Cathodal HD-tDCS and attention: A study on patients with intractable left lateral frontal lobe epilepsy.

OBJECTIVE: Defects in the attentional network in patients with epilepsy are influenced by factors such as the location of epileptic foci. Examining the impact of cathodal high-definition transcranial direct current stimulation (HD-tDCS) on attention components could provide insights into potential attention-related side effects of tDCS. This study aimed to investigate the effect of cathodal HD-tDCS on interictal epileptiform discharges (IEDs), auditory/visual (A/V) attention components, and reaction time (RT) in patients with intractable focal left lateral frontal lobe epilepsy (LFLE). METHODS: To control for variations in individual epilepsy syndrome, 12 adult participants diagnosed with drug-resistant left LFLE with focal cortical IEDs on C3 underwent repeated measurements at pretest, posttest, and follow-up steps. 4 × 1 ring electrodes (cathode on C3 and four anodes on F3, P3, T3, and Cz) delivered 2 mA DC for 20 min per session for 10 consecutive days. The integrated visual and auditory continuous performance test (IVA+) assessed the A/V attention components and RT. One-way repeated-measure ANOVA was used. RESULTS: The findings suggest a significant effect in reducing IEDs. The IVA+ results showed a significant improvement in auditory divided attention and visual selective and focused attention (p < 0.05). In the follow-up, these changes demonstrated lasting efficacy. A/V speed scales increased (p < 0.05), showing a significant decrease in reaction time. CONCLUSIONS: Cathodal HD-tDCS significantly reduced IEDs and improved the components of auditory divided attention, visual focused attention, and visual selective attention, with a reduction in patient reaction time. A significant lasting, side-effect-free positive effect was observed for up to one month after the intervention.

Frontal lobe seizures: overview and update.

Frontal lobe seizures (FLS) are debilitating for patients, highly diverse and often challenging for clinicians to evaluate. Frontal lobe epilepsy is the second most common localization for focal epilepsy, and if pharmacoresistant, can be amenable to resective surgery. Detailed study of frontal seizure semiology in conjunction with careful anatomical and electrophysiological correlation based on intracerebral recording with stereoelectroencephalography (SEEG) has allowed demonstration that ictal motor semiology reflects a hierarchical rostro-caudal axis of frontal lobe functional organization, thus helping with presurgical localization. Main semiological features allowing distinction between different frontal sublobar regions include motor signs and emotional signs. Frontal lobe seizure semiology also represents a valuable source of in vivo human behavioral data from a neuroscientific perspective. Advances in defining underlying etiologies of FLE are likely to be crucial for appropriate selection and exploration of potential surgical candidates, which could improve upon current surgical outcomes. Future research on investigating the genetic basis of epilepsies and relation to structural substrate (e.g. focal cortical dysplasia) and seizure organization and expression, could permit a "genotype-phenotype" approach that could be complementary to anatomical electroclinical correlations in better defining the spectrum of FLS. This could help with optimizing patient selection and prognostication with regards to therapeutic choices.

Female verbal memory advantage in temporal, but not frontal lobe epilepsy.

Women show better performance than men on a range of episodic memory tasks. Evidence regarding a neuroanatomical localization of this effect remains ambiguous. It has been suggested that anterior temporal lobe structures are responsible for sex differences in verbal memory, yet temporal lobe epilepsy (TLE) and TLE surgery do not affect women's verbal memory advantage. Instead, frontal lobe regions may be relevant for female verbal memory superiority, i.e. by enabling more efficient encoding and retrieval strategies in women. The aim of the present study was to investigate whether women's verbal memory advantage can be found in patients with frontal lobe epilepsy (FLE), and how patients with FLE and those with TLE differ with regard to sex differences in verbal memory. Fifty patients with unilateral FLE (26 women, 24 men) were compared with 183 patients with unilateral TLE (90 women, 93 men) on both verbal learning and delayed memory. We found that women showed better verbal memory than men in the TLE group, but not in the FLE group. In addition, we found that patients with TLE showed worse verbal learning than those with FLE. Our findings support the idea that women's advantage in verbal memory may be related to frontal lobe function.

