in 78 (74%) neonates within 2.5 min with a single dose, recurred in 55 (52%) and other AED was required in 30 (28%) neonates. 11% (10/89) required AED beyond discharge. The complete control of neonatal seizures within 2.5 min was similar with PB and PHT, but significantly more seizure control (89%) in the LZP group (P < 0.05). Adverse events (19%) were: PB - drowsiness 11; PHT - thrombophlebitis 3, nystagmus 1; LZP - drowsiness 2, hypotonia 3. 22 neonates expired (phenobarbitone 12, PHT 3, LZP 7). Conclusion: The complete control of 1st neonatal seizures within 2.5 min was similar with PB and PHT, but LZP had less treatment failure and less response time to control seizures. For control of recurrence and persistent seizure, none of the three drugs was better than the other. PB had the worst outcome as far as the deaths were concerned, followed by LZP and PHT.

Frontal gray matter abnormalities predict seizure outcome in refractory temporal lobe epilepsy patients.

Developing more reliable predictors of seizure outcome following temporal lobe surgery for intractable epilepsy is an important clinical goal. In this context, we investigated patients with refractory temporal lobe epilepsy (TLE) before and after temporal resection. In detail, we explored gray matter (GM) volume change in relation with seizure outcome, using a voxel-based morphometry (VBM) approach. To do so, this study was divided into two parts. The first one involved group analysis of differences in regional GM volume between the groups (good outcome (GO), e.g., no seizures after surgery; poor outcome (PO), e.g., persistent postoperative seizures; and controls, N = 24 in each group), pre- and post-surgery. The second part of the study focused on pre-surgical data only (N = 61), determining whether the degree of GM abnormalities can predict surgical outcomes. For this second step, GM abnormalities were identified, within each lobe, in each patient when compared with an ad hoc sample of age-matched controls. For the first analysis, the results showed larger GM atrophy, mostly in the frontal lobe, in PO patients, relative to both GO patients and controls, pre-surgery. When comparing pre-to-post changes, we found relative GM gains in the GO but not in the PO patients, mostly in the non-resected hemisphere. For the second analysis, only the frontal lobe displayed reliable prediction of seizure outcome. 81% of the patients showing pre-surgical increased GM volume in the frontal lobe became seizure free, post-surgery; while 77% of the patients with pre-surgical reduced frontal GM volume had refractory seizures, post-surgery. A regression analysis revealed that the proportion of voxels with reduced frontal GM volume was a significant predictor of seizure outcome (p = 0.014). Importantly, having less than 1% of the frontal voxels with GM atrophy increased the likelihood of being seizure-free, post-surgery, by seven times. Overall, our results suggest that using pre-surgical GM abnormalities within the frontal lobe is a reliable predictor of seizure outcome post-surgery in TLE. We believe that this frontal GM atrophy captures seizure burden outside the pre-existing ictal temporal lobe, reflecting either the development of epileptogenesis or the loss of a protective, adaptive force helping to control or limit seizures. This study provides evidence of the potential of VBM-based approaches to predict surgical outcomes in refractory TLE candidates.

Effect of connexin 36 blockers on the neuronal cytoskeleton and synaptic plasticity in kainic acid-kindled rats.

In this study we investigated the potential anti-epileptogenic effect of neuronal connexin Cx36 gap junction blockage via inhibition of microtubule-associated protein 2 (MAP-2) and synaptophysin (SYP) overexpression. Thirty adult male Wistar rats were divided into five groups (six animals per group): control, sham, carbenoxolone (CBX), quinine (QN), and quinidine (QND). An epilepsy model was produced by injecting kainic acid (KA) into the rat amygdala. Broad-spectrum and selective blockers of the Cx36 channel (CBX, QN, and QND) were administered via intraperitoneal injection. Expression of MAP-2 and SYP was assessed by immunofluorescent and immunohistochemical examination. Expression of MAP-2 and SYP was significantly increased after KA administration in the sham group compared with the control group. Expression of MAP-2 and SYP was significantly decreased in the CBX, QN, and QND groups compared with the sham group. The results provide new evidence regarding the key role of MAP-2 and SYP overexpression in three important mechanisms: the modulation of neuronal plasticity, hyperexcitability of the hippocampal neuronal network, and persistent seizure discharge. Furthermore, the reversal of MAP-2 and SYP overexpression following administration of Cx36 channel blockers indicates a potential role for Cx36 channel blockers in anti-epileptogenic treatment and in doing so, highlights a critical need for further investigation of these compounds.

