The main purpose of the study was to analyze the long-term outcomes and therapeutic approaches for patients with seizures within the first year after surgery. The secondary aim of the study was to evaluate the relationship between 1-year outcome and long-term outcome and choice of therapy.Methods
Our study was a retrospective investigation of the long-term outcomes of 95 patients (33.5% of all surgically treated patients) with seizure recurrence in the first year after surgery. The patients had follow-up visits for >5 years.Results
At the 5-year follow-up visit (FU5), 28 (29.5%) of the 95 patients were completely seizure-free (International League Against Epilepsy (ILAE) class 1), 17 (17.9%) had auras only (ILAE class 2), and 21 (22.1%) were unimproved (ILAE classes 5 and 6). Statistically significant factors for these long-term outcomes were the focus localization of the epilepsy, preoperative MRI findings, and postoperative follow-up results in the first year. The patients with <3 seizure days in the first postoperative year (ILAE 3) represented 53.6% of the seizure-free patients at FU5; the patients with auras in the first year constituted 64.7% of the patients with only auras at FU5; and the patients unimproved in the first year represented 76.2% of the unimproved patients at FU5.Significance
Postoperative outcome depends to a certain extent on the outcome achieved in the first postoperative year. More than one third of the patients with postoperative seizures reached a long-term seizure-free outcome, and more than half of them did not experience disabling seizures in the last outcome year. The most therapeutic options were used in patients who were minimally influenced by the operation; the majority of patients with considerable improvement because of the operation do not use any other add-on antiepileptic drugs or other kinds of therapy.
Brivaracetam: Rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment
Despite availability of effective antiepileptic drugs (AEDs), many patients with epilepsy continue to experience refractory seizures and adverse events. Achievement of better seizure control and fewer side effects is key to improving quality of life. This review describes the rationale for the discovery and preclinical profile of brivaracetam (BRV), currently under regulatory review as adjunctive therapy for adults with partial-onset seizures. The discovery of BRV was triggered by the novel mechanism of action and atypical properties of levetiracetam (LEV) in preclinical seizure and epilepsy models. LEV is associated with several mechanisms that may contribute to its antiepileptic properties and adverse effect profile. Early findings observed a moderate affinity for a unique brain-specific LEV binding site (LBS) that correlated with anticonvulsant effects in animal models of epilepsy. This provided a promising molecular target and rationale for identifying selective, high-affinity ligands for LBS with potential for improved antiepileptic properties. The later discovery that synaptic vesicle protein 2A (SV2A) was the molecular correlate of LBS confirmed the novelty of the target. A drug discovery program resulted in the identification of anticonvulsants, comprising two distinct families of high-affinity SV2A ligands possessing different pharmacologic properties. Among these, BRV differed significantly from LEV by its selective, high affinity and differential interaction with SV2A as well as a higher lipophilicity, correlating with more potent and complete seizure suppression, as well as a more rapid brain penetration in preclinical models. Initial studies in animal models also revealed BRV had a greater antiepileptogenic potential than LEV. These properties of BRV highlight its promising potential as an AED that might provide broad-spectrum efficacy, associated with a promising tolerability profile and a fast onset of action. BRV represents the first selective SV2A ligand for epilepsy treatment and may add a significant contribution to the existing armamentarium of AEDs.
Corpus callosum (CC) abnormalities are frequently reported in patients with refractory mesial temporal lobe epilepsy (rMTLE). However, whether CC structural alterations are related to the epileptic syndrome itself or to refractoriness is still unknown. Thus, we aimed to compare patterns of CC change in patients with rMTLE and benign MTLE (bMTLE), the latter of which represents a useful resource to better disentangle factors that contribute to refractoriness.Methods
The study group included 79 patients with bMTLE (mean age 43.2 ± 14. 8 years), 61 with rMTLE (mean age 45.2 ± 12.4 years) and 134 healthy volunteers. Structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) were performed to measure thickness, mean diffusivity (MD), and fractional anisotropy (FA) over 50 regions of interest along the cross-sectional CC profile. Statistical analysis comprised analysis of variance (ANOVA) followed by post hoc Tukey's Honest Significant Difference test.Results
We found that all imaging metrics of the CC splenium were altered in rMTLE patients compared to bMTLE and controls. We also found significantly reduced thickness and FA of the anterior CC in rMTLE compared to controls and that FA was reduced only in rMTLE compared to bMTLE. Patients with bMTLE did not differ from controls. Differences between disease subgroups were found in the midbody composed of sensorimotor fibers.Significance
We found altered multimodal imaging metrics of the CC in rMTLE but not in bMTLE. These findings were independent of the radiologic presence of hippocampal sclerosis, suggesting that differences in the distribution of such alterations might be related to refractoriness.