HD-tDCS in refractory lateral frontal lobe epilepsy patients.

PURPOSE: To evaluate the anticonvulsant effect of the novel high definition transcranial direct current stimulation (HD-tDCS) method on patients with refractory lateral frontal lobe epilepsy. The effects of HD-tDCS on working memory were also examined. METHOD: 10 adult patients with intractable lateral frontal lobe epilepsy were studied. A central cathode electrode was placed on the epileptogenic zone according to LTM, and 20-min sessions of 2mA HD-tDCS were applied for 10 consecutive days. The primary endpoint was to make changes in the epileptiform discharges (EDs) during a 1-h EEG. Moreover, the seizure frequency based on seizure diary and neuropsychiatric parameters was evaluated. RESULTS: All patients tolerated HD-tDCS stimulation course without any adverse reaction. The frequency of EDs increased immediately and one month after the stimulation course by an average of 6.4% and 1.2%, respectively. However, these changes in the EDs frequency were not statistically significant (p-value >0.05). The mean seizure frequency changes showed decrement by an average of 17.9% immediately, and increment by an average of 38.1% one month after the HD-tDCS. These changes were not significant statistically (p-value >0.05). One patient experienced exacerbation of seizures during the stimulations hence dropped out of the study. Attention and working memory improved significantly immediately and one month after the HD-tDCS in all patients. CONCLUSION: Changes of EDs and mean seizure frequency caused by HD-tDCS were not statistically significant for the whole group; however, this method could improve the patients' working memory scores.

The Role of Thalamus Versus Cortex in Epilepsy: Evidence from Human Ictal Centromedian Recordings in Patients Assessed for Deep Brain Stimulation.

BACKGROUND: The onset of generalized seizures is a long debated subject in epilepsy. The relative roles of cortex and thalamus in initiating and maintaining the different seizure types are unclear. OBJECTIVE: The purpose of the study is to estimate whether the cortex or the centromedian thalamic nucleus is leading in initiating and maintaining seizures in humans. METHODS: We report human ictal recordings with simultaneous thalamic and cortical electrodes from three patients without anesthesia being assessed for deep brain stimulation (DBS). Patients 1 and 2 had idiopathic generalized epilepsy whereas patient 3 had frontal lobe epilepsy. Visual inspection was combined with nonlinear correlation analysis. RESULTS: In patient 1, seizure onset was bilateral cortical and the belated onset of leading thalamic discharges was associated with an increase in rhythmicity of discharges, both in thalamus and cortex. In patient 2, we observed bilateral independent interictal discharges restricted to the thalamus. However, ictal onset was diffuse, with discharges larger in the cortex even though they were led by the thalamus. In patient 3, seizure onset was largely restricted to frontal structures, with belated lagging thalamic involvement. CONCLUSION: In human generalized seizures, the thalamus may become involved early or late in the seizure but, once it becomes involved, it leads the cortex. In contrast, in human frontal seizures the thalamus gets involved late in the seizure and, once it becomes involved, it lags behind the cortex. In addition, the centromedian nucleus of the thalamus is capable of autonomous epileptogenesis as suggested by the presence of independent focal unilateral epileptiform discharges restricted to thalamic structures. The thalamus may also be responsible for maintaining the rhythmicity of ictal discharges.

Deep brain stimulation of anterior nucleus thalami disrupts sleep in epilepsy patients.

In view of the regulatory function of the thalamus in the sleep-wake cycle, the impact of deep brain stimulation (DBS) of the anterior nucleus thalami (ANT) on sleep was assessed in a small consecutive cohort of epilepsy patients with standardized polysomnography (PSG). In nine patients treated with ANT-DBS (voltage 5 V, frequency 145 Hz, cyclic mode), the number of arousals during stimulation and nonstimulation periods, neuropsychiatric symptoms (npS), and seizure frequency were determined. Electroclinical arousals were triggered in 14.0 to 67.0% (mean 42.4 ± SD 16.8%) of all deep brain stimuli. Six patients reported npS. Nocturnal DBS voltages were reduced in eight patients (one patient without npS refused) and PSGs were repeated. Electroclinical arousals occurred between 1.4 and 6.7 (mean 3.3 ± 1.7) times more frequently during stimulation periods compared to nonstimulation periods; the number of arousals positively correlated with the level of DBS voltage (range 1 V to 5 V) (Spearman's rank coefficient 0.53121; p < 0.05). No patient experienced seizure deterioration and four patients reported remission of npS. This case-cohort study provides evidence that ANT-DBS interrupts sleep in a voltage-dependent manner, thus putatively resulting in an increase of npS. Reduction of nocturnal DBS voltage seems to lead to improvement of npS without hampering efficacy of ANT-DBS.

