Ambulatory Local Field Potential Recordings from the Thalamus in Epilepsy: A Feasibility Study.

INTRODUCTION: Stimulation of the thalamus is gaining favor in the treatment of medically refractory multifocal and generalized epilepsy. Implanted brain stimulators capable of recording ambulatory local field potentials (LFPs) have recently been introduced, but there is little information to guide their use in thalamic stimulation for epilepsy. This study sought to assess the feasibility of chronically recording ambulatory interictal LFP from the thalamus in patients with epilepsy. METHODS: In this pilot study, ambulatory LFP was recorded from patients who underwent sensing-enabled deep brain stimulation (DBS, 2 participants) or responsive neurostimulation (RNS, 3 participants) targeting the anterior nucleus of the thalamus (ANT, 2 electrodes), centromedian nucleus (CM, 7 electrodes), or medial pulvinar (PuM, 1 electrode) for multifocal or generalized epilepsy. Time-domain and frequency-domain LFP was investigated for epileptiform discharges, spectral peaks, circadian variation, and peri-ictal patterns. RESULTS: Thalamic interictal discharges were visible on ambulatory recordings from both DBS and RNS. At-home interictal frequency-domain data could be extracted from both devices. Spectral peaks were noted at 10-15 Hz in CM, 6-11 Hz in ANT, and 19-24 Hz in PuM but varied in prominence and were not visible in all electrodes. In CM, 10-15 Hz power exhibited circadian variation and was attenuated by eye opening. CONCLUSION: Chronic ambulatory recording of thalamic LFP is feasible. Common spectral peaks can be observed but vary between electrodes and across neural states. DBS and RNS devices provide a wealth of complementary data that have the potential to better inform thalamic stimulation for epilepsy.

Is thalamic deep brain stimulation synergistic with vagus nerve stimulation in drug-resistant genetic generalized epilepsy?

Neuromodulation in epilepsy is a proven treatment for people with drug-resistant focal epilepsy. Dual device therapies are increasingly utilized in people with drug-resistant epilepsy. Vagus nerve stimulation (VNS) and deep brain stimulation (DBS) target the thalamus involving the primary neurobiological network in patients with genetic generalized epilepsy (GGE). We report a novel case of combined neuromodulation in a patient with drug-resistant GGE who achieved a partial response with seizure reduction after VNS implantation yet following VNS-DBS polyneurostimulation gradually achieved prolonged seizure freedom. We speculate that by combining the indirect activating effects of VNS with the direct inhibitory effects of DBS, this may provide synergy to thalamic modulated networks. We hypothesize a "rational polytherapy" may exist in some patients with GGE undergoing dual neuromodulation.

Thalamocortical circuits in generalized epilepsy: Pathophysiologic mechanisms and therapeutic targets.

Generalized epilepsy affects 24 million people globally; at least 25% of cases remain medically refractory. The thalamus, with widespread connections throughout the brain, plays a critical role in generalized epilepsy. The intrinsic properties of thalamic neurons and the synaptic connections between populations of neurons in the nucleus reticularis thalami and thalamocortical relay nuclei help generate different firing patterns that influence brain states. In particular, transitions from tonic firing to highly synchronized burst firing mode in thalamic neurons can cause seizures that rapidly generalize and cause altered awareness and unconsciousness. Here, we review the most recent advances in our understanding of how thalamic activity is regulated and discuss the gaps in our understanding of the mechanisms of generalized epilepsy syndromes. Elucidating the role of the thalamus in generalized epilepsy syndromes may lead to new opportunities to better treat pharmaco-resistant generalized epilepsy by thalamic modulation and dietary therapy.

Optimally targeting the centromedian nucleus of the thalamus for generalized epilepsy: A meta-analysis.

BACKGROUND: Deep brain stimulation (DBS) of the centromedian nucleus (CM) is an effective therapeutic option for select patients with generalized epilepsy. However, several studies suggest that success varies with active contact location within the CM and the exact target remains undefined. OBJECTIVE: To quantify the association between active contact location and outcomes across all published series of CM DBS. METHODS: A literature search using PRISMA criteria was performed to identify all studies that reported active contact locations PLUS outcomes following DBS of the CM for epilepsy. Patient, disease, treatment, and outcome data were extracted for statistical analysis. Active contact locations were analyzed on a common reference frame and weighted by percent seizure reduction at last follow-up. RESULTS: From 184 studies that were screened for review, 3 studies comprising 47 patients met criteria for inclusion and were analyzed. At time of surgery, mean duration of epilepsy was 18 years. Pooled rates of atonic, atypical absence, generalized tonic-clonic, myoclonic, and tonic epilepsies were 38%, 74%, 68%, 14%, and 60%, respectively. Indirect targeting was used in all these studies. After a mean follow-up duration of 2.3 years, 87% of patients were deemed to be responders with mean seizure reduction of 73% (95% CI: [64%-81%]). Optimal location of the active contact was found to be at the dorsal border of the CM. CONCLUSIONS: Success following DBS of the CM for epilepsy varies by active contact location, even within the CM. Our findings suggest that stimulation within the dorsal region of the CM improves outcomes. Additional studies are needed to further refine these findings.