Imaging increased glutamate in children with Sturge-Weber syndrome: Association with epilepsy severity
Preresection intraoperative electrocorticography (ECoG) abnormalities predict seizure-onset zone and outcome in pediatric epilepsy surgery
The predictive value of intraoperative electrocorticography (ECoG) in pediatric epilepsy surgery is unknown. In a population of children undergoing ECoG followed typically by invasive extraoperative monitoring (IEM) and resection, we aimed to determine the relationship between frequent ECoG abnormalities and the seizure onset zone and outcome after resection.Methods
We retrospectively identified 103 children with preresection ECoG of sufficient technical quality. ECoG records were scored based on electrode location and frequency, blinded to the seizure-onset zone and outcome. Electrographic seizure and spike locations were identified. Locations of seizures and spike populations were then compared to the location of seizure-onset zone defined by IEM using subdural electrodes and resection margin.Results
Electrographic seizures were identified in 11 (11%) of 103 patients. A spike population of one or more was noted in 79 (77%) of 103 patients. In 50 (63%) of 79 patients, spike populations correlated with seizure-onset zone location. The overall surgical outcome was good (ILAE 1 to 3) in 53 (52%) of 101 patients. Outcome was good in seven (78%) of nine patients when electrographic seizure location was resected. The best outcomes were obtained with resection of both the seizure-onset zone and ECoG abnormalities to include seizures and spike locations (22/33 good outcome, 67%, p = 0.008). There was a significantly better outcome in children with complete resection of ECoG-identified spike populations (14/26, 62% good outcome) compared to when none were resected (4/14, 29%, p = 0.043).Significance
Electrographic seizures and frequent spikes are frequently seen on pre-resection ECoG in children. The brain locations corresponding to these discharges are highly concordant with the seizure-onset zone; resection of these regions is correlated with good seizure outcome. Further research is needed to design interventions that increase the reliability of ECoG prediction of the epileptogenic zone and obviate the need for IEM.
GABRA1 mutations have been identified in patients with familial juvenile myoclonic epilepsy, sporadic childhood absence epilepsy, and idiopathic familial generalized epilepsy. In addition, de novo GABRA1 mutations were recently reported in a patient with infantile spasms and four patients with Dravet syndrome. Those reports suggest that GABRA1 mutations are associated with infantile epilepsy including early onset epileptic encephalopathies. In this study, we searched for GABRA1 mutations in patients with infantile epilepsy to investigate the phenotypic spectrum of GABRA1 mutations.Methods
In total, 526 and 145 patients with infantile epilepsy were analyzed by whole-exome sequencing and GABRA1-targeted resequencing, respectively.Results
We identified five de novo missense GABRA1 mutations in six unrelated patients. A p.R112Q mutation in the long extracellular N-terminus was identified in a patient with infantile epilepsy; p.P260L, p.M263T, and p.M263I in transmembrane spanning domain 1 (TM1) were identified in three unrelated patients with West syndrome and a patient with Ohtahara syndrome, respectively; and p.V287L in TM2 was identified in a patient with unclassified early onset epileptic encephalopathy. Four of these mutations have not been observed previously.Significance
Our study suggests that de novo GABRA1 mutations can cause early onset epileptic encephalopathies, including Ohtahara syndrome and West syndrome.