Chemical corrector treatment ameliorates increased seizure susceptibility in a mouse model of familial epilepsy.

Epilepsy is one of the most common and intractable brain disorders. Mutations in the human gene LGI1, encoding a neuronal secreted protein, cause autosomal dominant lateral temporal lobe epilepsy (ADLTE). However, the pathogenic mechanisms of LGI1 mutations remain unclear. We classified 22 reported LGI1 missense mutations as either secretion defective or secretion competent, and we generated and analyzed two mouse models of ADLTE encoding mutant proteins representative of the two groups. The secretion-defective LGI1(E383A) protein was recognized by the ER quality-control machinery and prematurely degraded, whereas the secretable LGI1(S473L) protein abnormally dimerized and was selectively defective in binding to one of its receptors, ADAM22. Both mutations caused a loss of function, compromising intracellular trafficking or ligand activity of LGI1 and converging on reduced synaptic LGI1-ADAM22 interaction. A chemical corrector, 4-phenylbutyrate (4PBA), restored LGI1(E383A) folding and binding to ADAM22 and ameliorated the increased seizure susceptibility of the LGI1(E383A) model mice. This study establishes LGI1-related epilepsy as a conformational disease and suggests new therapeutic options for human epilepsy.

Nocturnal frontal lobe epilepsy.

Nocturnal frontal lobe epilepsy (NFLE) is a syndrome of heterogeneous etiology, characterized by the occurrence of sleep-related seizures with different complexity and duration. Genetic, lesional, and cryptogenetic NFLE forms have been described. NFLE is generally considered a benign clinical entity, although severe, drug-resistant forms do exist. A significant proportion of sleep-related complex motor seizures, hardly distinguishable from NFLE, originate outside the frontal lobe. Moreover, the distinction of NFLE from the non-rapid eye movement arousal parasomnias may be challenging. A correct diagnosis of NFLE should be based on a diagnostic approach that includes the anamnestic, video-polysomnographic, morphological, and genetic aspects. Studies on the relationships between genes, arousal regulatory mechanisms, and epileptogenesis, using both clinical and experimental models of NFLE might provide key insights in the interrelationship between sleep and epilepsy.

Posterior cingulate epilepsy: clinical and neurophysiological analysis.

OBJECTIVE: Posterior cingulate epilepsy (PCE) is misleading because the seizure onset is located in an anatomically deep and semiologically silent area. This type of epilepsy is rare and has not been well described yet. Knowledge of the characteristics of PCE is important for the interpretation of presurgical evaluation and better surgical strategy. The purpose of this study was to better characterise the clinical and neurophysiological features of PCE. METHODS: This retrospective analysis included seven intractable PCE patients. Six patients had postcingulate ictal onset identified by stereotactic EEG (SEEG) evaluations. One patient had a postcingulate tumour. We analysed clinical semiology, the scalp EEG/SEEG findings and cortico-cortical evoked potential (CCEP). RESULTS: The classifications of scalp EEG were various, including non-localisible, lateralised to the seizure onset side, regional parieto-occipital, regional frontocentral and regional temporal. Three of seven patients showed motor manifestations, including bilateral asymmetric tonic seizures and hypermotor seizures. In these patients, ictal activities spread to frontal (lateral premotor area, orbitofrontal cortex, supplementary motor area, anteior cingulate gyrus) and parietal (precuneus, posterior cingulate gyrus, inferior parietal lobule (IPL), postcentral gyrus) areas. Four patients showed dialeptic seizures or automotor seizures, with seizure spread to medial temporal or IPL areas. CCEP was performed in four patients, suggesting electrophysiological connections from the posterior cingulate gyrus to parietal, temporal, mesial occipital and mesial frontal areas. CONCLUSIONS: This study revealed that the network from the posterior cingulate gyrus and the semiology of PCE (motor manifestation vs dialeptic/automotor seizure) varies depending upon the seizure spread patterns.