Seizure outcome during bilateral, continuous, thalamic centromedian nuclei deep brain stimulation in patients with generalized epilepsy: a prospective, open-label study.

OBJECTIVE: We report on the seizure frequency and attention outcome during thalamic centromedian stimulation (CM-DBS) in patients with refractory generalized epilepsy (GE). METHODS: Twenty consecutive patients with GE who were submitted to CM-DBS and had at least one year of follow-up were prospectively studied. The CM was targeted bilaterally. Stimulation intensity was ramped up (bipolar, continuous, 130 Hz; 300µsec) until 4.5 V or until side effects developed. Contacts` position was determined on postoperative volumetric MRI scans. Attention was qualitatively evaluated using the SNAP-IV (Swanson, Nolan, and Pelham) questionnaire. Patients were considered responders during CM-DBS if an at least 50% seizure frequency reduction was obtained compared to baseline. RESULTS: Median age was 15.5 years (13 males). Median follow-up time was 2.55 years. EEG disclosed generalized spike-and wave discharges in all patients. MRI was normal in 10 patients, showed diffuse atrophy in 6 patients, and showed abnormalities in 4 patients (3 patients had bilateral cortical development abnormalities and one had unilateral hemispheric atrophy). Patients presented with daily multiple seizure types (8 to 66 per day; median: 37), including tonic, atonic, myoclonic, atypical absence and generalized tonic-clonic seizures. Mean DBS intensity was 4.3 V. An insertional effect was noted in 14 patients. CM-DBS was able to significantly reduce the frequency of tonic (p < 0.001), atypical absence seizures (p < 0.001), atonic seizures (p = 0.001) and bilateral generalized tonic-clonic seizures (p = 0.004). One patient became seizure-free. Ninety percent of the patients were considered responders (>50% seizure frequency reduction). All patients showed some improvement in attention. The mean number of items in which improvement was noted in the SNAP-IV questionnaire was 4.8. There was a significant relationship between overall seizure frequency reduction and improvement of attention (p = 0.033). DISCUSSION: This prospective, open label study included a large, homogeneous cohort and provided evidence on the efficacy of CM-DBS in reducing the seizure burden and increasing attention in patients with refractory generalized epilepsy.

Responsive Neurostimulation of the Thalamus Improves Seizure Control in Idiopathic Generalized Epilepsy: A Case Report.

BACKGROUND AND IMPORTANCE: At least 25% of patients with idiopathic generalized epilepsy do not obtain adequate seizure control with medication. This report describes the first use of responsive neurostimulation (RNS), bilaterally targeting the centromedian/ventrolateral (CM/VL) region in a patient with drug-refractory Jeavons syndrome (eyelid myoclonia with absences). CLINICAL PRESENTATION: A patient, diagnosed with eyelid myoclonia with absences (EMA) and refractory to medication, was offered RNS treatment in the CM/VL region of the thalamus. Stimulation was triggered by thalamic neural activity having morphological, spectral, and synchronous features that corresponded to 3- to 5-Hz spike-wave discharges recorded on prior scalp electroencephalography. CONCLUSION: RNS decreased daily absence seizures from a mean of 60 to ≤10 and maintained the patient's level of consciousness during the occurring episodes. This therapy should be evaluated further for its potential to treat patients with pharmaco-refractory generalized epilepsy.

Responsive neurostimulation targeting anterior thalamic nucleus in generalized epilepsy.

Responsive neurostimulation (RNS) has emerged as an adjunctive treatment modality for patients with intractable focal epilepsy who are not surgical candidates or have more than one ictal onset focus. We report a 34-year-old patient with intractable, childhood-onset, genetic generalized epilepsy (GGE) with tonic, atonic, myoclonic and absence seizures treated with RNS. Strip electrodes over the right posterior frontal cortex and depth electrodes placed in the right anterior nucleus were used for event detection and responsive stimulation. Two-year follow-up revealed 90-95% clinical seizure reduction. This case suggests that refractory GGE may be effectively treated with RNS targeting thalamocortical networks.

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.

Health care utilization and outpatient, out-of-pocket costs for active convulsive epilepsy in rural northeastern South Africa: a cross-sectional Survey.