Mislocalization of syntaxin-1 and impaired neurite growth observed in a human iPSC model for STXBP1-related epileptic encephalopathy
Syntaxin-binding protein 1 (STXBP1) is essential for synaptic vesicle exocytosis. Mutations of its encoding gene, STXBP1, are among the most frequent genetic causes of epileptic encephalopathies. However, the precise pathophysiology of STXBP1 haploinsufficiency has not been elucidated. Using patient-derived induced pluripotent stem cells (iPSCs), we aimed to establish a neuronal model for STXBP1 haploinsufficiency and determine the pathophysiologic basis for STXBP1 encephalopathy. We generated iPSC lines from a patient with Ohtahara syndrome (OS) harboring a heterozygous nonsense mutation of STXBP1 (c.1099C>T; p.R367X) and performed neuronal differentiation. Both STXBP1 messenger RNA (mRNA) and STXBP1 protein expression levels of OS-derived neurons were approximately 50% lower than that of control-derived neurons, suggesting that OS-derived neurons are a suitable model for elucidating the pathophysiology of STXBP1 haploinsufficiency. Through Western blot and immunocytochemistry assays, we found that OS-derived neurons show reduced levels and mislocalization of syntaxin-1, a component of soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins. In addition, OS-derived neurons have impaired neurite outgrowth. In conclusion, this model enables us to investigate the neurobiology of STXBP1 encephalopathy throughout the stages of neurodevelopment. Reduced expression of STXBP1 leads to changes in the expression and localization of syntaxin-1 that may contribute to the devastating phenotype of STXBP1 encephalopathy.
Pharmacoresistant temporal lobe epilepsy modifies histamine turnover and H3 receptor function in the human hippocampus and temporal neocortex
Experiments were designed to evaluate the tissue content of tele-methylhistamine (t-MeHA) and histamine as well as H3 receptor (H3Rs) binding and activation of the heterotrimeric guanine nucleotide binding αi/o proteins (Gαi/o) coupled to these receptors in the hippocampus and temporal neocortex of patients (n = 10) with pharmacoresistant mesial temporal lobe epilepsy (MTLE). Patients with MTLE showed elevated tissue content of t-MeHA in the hippocampus. Analyses revealed that a younger age at seizure onset was correlated with a higher tissue content of t-MeHA, lower H3R binding, and lower efficacy of Gαi/o protein activation in the hippocampus. We conclude that the hippocampus shows a reduction in the H3R function associated with enhanced histamine. In contrast, the temporal neocortex displayed a high efficacy of H3Rs Gαi/o protein activation that was associated with low tissue contents of histamine and t-MeHA. These results indicate an overactivation of H3Rs leading to decreased histamine in the temporal neocortex. However, this situation was lessened in circumstances such as a longer duration of epilepsy or higher seizure frequency. It is concluded that decrease in H3Rs function and enhanced levels of histamine may contribute to the epileptic activity in the hippocampus and temporal neocortex of patients with pharmacoresistant MTLE.
Predictors of and attitudes toward counseling about SUDEP and other epilepsy risk factors among Austrian, German, and Swiss neurologists and neuropediatricians
To examine the attitudes toward counseling about sudden unexpected death in epilepsy (SUDEP) and other epilepsy risk factors among Austrian, German, and Swiss neurologists and neuropediatricians, and to determine factors associated with not discussing SUDEP.Methods
Questionnaires were sent to approximately 5,000 neurologists and neuropediatricians in 2014 regarding respondents’ demographics, their working environments, and how often they discussed SUDEP, suicidal ideations on anticonvulsive medication, driving restrictions, and risks in daily life activities.Results
In total, 519 surveys were completed (respondents’ mean age: 45.5 years, 41.6% female, 66.9% adult neurologists, 31.0% neuropediatricians). A minority of 2.7% reported that they counseled all of their patients on SUDEP, 8.7% counseled most of the time (50–90%), 20.8% sometimes (10–49%), 44.5% rarely (1–9%), and 23.3% reported not counseling about SUDEP at all. In contrast, 92.9% reported that they counseled all patients about driving restrictions and 81.5% about risks in daily life activities. Suicidal ideations were discussed in 59.0% for some and in 3.3% for all patients, whereas 35.1% of respondents reported never discussing suicidal ideations. Independent predictors of not discussing SUDEP were no additional epilepsy training, no or uncertain SUDEP cases in the past, <10 years in practice, <25 epilepsy patients seen per quarter, and the opinion of a lack of consequences in SUDEP prevention. The opinion that SUDEP is a risk factor in particular patient groups and the attitude that all risks should be discussed predicted counseling on SUDEP.Significance
Our findings show a discrepancy between guidelines and practice regarding the discussion of premature mortality due to SUDEP or suicidality. Both are not discussed at all by a substantial proportion of neurologists and neuropediatricians. This is in contrast to ubiquitous education about driving restrictions. Dissemination of knowledge among physicians about potential preventive strategies might increase the likelihood of discussion. Clinical practice guidelines are welcomed by the majority of physicians in this process.
