Mutations in the DEPDC5 (DEP domain–containing protein 5) gene are a major cause of familial focal epilepsy with variable foci (FFEVF) and are predicted to account for 12–37% of families with inherited focal epilepsies. To assess the clinical impact of DEPDC5 mutations in familial temporal lobe epilepsy, we screened a collection of Italian families with either autosomal dominant lateral temporal epilepsy (ADLTE) or familial mesial temporal lobe epilepsy (FMTLE). The probands of 28 families classified as ADLTE and 17 families as FMTLE were screened for DEPDC5 mutations by whole exome or targeted massive parallel sequencing. Putative mutations were validated by Sanger sequencing. We identified a DEPDC5 nonsense mutation (c.918C>G; p.Tyr306*) in a family with two affected members, clinically classified as FMTLE. The proband had temporal lobe seizures with prominent psychic symptoms (déjà vu, derealization, and forced thoughts); her mother had temporal lobe seizures, mainly featuring visceral epigastric auras and anxiety. In total, we found a single DEPDC5 mutation in one of (2.2%) 45 families with genetic temporal lobe epilepsy, a proportion much lower than that reported in other inherited focal epilepsies.
Hippocampal-thalamic wiring in medial temporal lobe epilepsy: Enhanced connectivity per hippocampal voxel
Medial temporal lobe epilepsy (TLE) with hippocampal sclerosis is often accompanied by widespread changes in ipsilateral and contralateral white matter connectivity. Recent studies have proposed that patients may show pathologically enhanced wiring of the limbic circuits. To better address this issue, we specifically probed connection patterns between hippocampus and thalamus and examined their impact on cognitive function.Methods
A group of 44 patients with TLE (22 with right and 22 with left hippocampal sclerosis) and 24 healthy control participants were examined with high-resolution T1 imaging, memory functional magnetic resonance imaging (fMRI) and probabilistic diffusion tractography. Thirty-four patients had further extensive neuropsychological testing. After whole brain segmentation with FreeSurfer, tractography streamline samples were drawn with hippocampus as the seed and thalamus as the target region. Two tractography strategies were applied: The first targeted the anatomic thalamic volume segmented in FreeSurfer and the second a functional region of interest in the mediodorsal thalamus derived from the activation during delayed recognition memory.Results
We found a pronounced enhancement of connectivity between the sclerotic hippocampus and the ipsilateral thalamus both in the right and left TLE as compared to healthy control participants. This finding held for both the anatomically and the functionally defined thalamic target. Although differences were apparent in the number of absolute fibers, they were most pronounced when correcting for hippocampal volume. In terms of cognitive function, the number of hippocampal-thalamic connections was negatively correlated with performance in a variety of executive tasks, notably in the Trail Making Test, thus suggesting that the pathologic wiring did not compensate cognitive curtailing.Significance
We suggest that TLE is accompanied by an abnormal and dysfunctional enhancement of connectivity between the hippocampus and the thalamus, which is maximal on the side of the sclerosis. This pathologic pattern of limbic wiring might reflect structural remodeling along common pathways of seizure propagation.
Epilepsy Surgery In The United States: Analysis Of Data From The National Association Of Epilepsy Centers
Recurrent secondary generalization in frontal lobe epilepsy: Predictors and a potential link to surgical outcome?
Frontal lobe epilepsy (FLE) frequently leads to secondary generalized tonic–clonic seizures (SGTCS). However, little is known about the clinical, electrophysiologic, and radiologic correlates of SGTCS and whether these could influence diagnosis and treatment.Methods
A cohort of 48 patients with confirmed FLE was retrospectively identified and dichotomized into a group with and a group without SGTCS defined by history (≥1/year) or video–electroencephalography (vEEG). Demographics, seizure semiology, vEEG, neuroimaging data, and estimated seizure-onset zone were tabulated, and their association with the occurrence of SGTCS was evaluated with use of a chi-square test. Independent predictors of SGTCS were confirmed using a stepwise multivariate analysis. Similarly, these predictors as well as a history of SGTCS were tested as multivariate predictors of the postoperative International League Against Epilepsy (ILAE) score in the surgical subgroup (n = 25).Results
We identified three independent predictors of a history of SGTCS in FLE, including loss of responsiveness at seizure onset (corrected p = 0.04), a semiology involving early elementary motor signs (corrected p = 0.01), and multifocal spikes on EEG (corrected p = 0.02). A seizure-free outcome occurred in 57% of surgical cases and was more likely in the group without SGTCS (100%, p = 0.001). When considering only SGTCS occurring during video-EEG monitoring, the association with semiology and surgical outcome vanished, but the association with preserved awareness and a multifocal EEG persisted.Significance
A history of SGTCS is related to a specific ictal semiology and interictal EEG, and may have a role in surgical risk stratification.