BACKGROUND: Epilepsy is a common neurological disorder, with over 80 % of cases found in low- and middle-income countries (LMICs). Studies from high-income countries find a significant economic burden associated with epilepsy, yet few studies from LMICs, where out-of-pocket costs for general healthcare can be substantial, have assessed out-of-pocket costs and health care utilization for outpatient epilepsy care. METHODS: Within an established health and socio-demographic surveillance system in rural South Africa, a questionnaire to assess self-reported health care utilization and time spent traveling to and waiting to be seen at health facilities was administered to 250 individuals, previously diagnosed with active convulsive epilepsy. Epilepsy patients' out-of-pocket, medical and non-medical costs and frequency of outpatient care visits during the previous 12-months were determined. RESULTS: Within the last year, 132 (53 %) individuals reported consulting at a clinic, 162 (65 %) at a hospital and 34 (14 %) with traditional healers for epilepsy care. Sixty-seven percent of individuals reported previously consulting with both biomedical caregivers and traditional healers. Direct outpatient, median costs per visit varied significantly (p < 0.001) between hospital (2010 International dollar ($) 9.08; IQR: $6.41-$12.83) and clinic consultations ($1.74; IQR: $0-$5.58). Traditional healer fees per visit were found to cost $52.36 (IQR: $34.90-$87.26) per visit. Average annual outpatient, clinic and hospital out-of-pocket costs totaled $58.41. Traveling to and from and waiting to be seen by the caregiver at the hospital took significantly longer than at the clinic. CONCLUSIONS: Rural South Africans with epilepsy consult with both biomedical caregivers and traditional healers for both epilepsy and non-epilepsy care. Traditional healers were the most expensive mode of care, though utilized less often. While higher out-of-pocket costs were incurred at hospital visits, more people with ACE visited hospitals than clinics for epilepsy care. Promoting increased use and effective care at clinics and reducing travel and waiting times could substantially reduce the out-of-pocket costs of outpatient epilepsy care.

[Neurofeedback therapy influence on clinical status and some EEG parameters in children with primary generalized epilepsy]. / Wplyw terapii neurofeedback na stan kliniczny i wybrane parametry zapisu EEG u dzieci chorych na padaczke z napadami pierwotnie uogólnionymi.

INTRODUCTION: Pharmacological treatment of epilepsy in some patients is ineffective and alternative methods of treatment are need. These include neurofeedback (EEG biofeedback, NF). The aim of this study was to evaluate the clinical and neurophysiological effectiveness of NF in children with epilepsy with primary generalized seizures. MATERIAL AND METHODS: The study involved a group of 63 children with primary generalized seizures, aged 6-16 years, including 39 girls and 24 boys. As the efficacy of pharmacotherapy was not satisfactory for them, they have been referred to Neuromedica Institute in Krakow for NF treatment. The evaluation of preliminary clinical and neurophysiological parameters was performed. Individual NF therapy protocols were elaborated and trainings were conducted for 0.5-4 years. Individual therapy protocols were prepared by biofeedback specialist and trainings were conducted by biofeedback therapists. The same specialist also made a comparison of selected elements of the EEG in children before and after NF therapy. RESULTS: The children enrolled into the study were diagnosed with epilepsy at the age of 6 months to the age of 16 years Tonic-clonic seizures and absence seizures were the most often seizure types in the examined group. Seizures occurred in 19 children every day. In 33/63 children clinical manifestation of seizures and EEG pattern when taken together allow the specific epilepsy syndrome diagnosis in 7 cases. In 27 children two or more antiepileptic drugs were used, and in 36 monotherapy was used. NF therapy had a significant impact on the clinical condition of the children, causing subsidence of seizures in most of them. In 23/63 children antiepileptic treatment was withdrawn and in 15 reduction of treatment was achieved. The impact of the NF therapy on the EEG parameters was beneficial, both in terms of the background activity and other parameters. Paroxysmal EEG pattern subsided in the vast majority of children (63 to 16) including a continuous paroxysmal activity from 12 to 4, interrupted from 51 to 12 and generalized from 63 to 21, with reduced susceptibility to photostimulation from 31 to 18 and hyperventilation from 39 to 17. CONCLUSIONS: In half of children with primary generalized epilepsy with a characteristic EEG pattern specific epilepsy syndrome was diagnosed. In half of children subsidence of epileptic graphoelements in EEG was observed after NF therapy. In % of children paroxysmal bioelectric pattern subsided and sensitivity of EEG to hyperventilation and photostimulation decreased significantly. NF therapy had a positive impact on all the parameters of background bioelectrical activity. In 1/3 of children treated with NF pharmacotherapy of epilepsy was discontinued and in 1/4 reduced.

[Neurofeedback therapy influence on clinical status and some EEG parameters in children with localized epilepsy]. / Wplyw terapii neurofeedback na stan kliniczny i wybrane parametry zapisu EEG u dzieci chorych na padaczke z napadami czesciowymi.