Cognitive development in females with PCDH19 gene-related epilepsy

Mutations in the PCDH19 gene are now recognized to cause epilepsy in females and are claiming increasing interest in the scientific world. Clinical features and seizure semiology have been described as heterogeneous. Intellectual disability might be present, ranging from mild to severe; behavioral and psychiatric problems are a common feature of the disorder, including aggressiveness, depressed mood, and psychotic traits.The purpose of our study was to describe the cognitive development in 11 girls with a de novo mutation in PCDH19 and early-onset epilepsy.Six patients had average mental development or mild intellectual disability regardless of persistence of seizures in clusters. Five patients presented moderate or severe intellectual disability and autistic features. In younger patients, we found that despite an average developmental quotient, they all presented a delay of expressive language acquisition and lower scores at follow-up testing completed at older ages, underlining that subtle dysfunctions might be present.Larger cohort and long-term follow-up might be useful in defining cognitive features and in improving the care of patients with PCDH19.

Standard dose valproic acid does not cause additional cognitive impact in a rodent model of intractable epilepsy

Children with epilepsy face significant cognitive and behavioral impairments. These impairments are due to a poorly characterized interaction between the underlying etiology, the effect of seizures and the effect of medication. The large variation in these factors make understanding the main drivers of cognitive impairment in humans extremely difficult. Therefore, we investigated the cognitive effect of seizures and the antiepileptic drug valproic acid in a rodent model of cortical dysplasia. Rats were divided into seizure-receiving and non-receiving groups. Rats experienced frequent early life seizures using the flurothyl inhalation method: 50 seizures between postnatal day 5 and 15 and then one seizure a day following that. Rats were further divided into drug-treated and vehicle treated groups. Valproic acid treated animals were treated from 5 days preceding behavioral testing in the Morris water maze at a clinically relevant concentration. We show here that the main driver of cognitive impairments are the brain malformations, and that persistent seizures in animals with brain malformations and valproic acid caused no additional impact. These findings suggest that neither an appropriate dose of a standard antiepileptic drug or intractable seizures worsen cognition associated with a malformation of cortical development and that alternative treatment strategies to improve cognition are required.

Risk factors for apnea in children presenting with out-of-hospital seizure.

This study aimed to quantify risk factors for apnea in children 0 to 5 years of age with out-of-hospital seizure. This is a retrospective study of pediatric patients with seizure transported by paramedics to the pediatric emergency department (PED) of a tertiary center from July 2008 to June 2009. Patients with traumatic injury and those with another diagnosis after PED evaluation were excluded. We evaluated the effect of field diazepam and other potential risk factors on the occurrence of apnea, defined as the need for airway management, that is, bag-mask ventilation by paramedics or bag-mask ventilation or intubation by PED staff within 30 minutes of arrival. There were 336 pediatric patients meeting inclusion criteria. The median age was 1.9 years (interquartile range,1.3-3.0 years); 193 patients (57%) were male. Fifty-four patients (16%) were treated with diazepam before PED arrival. There were 28 apneic events (8.3%). The adjusted relative risk for apnea given diazepam in the field by any route was 10.2 (95% confidence interval, 3.9-21.8; P < 0.0001), adjusted for age and seizure on arrival. Persistent seizure on PED arrival was also highly associated with apnea, with an adjusted relative risk of 15.8 (95% confidence interval, 6.5-28.9; P < 0.0001). Field treatment with diazepam and seizing at the time of PED arrival are associated with the occurrence of apnea in children 0 to 5 years of age with out-of-hospital seizure. Larger studies are needed to determine what other factors may contribute to this risk.

Unilateral Eye Blinking Arising From the Ictal Ipsilateral Occipital Area

We report on an 18-month-old boy with unilateral left eye blinking as a single ictal manifestation without facial twitching. The clinical onset of this phenomenon was first recorded (as an occasional event) at age 3 months, and it was overlooked. By age 6 months, the child's blinking increased to almost daily occurrence in clusters: during blinking the infant showed intact awareness and occasional jerks in the upper limbs and right leg. A video-electroencephalography (video-EEG) documented clinical correlation with a focal pattern arising from the left occipital region, and brain magnetic resonance imaging (MRI) revealed severe brain damage, consisting in poroencephalic hollows and increased spaces in the convexities involving a large area of the left cerebral hemisphere. The boy was prescribed sodium valproate (30 mg/kg/d), resulting in drastic reduction of his clinical seizures. Follow-up to his current age documented good general status, with persistent partial right hemilateral seizures. The blinking progressively disappeared, and is no longer recorded. The pathogenic hypotheses of the unilateral ictal blinking include involvement of the ipsilateral cerebral hemisphere and/or the cerebellar pathways. Review of previous reports of unilateral eye blinking, arising from the ictal ipsilateral brain, revealed that different damaged regions may give rise to blinking ictal phenomena, likely via the trigeminal fibres innervating the subdural intracranial structures and the pial vessels in the ipsilateral affected brain. The eye blinking in the present child represents a further example of an ictal phenomenon, which is predictive of the damaged brain region.