Deep brain stimulation of the centromedian thalamic nucleus for the treatment of generalized and frontal epilepsies.

PURPOSE: Deep brain stimulation (DBS) of the thalamus is an emerging surgical option for people with medically refractory epilepsy that is not suitable for resective surgery, or in whom surgery has failed. Our main aim was to evaluate the efficacy of bilateral centromedian thalamic nucleus (CMN) DBS for seizure control in generalized epilepsy and frontal lobe epilepsy with a two-center, single-blind, controlled trial. METHODS: Participants were adults with refractory generalized or frontal lobe epilepsy. Seizure diaries were kept by patients/carers prospectively from enrollment. The baseline preimplantation period was followed by a control period consisting of a blind stimulation-OFF phase of at least 3 months, a 3-month blind stimulation-ON phase, and a 6-month unblinded stimulation-ON phase. The control period was followed by an unblinded long-term extension phase with stimulation-ON in those patients in whom stimulation was thought to be effective. KEY FINDINGS: Eleven patients were recruited at King's College Hospital (London, United Kingdom United Kingdom) and at University Hospital La Princesa (Madrid, Spain). Among the five patients with frontal lobe epilepsy, only one patient had >50% improvement in seizure frequency during the blind period. In the long-term extension phase, two patients with frontal lobe epilepsy had >50% improvement in seizure frequency. All six patients with generalized epilepsy had >50% improvement in seizure frequency during the blind period. In the long-term extension phase, five of the six patients showed >50% improvement in the frequency of major seizures (one became seizure free, one had >99% improvement, and three had 60-95% reduction in seizure frequency). Among patients with generalized epilepsy, the DBS implantation itself appears to be effective, as two patients remained seizure free during 12 and 50 months with DBS OFF, and the remaining four had 50-91% improvement in the initial 3 months with DBS OFF. SIGNIFICANCE: DBS implantation and stimulation of the CMN appears to be a safe and efficacious treatment, particularly in patients with refractory generalized epilepsy. CMN stimulation was not as effective in frontal lobe epilepsy, which requires further studies. DBS of the CMN should be considered as a treatment option, particularly in patients with refractory generalized epilepsy syndromes.

Mapping of cingulate motor function by cortical stimulation.

An 8-year-old boy with intractable left mesiofrontal lobe epilepsy underwent placement of stereotactic intracerebral depth electrodes to better localise the epileptogenic zone. Co-registration of preoperative MRI and post-electrode implantation CAT allowed for anatomical localisation of electrode contacts. Electrical stimulation of electrodes over the dorsal and ventral banks of the cingulate cortex on the left produced right foot dorsiflexion and right wrist and elbow flexion, respectively, demonstrating detailed representation of cingulate motor function in humans, somatotopically distributed along the banks of the cingulate sulcus, as seen in the non-human primate. [Published with video sequences].

Transcranial magnetic stimulation (TMS) modulates epileptiform discharges in patients with frontal lobe epilepsy: a preliminary EEG-TMS study.

BACKGROUND: TMS is being increasingly used as a noninvasive brain stimulation technique for the therapeutic management of partial epilepsies. However, the acute effects of TMS on epileptiform discharges (EDs, i.e. interictal epileptiform activity and subclinical electrographic seizure patterns) remain unexplored. OBJECTIVE: To investigate whether TMS can modulate EDs in partial epilepsy. METHODS: In Experiment Set 1, the safety of the TMS protocol was investigated in 10 well-controlled by anti-epileptic drugs (AEDs) epileptic patients. In Experiment Set 2, the effects of TMS on EDs were studied in three subjects with intractable frontal lobe epilepsies, characterized by particularly frequent EDs. TMS was applied over the electrographic focus with a circular and a figure of eight coil while recording EEG with a 60-channel TMS-compatible EEG system. The effectiveness of TMS in aborting EDs was investigated using survival analysis and brain connectivity analysis. RESULTS: The TMS protocol was well-tolerated. TMS was an effective method to abort EDs even when adjusting for its latency with respect to ED onset (CMH test, p < 0.0001). While the effective brain connectivity around the epileptic focus increased significantly during EDs (p < 0.01), with TMS administration the increase was not statistically significant. CONCLUSION: TMS can modulate EDs in patients with epileptogenic foci in the cortical convexity and is associated with reversal of ED-induced changes in brain connectivity.

