Outcomes after changing antiepileptic drugs (AEDs) have largely been studied in single cohort series. We recently reported the first study to examine this question in a controlled manner. Here we expand on these results by using a matched, prospective methodology applied to both uncontrolled and well-controlled patients taking any AED.Methods
We reviewed all outpatient notes over a 9-month period and identified patients with focal epilepsy who were on monotherapy. We classified those who switched AEDs as case patients, with those remaining on the same drug serving as controls. We matched cases with controls for seizure status (seizure-free in the preceding 6 months or not), current AED, and number of failed AEDs. We subsequently assessed outcome 6 months later.Results
Seizure-free patients who switched drug (n = 12) had a 16.7% rate of seizure recurrence at 6 months, compared to 2.8% among controls remaining on the same drug (n = 36, p = 0.11). There was a 37% remission rate among uncontrolled patients who switched drug compared to 55.6% among controls (n = 27 per group, p = 0.18). Uncontrolled patients who had previously tried more than one AED were somewhat less likely to enter remission (p = 0.057). Neither AED mechanism of action nor change in dosage impacted outcome.Significance
Herein we provide further estimation of the modest risk (~14%) associated with switching AEDs in patients in remission compared to being maintained on the same regimen. Uncontrolled patients were no more likely to enter remission after a drug switch than they were after remaining on the same drug, suggesting that spontaneous changes in disease state, and not drug response, underlie remission in this population.
Circadian and ultradian patterns of epileptiform discharges differ by seizure-onset location during long-term ambulatory intracranial monitoring
Previous studies reporting circadian patterns of epileptiform activity and seizures are limited by (1) short-term recording in an epilepsy monitoring unit (EMU) with altered antiepileptic drugs (AEDs) and sleep, or (2) subjective seizure diary reports. We studied circadian patterns using long-term ambulatory intracranial recordings captured by the NeuroPace RNS System.Methods
Retrospective study of RNS System trial participants with stable detection parameters over a continuous 84-day period. We analyzed all detections and long device–detected epileptiform events (long episodes) and defined a subset of subjects in whom long episodes represented electrographic seizures (LE-SZ). Spectrum resampling determined the dominant frequency periodicity and cosinor analysis identified significant circadian peaks in detected activity. Chi-square analysis was used to compare subjects grouped by region of seizure onset.Results
In the 134 subjects, detections showed a strongly circadian and uniform pattern irrespective of region of onset that peaked during normal sleep hours. In contrast, long episodes and LE-SZ patterns varied by region. Neocortical regions had a monophasic, nocturnally dominant rhythm, whereas limbic regions showed a more complex pattern and diurnal peak. Rhythms in some individual limbic subjects were best fit by a dual oscillator (circadian + ultradian) model.Significance
Epileptiform activity has a strong 24 h periodicity with peak nocturnal occurrence. Limbic and neocortical epilepsy show divergent circadian influences. These findings confirm that circadian patterns of epileptiform activity vary by seizure-onset zone, with implications for treatment and safety, including SUDEP.
The diagnostic utility of 3D-ESI rotating and moving dipole methodology in the pre-surgical evaluation of MRI-negative childhood epilepsy due to focal cortical dysplasia
This study investigates whether a combined rotating dipole (RD) and moving dipole (MD) solution enhances three-dimensional electroencephalography (EEG) source imaging (3D-ESI) localization in magnetic resonance imaging (MRI)–negative pediatric patients with focal cortical dysplasia (FCD).Methods
We retrospectively selected 14 MRI-negative patients with FCD from a cohort of 60 pediatric patients previously used to evaluate the diagnostic utility of 3D-ESI in epilepsy surgery. Patients were younger than 18 years at time of surgery and had at least 1 year of outcome data. RD and MD models were constructed for each interictal spike or sharp wave, and it was determined whether each inverse algorithm localized within the surgical resection cavity (SRC). We also compared the 3D-ESI findings and surgical outcome with positron emission tomography (PET) and ictal single photon emission computed tomography (iSPECT).Results
RD analyses revealed a high concordance with the SRC (78.6%), particularly for temporal lobe resection (100.0%), and showed superior localization compared to PET and iSPECT, with the highest correlation in FCD type I and temporal lobe resection. Furthermore, the RD method was superior to iSPECT in FCD type II cases and to PET in extratemporal resections. RD and MD results were comparable, but in 18.2% of patients with FCD type I with localizing RDs, the MD solution was only partially within the SRC; in all of these patients 3D-ESI also correlated with superior surgical outcome compared to PET and iSPECT, especially when RD and MD solutions were analyzed together.Significance
3D-ESI in MRI-negative cases showed superior localization compared to iSPECT or PET, especially in FCD type I and temporal lobe epilepsy, and correlated with superior surgical outcome compared to iSPECT and PET at 1 year and 2 years postoperatively, especially when RD and MD solutions were analyzed together. These findings suggest that 3D-ESI based on a combined RD-MD solution improves surgical accuracy in MRI-negative patients with FCD.