Intravenous Anesthesia in Treatment of Nonconvulsive Status Epilepticus: Characteristics and Outcomes
Generic lamotrigine versus brand-name Lamictal bioequivalence in patients with epilepsy: A field test of the FDA bioequivalence standard
To test the current U.S. Food and Drug Administration (FDA) bioequivalence standard in a comparison of generic and brand-name drug pharmacokinetic (PK) performance in “generic-brittle” patients with epilepsy under clinical use conditions.Methods
This randomized, double-blind, multiple-dose, steady-state, fully replicated bioequivalence study compared generic lamotrigine to brand-name Lamictal in “generic-brittle” patients with epilepsy (n = 34) who were already taking lamotrigine. Patients were repeatedly switched between masked Lamictal and generic lamotrigine. Intensive PK blood sampling at the end of each 2-week treatment period yielded two 12-h PK profiles for brand-name and generic forms for each patient. Steady-state area under the curve (AUC), peak plasma concentration (Cmax), and minimum plasma concentration (Cmin) data were subjected to conventional average bioequivalence (ABE) analysis, reference-scaled ABE analysis, and within-subject variability (WSV) comparisons. In addition, generic-versus-brand comparisons in individual patients were performed. Secondary clinical outcomes included seizure frequency and adverse events.Results
Generic demonstrated bioequivalence to brand. The 90% confidence intervals of the mean for steady-state AUC, Cmax, and Cmin for generic-versus-brand were 97.2–101.6%, 98.8–104.5%, and 93.4–101.0%, respectively. The WSV of generic and brand were also similar. Individual patient PK ratios for generic-versus-brand were similar but not identical, in part because brand-versus-brand profiles were not identical, even though subjects were rechallenged with the same product. Few subjects had seizure exacerbations or tolerability issues with product switching. One subject, however, reported 267 focal motor seizures, primarily on generic, although his brand and generic PK profiles were practically identical.Significance
Some neurologists question whether bioequivalence in healthy volunteers ensures therapeutic equivalence of brand and generic antiepileptic drugs in patients with epilepsy, who may be at increased risk for problems with brand-to-generic switching. Bioequivalence results in “generic-brittle” patients with epilepsy under clinical conditions support the soundness of the FDA bioequivalence standards. Adverse events on generic were not related to the small, allowable PK differences between generic and brand.
The ketogenic diet (KD) is currently a well-established treatment for patients with medically refractory, nonsurgical epilepsy. However, despite its efficacy, the KD is highly restrictive and constitutes a treatment with serious potential adverse effects, and often with difficulties in its implementation and compliance. Patients on the KD require strict follow-up and constant supervision by a medical team highly experienced in its management in order to prevent complications. Other alternative treatments for patients with refractory epilepsy include vagus nerve stimulation (VNS), new-generation antiepileptic drugs (AEDs), corpus callosotomy (CC), and responsive focal cortical stimulation (RNS). In this review, we explain not only the difficulties of the KD as a therapeutic option for refractory epilepsy but also the benefits of other therapeutic strategies, which, in many cases, have proven to have better efficacy than the KD itself.
Ketogenic diet therapies for epilepsy have been described since the fifth century and published in scientific literature since the early 1900s. Since that time, the diet's popularity has waxed and waned as newer drugs and other treatments have been introduced. However, in recent years, dietary therapy for epilepsy has been increasingly accepted by physicians and desired by patients as an alternative to new drugs and neurostimulation. The introduction of less restrictive versions of the classic ketogenic diet, such as the modified Atkins diet (MAD), have led to increased numbers of adult patients with refractory epilepsy who are initiating dietary treatment. Approximately half of adults and children who start a ketogenic diet have a >50% seizure reduction, which is impressive given that these patients typically have medically refractory epilepsy. We believe that ketogenic dietary treatment is the best option for children and adults with refractory nonsurgical epilepsy due to its efficacy, rapid seizure reduction, synergistic effects with other antiseizure treatments, known and treatable side effects, potential to treat comorbid medical conditions, and worldwide availability.