Orbitofrontal and insular epilepsy.

PURPOSE: Orbitofrontal and insular epilepsy are difficult to recognize because clinical presentations are variable and surgical approaches remain difficult. METHODS: Literature review and review of our own case series including selected cases regarding the clinical manifestation and diagnostic utility of diagnostic tests in orbitofrontal and insular epilepsy. RESULTS: Orbitofrontal epilepsy presents with either frontal lobe type seizures with hypermotor automatism or temporal lobe type seizures with oroalimentary and manual automatisms depending on the spread pattern. Ictal single photon emission computed tomography (SPECT) and other functional imaging can be helpful, but intracranial electroencephalograms (EEGs) are still required to identify orbitofrontal seizure onset. Insular epilepsy presents with throat constriction and unilateral paresthesias. Preoperative functional imaging methods can be helpful, but exploration of the insula is required to identify unequivocal insular onset. Intracranial EEG in the insula can be performed safely and should be considered in atypical temporal lobe cases. CONCLUSIONS: Intracranial EEG remains the main diagnostic modality to identify orbitofrontal and insular epilepsy. Newer diagnostic modalities such as high-frequency oscillations, EEG, functional magnetic resonance imaging (fMRI), magnet resonance spectroscopy, and magnet source imaging need to be examined further to establish their diagnostic utility.

Dorsolateral frontal lobe epilepsy.

Dorsolateral frontal lobe seizures often present as a diagnostic challenge. The diverse semiologies may not produce lateralizing or localizing signs and can appear bizarre and suggest psychogenic events. Unfortunately, scalp electroencephalographic (EEG) and magnetic resonance imaging (MRI) are often unsatisfactory. It is not uncommon that these traditional diagnostic studies are either unhelpful or even misleading. In some cases, SPECT and positron emission tomography imaging can be an effective tool to identify the origin of seizures. However, these techniques and other emerging techniques all have limitations, and new approaches are needed to improve source localization.

Frontal lobe seizures.

BACKGROUND AND OBJECTIVE: Frontal lobe epilepsy is the second most common localization-related or focal epilepsy. Frontal lobe seizures are challenging to diagnose as the clinical manifestations are diverse due to the complexity and variability of the patterns of epileptic discharges, and the scalp electroencephalograph (EEG) can often be normal or misleading. This review focuses on the clinical and EEG features of seizures arising from the frontal lobe. REVIEW SUMMARY: The clinical manifestations in patients with frontal lobe epilepsy are varied. Frontal lobe seizures can be divided into perirolandic, supplementary sensorimotor area, dorsolateral, orbitofrontal, anterior frontopolar, opercular, and cingulate types. Seizures originating from the perirolandic and supplementary sensorimotor areas are clinically distinct, characterized by motor activity or asymmetric tonic posturing with preserved awareness. Seizures arising from dorsolateral, orbitofrontal, frontopolar, and cingulate areas are not as well characterized and have more variable clinical manifestations. Scalp EEG recording is sometimes helpful in localization but is usually normal or misleading in frontal lobe epilepsy. The treatment is similar to other localization-related or focal epilepsies. Medications are the first line of therapy, and surgery is considered for patients who fail to respond to medications. The surgical outcome in frontal lobe resections is less favorable than in anterior temporal lobectomies due to the challenge in locating the epileptogenic zone and the presence of functional areas (eloquent cortex) that can limit the resection. CONCLUSIONS: Frontal lobe seizures are characterized by diverse behavioral manifestations. Only a few well-described frontal lobe syndromes exist. The variety of clinical manifestations reflects both the varying sites of seizure origin and propagation routes that seizures may take. Although this review provides a framework for the understanding of these seizures, one should remain cautious in diagnosing seizure localization based on clinical or EEG description. Only a few patients have well-described syndromes and can be diagnosed with confidence. For most patients, new diagnostic methods and genetic testing may help improve our ability to diagnose and treat the conditions discussed in this study.