Is SEEG safe? A systematic review and meta-analysis of stereo-electroencephalography–related complications
Stereo-electroencephalography (SEEG) is a procedure performed for patients with intractable epilepsy in order to anatomically define the epileptogenic zone (EZ) and the possible related functional cortical areas. By avoiding the need for large craniotomies and due to its intrinsic precision placement features, SEEG may be associated with fewer complications. Nevertheless, intracerebral electrodes have gained a reputation of excessive invasiveness, with a “relatively high morbidity” associated with their placement. A systematic literature review and meta-analysis of SEEG complications has not been previously performed. The goal of this study is to quantitatively review the incidence of various surgical complications associated with SEEG electrode implantation in the literature and to provide a summary estimate. This will allow physicians to accurately counsel their patients about the potential complications related to this method of extraoperative invasive monitoring.Methods
The systematic review was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We conducted MEDLINE, Scopus, and Web of Science database searches with the search algorithm. We analyzed complication rates using a fixed-effects model with inverse variance weighting. Calculations for the meta-analysis and construction of forest plots were completed using an established spreadsheet. The principal summary measures were the effect summary value and 95% confidence intervals (CIs).Results
The initial 1,901 retrieved citations were reviewed. After removing 787 duplicates, the titles and abstracts of 1,114 publications were screened. At this stage, studies that did not mention the absence or presence of complications following SEEG or that did not fulfill the inclusion criteria in any manner were excluded. After excluding 1,057 citations, the full text was assessed in the resulting 57 articles for eligibility criteria. The most common complications were hemorrhagic (pooled prevalence 1.0%, 95% confidence interval [CI] 0.6–1.4%) or infectious (pooled prevalence 0.8%, 95% CI 0.3–1.2%). Five mortalities were identified (pooled prevalence 0.3%, 95% CI −0.1–0.6%). Overall, our analysis identified 121 surgical complications related to SEEG insertion and monitoring (pooled prevalence 1.3%, 95% CI 0.9–1.7%).Significance
This review represents a comprehensive estimation of the actual incidence of complications related to SEEG. We report a rate substantially lower than the complication rates reported for other methods of extraoperative invasive monitoring. These data should alleviate the concerns of some regarding the safety of the “stereotactic” method, allowing a better decision process among the different methods of invasive monitoring and ameliorating the fear associated with the placement of depth electrodes.
Altered directed functional connectivity in temporal lobe epilepsy in the absence of interictal spikes: A high density EEG study
In patients with epilepsy, seizure relapse and behavioral impairments can be observed despite the absence of interictal epileptiform discharges (IEDs). Therefore, the characterization of pathologic networks when IEDs are not present could have an important clinical value. Using Granger-causal modeling, we investigated whether directed functional connectivity was altered in electroencephalography (EEG) epochs free of IED in left and right temporal lobe epilepsy (LTLE and RTLE) compared to healthy controls.Methods
Twenty LTLE, 20 RTLE, and 20 healthy controls underwent a resting-state high-density EEG recording. Source activity was obtained for 82 regions of interest (ROIs) using an individual head model and a distributed linear inverse solution. Granger-causal modeling was applied to the source signals of all ROIs. The directed functional connectivity results were compared between groups and correlated with clinical parameters (duration of the disease, age of onset, age, and learning and mood impairments).Results
We found that: (1) patients had significantly reduced connectivity from regions concordant with the default-mode network; (2) there was a different network pattern in patients versus controls: the strongest connections arose from the ipsilateral hippocampus in patients and from the posterior cingulate cortex in controls; (3) longer disease duration was associated with lower driving from contralateral and ipsilateral mediolimbic regions in RTLE; (4) aging was associated with a lower driving from regions in or close to the piriform cortex only in patients; and (5) outflow from the anterior cingulate cortex was lower in patients with learning deficits or depression compared to patients without impairments and to controls.Significance
Resting-state network reorganization in the absence of IEDs strengthens the view of chronic and progressive network changes in TLE. These resting-state connectivity alterations could constitute an important biomarker of TLE, and hold promise for using EEG recordings without IEDs for diagnosis or prognosis of this disorder.