Conversion from immediate-release to extended-release lamotrigine improves seizure control

BackgroundImmediate release lamotrigine (LTG-IR) dosing can be limited by peak toxicity. It is thought that peak levels are responsible for some adverse effects such as dizziness, blurred vision, double vision and unsteadiness. At the same time, trough levels may be associated with reduced seizure threshold. The use of extended release lamotrigine (LTG-XR) to replace LTG-IR will be associated with less fluctuation in drug levels-lower peak levels may reduce adverse effects and higher trough levels may improve seizure control. This hypothesis was tested by analyzing seizure control and adverse effects before and after conversion from LTG-IR to LTG-XR in patients who underwent such conversion in 2009–2011. MethodsWe searched our patient database to identify patients converted from LTG-IR to LTG-XR for persistent seizures or adverse effects from August 2009 until December 31, 2011. We included only patients who took LTG-IR and LTG-XR for at least 6 months each. We excluded patients with nonepileptic seizures, progressive cause of epilepsy, or not keeping a seizure record. We collected the following parameters: age at conversion, LTG-IR dose and dosing schedule, duration on that dose, LTG-XR dose and dosing schedule, LTG serum level before and after conversion, duration of LTG-XR treatment, seizure frequency before and after conversion, and change in adverse experience profile. We also recorded baseline AEDs and any AED change during the course of the analysis. ResultsFifty five patients (26 female) satisfied the inclusion/exclusion criteria. Their mean age was 45 years (range 23 to 86). Ten were on LTG-IR monotherapy, 24 took LTG-IR plus one other AED, most commonly levetiracetam, and the remaining 21 took LTG-IR plus at least 2 other AEDs. The mean LTG-IR dose was 544mg/day (range 150–1100mg/day). The mean LTG-IR serum level was 11.6 (available in 53 patients-range 4.6–21mcg/ml). Twenty six patients were converted to the same dose and one patient took a mixture of LTG-XR and LTG-IR at the same total daily dose, while 21 had their dose slightly increased and 7 had their dose slightly decreased due to adverse effects. The mean serum level after conversion was 11.8 (available in 49 patients-range 2.6–21.2mcg/ml). As a result of the conversion, 26 patients (47%) experienced >50% reduction in seizure frequency. There was a 46% median reduction in seizure frequency overall. Seven patients reported improvement in adverse effects. ConclusionA conversion from LTG-IR to LTG-XR can help improve seizure control in some individuals with drug-resistant epilepsy, in addition to improving tolerability. While it is indicated in individuals experiencing peak adverse effects, it should also be considered in patients who have received incomplete seizure control from LTG-IR.

Epilepsy surgery failure in children: a quantitative and qualitative analysis.

Resection is a safe and effective treatment option for children with pharmacoresistant focal epilepsy, but some patients continue experience seizures after surgery. While most studies of pediatric epilepsy surgery focus on predictors of postoperative seizure outcome, these factors are often not modifiable, and the reasons for surgical failure may remain unclear. The authors performed a retrospective cohort study of children and adolescents who received focal resective surgery for pharmacoresistant epilepsy. Both quantitative and qualitative analyses of factors associated with persistent postoperative seizures were conducted. Records were reviewed from 110 patients, ranging in age from 6 months to 19 years at the time of surgery, who underwent a total of 115 resections. At a mean 3.1-year follow-up, 76% of patients were free of disabling seizures (Engel Class I outcome). Seizure freedom was predicted by temporal lobe surgery compared with extratemporal resection, tumor or mesial temporal sclerosis compared with cortical dysplasia or other pathologies, and by a lower preoperative seizure frequency. Factors associated with persistent seizures (Engel Class II-IV outcome) included residual epileptogenic tissue adjacent to the resection cavity (40%), an additional epileptogenic zone distant from the resection cavity (32%), and the presence of a hemispheric epilepsy syndrome (28%). While seizure outcomes in pediatric epilepsy surgery may be improved by the use of high-resolution neuroimaging and invasive electrographic studies, a more aggressive resection should be considered in certain patients, including hemispherectomy if a hemispheric epilepsy syndrome is suspected. Family counseling regarding treatment expectations is critical, and reoperation may be warranted in select cases.