Malignant autosomal dominant frontal lobe epilepsy with repeated episodes of status epilepticus: successful treatment with vagal nerve stimulation.

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a familial partial epilepsy syndrome characterized by seizures suggesting a frontal lobe origin occurring predominantly during sleep. Up to a third of patients may have refractory seizures, with repeated episodes of status epilepticus, intellectual disability of variable degree and psychiatric disturbances. We report a patient with ADNFLE, refractory seizures and repeated episodes of life-threatening convulsive status epilepticus who underwent prolonged video-EEG monitoring and was implanted with a vagal nerve stimulator. At 3.5 years of follow-up, a decrease of more than 80% in seizure frequency was achieved, episodes of status were completely controlled and he displayed improved mood and alertness. Vagal nerve stimulation may be considered as therapy for patients with refractory epilepsies of genetic cause, as well as repeated status epilepticus.

[Psychogenic non epileptic events and frontal lobe seizures]. / Eventos no epilépticos psicogénicos y la clínica de la epilepsia del lóbulo frontal.

The distinction between epilepsy and psychogenic non epileptic events or seizures (PNES) has been made since the middle of the first millennium (B.C.) Psychogenic non epileptic seizures (PNES) resemble epileptic seizures presenting as paroxysmal, involuntary, time-limited alterations in behaviour, motor activity, autonomic function, consciousness, or sensation. However, unlike epilepsy, NES do not result from epileptogenic pathology and are not accompanied by an epileptiform pattern during an ictal electroencephalogram (EEG). This article reviews the concept of psychogenic non epileptic events, its contemporary assessment including diagnostic and therapeutic issues, as well as the complexity related to various nosological topics. The PNES are a hallmark of an ancient illness, hysteria, which wanders between the somatoform and the dissociative disorders in the contemporary classification systems. With the availability of video electroencephalography (video-EEG), it has been possible to define more strictly the limits between epileptic and non epileptic disorders, avoiding unnecessary and even iatrogenic and invasive treatments. We also describe the clinical presentation and diagnosis of frontal lobe seizures, especially those that might be mistakenly diagnosed as psychogenic events. The frontal lobes are the largest cortical region from which seizures can arise; complex and/ or bizarre behavioural clinical presentations are frequent. In addition, some patients with epilepsy can also present non epileptic events.

Reversible acquired epileptic frontal syndrome and CSWS suppression in a child with congenital hemiparesis treated by hemispherotomy.

A boy with a right congenital hemiparesis due to a left pre-natal middle cerebral artery infarct developed focal epilepsy at 33 months and then an insidious and subsequently more rapid, massive cognitive and behavioural regression with a frontal syndrome between the ages of 4 and 5 years with continuous spike-waves during sleep (CSWS) on the EEG. Both the epilepsy and the CSWS were immediately suppressed by hemispherotomy at the age of 5 years and 4 months. A behavioural-cognitive follow-up prior to hemispherotomy, an per-operative EEG and corticography and serial post-operative neuropsychological assessments were performed until the age of 11 years. The spread of the epileptic activity to the "healthy" frontal region was the cause of the reversible frontal syndrome. A later gradual long-term but incomplete cognitive recovery, with moderate mental disability was documented. This outcome is probably explained by another facet of the epilepsy, namely the structural effects of prolonged epileptic discharges in rapidly developing cerebral networks which are, at the same time undergoing the reorganization imposed by a unilateral early hemispheric lesion. Group studies on the outcome of children before and after hemispherectomy using only single IQ measures, pre- and post-operatively, may miss particular epileptic cognitive dysfunctions as they are likely to be different from case to case. Such detailed and rarely available complementary clinical and EEG data obtained in a single case at different time periods in relation to the epilepsy, including per-operative electrophysiological findings, may help to understand the different cognitive deficits and recovery profiles and the limits of full cognitive recovery.