In temporal lobe epilepsy (TLE), the thalamus is well known for its role in the propagation and spread of epileptiform activity. However, the integrity of thalamocortical functional connectivity (FC) in TLE and its relation to specific seizure patterns have not yet been determined. We address these issues with resting-state functional magnetic resonance imaging (fMRI).Methods
Resting-state fMRI was performed on two groups of unilateral TLE patients: those with focal seizures only (16 left TLE, 16 right TLE) and those with additional generalized seizures (16 left TLE, 10 right TLE), and 16 matched controls. A thalamic parcellation based on FC between five nonoverlapping cortical seeds (prefrontal, motor, somatosensory, parietal-occipital, and temporal) and the ipsilateral thalamus was carried out to parcel each thalamus into five corresponding segments. FCs between each segment and its ipsilateral cortical seed were extracted and compared across groups using analyses of variance (ANOVAs).Results
Compared to healthy controls, patients with TLE displayed decreased thalamocortical FC in multiple posterior and ventromedial thalamic segments of both the ictal and nonictal hemispheres. Our parcellation analysis revealed that these thalamic regions were functionally connected to the parietal/occipital and temporal lobes. In patients with TLE with focal seizures these regional thalamocortical FC decreases were limited to the ictal hemisphere. In contrast, TLE patients with both focal and generalized epileptiform activity displayed FC decreases in both the ictal and nonictal thalamus involving the dorsolateral pulvinar, a region preferentially connected to the parietal and occipital lobes.Significance
Our data provide the first evidence of regional specific thalamocortical FC decreases in patients with unilateral TLE. Furthermore, our results demonstrate that patients with different seizure types present different thalamoparietal/occipital FC decrease patterns. While patients with focal seizures present thalamocortical FC decreases in the ictal hemisphere only, patients with additional generalized seizure activity also show thalamocortical FC decreases involving the thalamus in the nonictal hemisphere.
The objective of this study was to determine the prevalence of seizures in children with tectal gliomas and to determine if there are common clinical, electroencephalography (EEG), or radiologic findings that predict risk of seizures in these patients. We conducted a retrospective review of all patients with tectal gliomas over a 22-year period at a single institution. Data extraction included sex, age at presentation of tectal glioma and age of presentation with seizures, magnetic resonance imaging (MRI) findings, seizure frequency and semiology, and EEG findings. We identified 79 patients, 66 of whom had adequate imaging and clinical data for further analysis. Eight patients (12.1%) had a history of seizures. Three patients had a clear symptomatic cause of seizures. Three patients were diagnosed with a tectal glioma as an incidental finding after a first seizure. One patient had a history of febrile convulsions. One patient had a generalized seizure 5 years after presenting with macrocephaly. Although the risk of seizure in children with known tectal glioma was relatively high, we did not identify specific clinical, radiologic, EEG, or MRI features that are predictive of increased risk. Thus, in children with tectal gliomas who have seizures, alternative causes for the seizures must be sought.
Electromyography-based seizure detector: Preliminary results comparing a generalized tonic–clonic seizure detection algorithm to video-EEG recordings
Automatic detection of generalized tonic–clonic seizures (GTCS) will facilitate patient monitoring and early intervention to prevent comorbidities, recurrent seizures, or death. Brain Sentinel (San Antonio, Texas, USA) developed a seizure-detection algorithm evaluating surface electromyography (sEMG) signals during GTCS. This study aims to validate the seizure-detection algorithm using inpatient video–electroencephalography (EEG) monitoring.Methods
sEMG was recorded unilaterally from the biceps/triceps muscles in 33 patients (17white/16 male) with a mean age of 40 (range 14–64) years who were admitted for video-EEG monitoring. Maximum voluntary biceps contraction was measured in each patient to set up the baseline physiologic muscle threshold. The raw EMG signal was recorded using conventional amplifiers, sampling at 1,024 Hz and filtered with a 60 Hz noise detection algorithm before it was processed with three band-pass filters at pass frequencies of 3–40, 130–240, and 300–400 Hz. A seizure-detection algorithm utilizing Hotelling's T-squared power analysis of compound muscle action potentials was used to identify GTCS and correlated with video-EEG recordings.Results
In 1,399 h of continuous recording, there were 196 epileptic seizures (21 GTCS, 96 myoclonic, 28 tonic, 12 absence, and 42 focal seizures with or without loss of awareness) and 4 nonepileptic spells. During retrospective, offline evaluation of sEMG from the biceps alone, the algorithm detected 20 GTCS (95%) in 11 patients, averaging within 20 s of electroclinical onset of generalized tonic activity, as identified by video-EEG monitoring. Only one false-positive detection occurred during the postictal period following a GTCS, but false alarms were not triggered by other seizure types or spells.Significance
Brain Sentinel's seizure detection algorithm demonstrated excellent sensitivity and specificity for identifying GTCS recorded in an epilepsy monitoring unit. Further studies are needed in larger patient groups, including children, especially in the outpatient setting.