Selective suppression of excessive GluN2C expression rescues early epilepsy in a tuberous sclerosis murine model.

Tuberous sclerosis complex (TSC), caused by dominant mutations in either TSC1 or TSC2 tumour suppressor genes is characterized by the presence of brain malformations, the cortical tubers that are thought to contribute to the generation of pharmacoresistant epilepsy. Here we report that tuberless heterozygote Tsc1+/− mice show functional upregulation of cortical GluN2C-containing N-methyl-D-aspartate receptors (NMDARs) in an mTOR-dependent manner and exhibit recurrent, unprovoked seizures during early postnatal life (<P19). Seizures are generated intracortically in the granular layer of the neocortex. Slow kinetics of aberrant GluN2C-mediated currents in spiny stellate cells promotes excessive temporal integration of persistent NMDAR-mediated recurrent excitation and seizure generation. Accordingly, specific GluN2C/D antagonists block seizures in Tsc1+/− mice in vivo and in vitro. Likewise, GluN2C expression is upregulated in TSC human surgical resections, and a GluN2C/D antagonist reduces paroxysmal hyperexcitability. Thus, GluN2C receptor constitutes a promising molecular target to treat epilepsy in TSC patients.

103 Stereotactic Laser Amygdalohippocampotomy for Mesial Temporal Lobe Epilepsy

INTRODUCTION: Stereotactic laser amygdalohippocampotomy (SLAH) is a minimally-invasive potential alternative to open resection for mesial temporal lobe epilepsy (MTLE), but outcome data are limited (Willie et al, 2014). Here we present data on effectiveness, safety, and related findings collected from investigator-initiated, prospective, observational studies at 7 centers. METHODS: Fifty-one subjects who met entry criteria for surgical treatment of MTLE were enrolled in IRB-approved prospective data collection and underwent SLAH. Screening and follow-up visits were arranged per protocol at a given center, typically at 1, 3, 6, and/or 12-months, with some variation by center. Data captured via case report forms included medical/surgical history, number of anti-epileptic drugs (AEDs) tried, duration from epilepsy diagnosis to screening for this study, seizure count since last visit, concomitant medications, adverse events, radiographic findings, neuropsychological tests, and healthcare utilization variables including length-of-stay and level-of-care during hospitalization. RESULTS: Median age was 40 years (5-70 years). AEDs were kept constant throughout the 1-year course by most centers. At 6-month follow-up of all available consecutive subjects (ie, since 10/20/10) for whom data was available, 52% (20/39) at 6-months and 48% (14/29) at 12-months follow-up were seizure-free. However, for procedures performed after 7/1/12, at 6-month follow-up 63% (15/24), and at 12-months 69% (9/13) were seizure-free, suggesting improved outcome with experience. Similarly, 64% (9/14) for procedures performed after 1/1/13 were seizure-free at 6-months. Procedure-related adverse events recorded in all patients included headache (N = 10), visual field disturbance (N = 3), psychiatric disturbance (N = 3), hemorrhage (N = 2), and cellulitis (N = 1). Median length-of-stay was 1 day. Four patients underwent anterior temporal lobectomy for persistent seizures. CONCLUSION: SLAH appears to be a safe procedure and achieves seizure-freedom for a substantial proportion of patients with MTLE. Data support a procedural “learning curve,” plateauing at ∼65% seizure-free. Further prospective study, with greater numbers of subjects, could help elucidate and/or strengthen these findings.

Management of pediatric status epilepticus.

Status epilepticus (SE) is a medical emergency consisting of persistent or recurring seizures without a return to baseline mental status. SE can be divided into subtypes based on seizure types and underlying etiologies. Management should be implemented rapidly and based on pre-determined care pathways. The aim is to terminate seizures while simultaneously identifying and managing precipitant conditions. Seizure management involves "emergent" treatment with benzodiazepines (lorazepam intravenously, midazolam intramuscularly, or diazepam rectally) followed by "urgent" therapy (phenytoin/fosphenytoin, phenobarbital, levetiracetam or valproate sodium). If seizures persist, "refractory" treatments include infusions of midazolam or pentobarbital. Prognosis is dependent on the underlying etiology and seizure persistence. This article reviews the current management strategies for pediatric convulsive SE.