Epilepsy in cerebrovascular diseases: Review of experimental and clinical data with meta-analysis of risk factors
Seizures may occur in close temporal association with a stroke or after a variable interval. Moreover, epilepsy is often encountered in patients with leukoaraiosis. Although early post-stroke seizures have been studied extensively, less attention has been paid to post-stroke epilepsy (PSE) and to epilepsy associated with leukoaraiosis (EAL). The aim of this paper is to review data concerning pathophysiology, prognosis, and treatment of PSE and EAL.Methods
We performed an extensive literature search to identify experimental and clinical articles on PSE and EAL. We also conducted a systematic review of risk factors for PSE and EAL among eligible studies.Results
PSE is caused by enhanced neuronal excitability within and near the scar leads. The role played by white matter changes in EAL remains to be elucidated. Meta-analysis showed that cortical involvement (odds ratio [OR] 3.71, 95% confidence interval [CI] 2.34–5.90, p < 0.001), cerebral hemorrhage (OR 2.41, 95% CI 1.57–3.70, p < 0.001), and early seizures (OR 4.43, 95% CI 2.36–8.32, p < 0.001) are associated with an increased risk of PSE. As regards EAL, no prospective, population-based studies evaluated the role of different variables on seizure risk. Studies about the management of PSE are limited. PSE is generally well controlled by drugs. Data about risk factors, prognosis, and treatment of EAL are lacking.Significance
Pathophysiology and risk factors are well defined for PSE but need to be elucidated for EAL. Management of PSE and EAL relies on the clinician's judgment and should be tailored on an individual basis.
In animal models, inflammation is both a cause and consequence of seizures. Less is known about the role of inflammation in human epilepsy. We performed positron emission tomography (PET) using a radiotracer sensitive to brain inflammation in a patient with frontal epilepsy ~36 h after a seizure as well as during a seizure-free period. When statistically compared to a group of 12 matched controls, both of the patient's scans identified a frontal (supplementary motor area) region of increased inflammation corresponding to his clinically defined seizure focus, but the postseizure scan showed significantly greater inflammation intensity and spatial extent. These results provide new information about transient and chronic neuroinflammation in human epilepsy and may be relevant to understanding the process of epileptogenesis and guiding therapy.
Long-term use of antiepileptic drugs (AEDs) is a significant risk factor for vitamin D deficiency in children with epilepsy. The aims of our study were to evaluate the prevalence and risk factors for vitamin D deficiency among Malaysian children with epilepsy.Methods
Cross-sectional study of ambulant children with epilepsy on long-term AEDs for >1 year seen in three tertiary hospitals in Malaysia from April 2014 to April 2015. Detailed assessment of pubertal status, skin pigmentation, sunshine exposure behavior, physical activity, dietary vitamin D and calcium intake, anthropometric measurements and bone health blood tests (vitamin D, alkaline phosphatase, calcium, phosphate, and parathyroid hormone levels) were obtained on all patients. Vitamin D deficiency was defined as 25-hydroxy vitamin D [25(OH)D] levels ≤35 nmol/L and insufficiency as 25(OH)D levels of 36–50 nmol/L.Results
A total of 244 children (146 male) participated in the study. Ages ranged between 3.7 and 18.8 years (mean 12.3 years). 25(OH)D levels ranged between 7.5 and 140.9 nmol/L (mean 53.9 nmol/L). Vitamin D deficiency was identified in 55 patients (22.5%), and a further 48 (19.7%) had vitamin D insufficiency. Multivariate logistic regression analysis identified polytherapy >1 AED (odds ratio [OR] 2.16, 95% confidence interval [CI] 1.07–4.36), age >12 years (OR 4.16, 95% CI 1.13–15.30), Indian ethnicity (OR 6.97, 95% CI 2.48–19.55), sun exposure time 30–60 min/day (OR 2.44, 95% CI 1.05–5.67), sun exposure time <30 min/day (OR 3.83, 95% CI 1.61–9.09), and female (OR 2.61, 95% CI 1.31–5.20) as statistically significant (p < 0.05) risk factors for vitamin D deficiency.Significance
Despite living in the tropics, a high proportion of Malaysian children with epilepsy are at risk of vitamin D deficiency. Targeted strategies including vitamin D supplementation and lifestyle advice of healthy sunlight exposure behavior should be implemented among children with epilepsy, particularly for those at high risk of having vitamin D deficiency.
Ghrelin has anticonvulsant and neuroprotective effects in models of chemoconvulsant-induced seizures and status epilepticus. In this study we investigated whether deletion of the ghrelin receptor could alter the kindling process in the 6 Hz corneal kindling model and whether ghrelin receptor ligands possess anticonvulsant effects in fully kindled mice. Ghrelin receptor wild-type and knockout mice were electrically stimulated at a subconvulsive current twice daily via corneal electrodes until they reached the fully kindled state. Mice lacking the ghrelin receptor showed similar seizure severity during kindling acquisition as well as in the maintenance phase when compared to their wild-type littermates. Subsequently we proceeded by investigating possible anticonvulsant effects of the ghrelin receptor ligands in the acute 6 Hz seizure model and the fully 6 Hz kindled mice. The ghrelin receptor agonist JMV-1843 decreased the seizure severity score both in acutely 6 Hz stimulated mice and in fully kindled ghrelin receptor wild-type mice, but not in fully kindled ghrelin receptor knockout mice. No effect on seizure severity was observed following the ghrelin receptor antagonist JMV-2959 in both models. This finding indicates that JMV-1843 exerts an anticonvulsant effect in kindled mice via the ghrelin receptor.
Infant crying is a series of innate vocal patterns intended to elicit the attention of adult caregivers for fulfillment of specific needs such as pain, hunger, or hypostimulation. It is one of the earliest forms of observable communication. In neonatal rodents, this behavior has recently been investigated as a potential early behavioral marker of neural deficits in neurodevelopmental disorders. However, few studies have examined the effects of seizures on vocalization behavior during the neonatal period. The purpose of this study is to investigate the effect of a single kainate-induced early life seizure on vocalization behavior in mice. This study also investigates the subsequent effect of seizures on two pathways critical for early neural development and epileptogenesis: the phosphoinositide 3-kinase|serine/threonine kinase|mammalian target of rapamycin (PI3K-Akt-mTOR) and canonical (Wingless-Int Wnt) intracellular signaling pathways.Methods
On postnatal day 10, male and female 129SvEvTac mice received a single intraperitoneal injection of kainic acid (2.5 mg/kg) or vehicle injection. The kainate administration resulted in 1–2 h of status epilepticus. On postnatal days 11 and 12, the quantity and duration of isolation-induced ultrasonic vocalizations were recorded. Western blotting analyses were performed using male and female pups on postnatal day 12.Results
There was significant, male-specific suppression in the quantity and total duration of 50-kHz calls on postnatal day 12 following seizures. The hippocampi of male mice on this postnatal day also revealed male-specific changes in the PI3K-Akt-mTOR intracellular signaling pathway, as well as changes in phosphorylated fragile × mental retardation protein.Significance
These findings demonstrate that early life seizures can disrupt communication behavior in neonatal mice.
We assessed whether presurgical resting state functional magnetic resonance imaging (fMRI) provides information for distinguishing temporal lobe epilepsy (TLE) with mesial temporal sclerosis (TLE-MTS) from TLE without MTS (TLE-noMTS).Methods
Thirty-four patients with TLE and 34 sex-/age-matched controls consented to a research imaging protocol. MTS status was confirmed by histologic evaluation of surgical tissue (TLE-MTS = 16; TLE-noMTS = 18). The fractional amplitude of low-frequency fluctuations (fALFFs) in the blood oxygen level–dependent (BOLD) resting-state fMRI signal, a marker of local metabolic demand at rest, was averaged at five regions of interest (ROIs; hippocampus, amygdala, frontal, occipital, and temporal lobe), along with corresponding volume and cortical thickness estimates. ROIs were labeled ipsilateral or contralateral according to seizure lateralization and compared across TLE-MTS, TLE-noMTS, and healthy controls (HCs). MTS status was regressed on ipsilateral hippocampal volume and fALFF to test for independent contributions.Results
The TLE-MTS group had reduced fALFF in the ipsilateral amygdala and hippocampus; whereas, the TLE-noMTS group had marginally reduced fALFF in the ipsilateral amygdala but not hippocampus. These results were consistently obtained with and without application of global signal regression (GSR). Ipsilateral hippocampal volume contributed to 37% of the variance in MTS status (p < 0.001) and fALFF contributed an additional 10% (p = 0.021). Two MTS cases were accurately classified with fALFF but not volume, and three were accurately classified with volume but not fALFF. At the lobar level, fALFF (with GSR) was reduced in the ipsilateral temporal and bilateral frontal lobes of patients with TLE-MTS and bilateral frontal lobes of patients with TLE-noMTS in the context of normal cortical thickness.Significance
This study indicates that resting-state fMRI provides complementary functional information for MTS classification. Findings validate fALFF as a measure of regional brain integrity in TLE and highlight the value of using multi-modal imaging to provide independent diagnostic information in presurgical epilepsy evaluations.
The SCN8A encephalopathy mutation p.Ile1327Val displays elevated sensitivity to the anticonvulsant phenytoin
SCN8A encephalopathy (early infantile epileptic encephalopathy; EIEE13) is caused by gain-of-function mutations resulting in hyperactivity of the voltage-gated sodium channel Nav1.6. The channel is concentrated at the axon initial segment (AIS) and is involved in establishing neuronal excitability. Clinical features of SCN8A encephalopathy include seizure onset between 0 and 18 months of age, intellectual disability, and developmental delay. Seizures are often refractory to treatment with standard antiepileptic drugs, and sudden unexpected death in epilepsy (SUDEP) has been reported in approximately 10% of patients. In a recent study, high doses of phenytoin were effective in four patients with SCN8A encephalopathy. In view of this observation, we have investigated the relationship between the functional effect of the SCN8A mutation p.Ile1327Val and its response to phenytoin.Methods
The mutation was introduced into the Scn8a cDNA by site-directed mutagenesis. Channel activity was characterized in transfected ND7/23 cells. The effects of phenytoin (100 μm) on mutant and wild-type (WT) channels were compared.Results
Channel activation parameters were shifted in a hyperpolarizing direction in the mutant channel, whereas inactivation parameters were shifted in a depolarizing direction, increasing Na channel window current. Macroscopic current decay was slowed in I1327V channels, indicating an impairment in the transition from open state to inactivated state. Channel deactivation was also delayed, allowing more channels to remain in the open state. Phenytoin (100 μm) resulted in hyperpolarized activation and inactivation curves as well as greater tonic block and use-dependent block of I1327V mutant channels relative to WT.Significance
SCN8A – I1327V is a gain-of-function mutation with altered features that are predicted to increase neuronal excitability and seizure susceptibility. Phenytoin is an effective inhibitor of the mutant channel and may be of use in treating patients with gain-of-function mutations of SCN8A.
Peripheral biomarkers have myriad potential uses for treatment, prediction, prognostication, and pharmacovigilance in epilepsy. To date, no single peripheral biomarker has demonstrated proven effectiveness, although multiple candidates are in development. In this review, we discuss the major areas of focus including inflammation, blood–brain barrier dysfunction, redox alterations, metabolism, hormones and growth factors.