UNLABELLED: Neurofeedback (EEG biofeedback, NF) is one of the methods of non-pharmacological instrumental therapy. In the treatment of epilepsy it is considered as a complementary method, reducing the number of seizures. The aim of this study was to investigate the effect of NF on the incidence of clinical attacks and bioelectrical activity of the brain in children with epilepsy with partial seizures and secondarily generalized seizures. MATERIAL AND METHODS: The study involved a group of 78 children with partial seizures, additionally 30 of them had second-ry generalized seizures. There were 35 girls and 43 boys ranging in age from 5 to 17.5 years. They were treated with NF in the Neuromedica Institute in Krakow, in the period 2005-2015. Treatment time ranged from 6 months to 3 years. We have evaluated the incidence of seizures before and after NF therapy. Visual analysis of EEG recordings with assessment of background activity, location of focal changes, presence of paroxysmal pattern and epileptic graphoelements. RESULTS: In 41/78 children seizures occurred 1-2 times a month, in 19/78 every day and 9 children were diagnosed with epileptic syndrome. During NF therapy 52/78 children experienced resolution of clinical seizures. NF therapy was ineffective in only one child. In 18 child withdrawal of antiepileptic treatment was achieved and in 22 reduction of drug doses. Epileptic graphoelements occurred in 46/78 children before treatment and in 21/78 children after treatment. Before NF therapy irregular bio-electrical activity was found in 51 children versus 27 children with regular bioelectric activity and in 27 children versus 51 children after the therapy. The amplitude of this activity returned to normal in 19 children, and in 29 children the frequency of background activity. Particularly surprising was to restore synchrony and symmetry of EEG pattern in 44 children (11 children before NF treatment to 55 children after the treatment). Even more significant effect of NF therapy was observed in EEG patterns, abolition of paroxysmal pattern and reduction of continuous, localized and generalized changes. NF therapy also advantageously reduced the number of localized changes and decreased sensitivity of EEG pattern to hyperventilation and photostimulation. CONCLUSIONS: During NF therapy in almost all children with epileptic partial seizures and secondarily generalized seizures resolution or reduction of clinical seizures was observed. In nearly 1/4 of children withdrawal of antiepileptic treatment was achieved and in higher number reduction of pharmacotherapy. All parameters of the background EEG bioelectric activity in these children have improved, especially synchrony and symmetry of EEG pattern and paroxysmal changes subsided.

Acupuncture for epilepsy.

BACKGROUND: Acupuncture is increasingly used in people with epilepsy. It remains unclear whether existing evidence is rigorous enough to support its use. This is an update of a Cochrane review first published in 2008. OBJECTIVES: To determine the effectiveness and safety of acupuncture in people with epilepsy. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialised Register (June 2013) and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2013, Issue 5), MEDLINE, EMBASE, CINAHL, AMED and other databases (from inception to June 2013). We reviewed reference lists from relevant trials. We did not impose any language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing acupuncture with placebo or sham treatment, antiepileptic drugs or no treatment; or comparing acupuncture plus other treatments with the same other treatments, involving people of any age with any type of epilepsy. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We included 17 RCTs with 1538 participants that had a wide age range and were suffering mainly from generalized epilepsy. The duration of treatment varied from 7.5 weeks to 1 year. All included trials had a high risk of bias with short follow-up. Compared with Chinese herbs, needle acupuncture plus Chinese herbs was not effective in achieving at least 50% reduction in seizure frequency (80% in control group versus 90% in intervention group, RR 1.13, 95% CI 0.97 to 1.31, 2 trials; assumed risk 500 per 1000, corresponding risk 485 to 655 per 1000). Compared with valproate, needle acupuncture plus valproate was not effective in achieving freedom from seizures (44% in control group versus 42.7% in intervention group, RR 0.97, 95% CI 0.72 to 1.30, 2 trials; assumed risk 136 per 1000, corresponding risk 97 to 177 per 1000) or at least 50% reduction in seizure frequency (69.3% in control group versus 81.3% in intervention group, RR 1.34, 95% CI 0.52 to 3.48, 2 trials; assumed risk 556 per 1000, corresponding risk 289 to 1000 per 1000) but may have achieved better quality of life (QOL) after treatment (QOLIE-31 score (higher score indicated better QOL) mean 170.22 points in the control group versus 180.32 points in the intervention group, MD 10.10 points, 95% CI 2.51 to 17.69 points, 1 trial). Compared with phenytoin, needle acupuncture was not effective in achieving at least 50% reduction in seizure frequency (70% in control group versus 94.4% in intervention group, RR 1.43, 95% CI 0.46 to 4.44, 2 trials; assumed risk 700 per 1000, corresponding risk 322 to 1000 per 1000). Compared with valproate, needle acupuncture was not effective in achieving seizure freedom (14.1% in control group versus 25.2% in intervention group, RR 1.75, 95% CI 0.93 to 3.27, 2 trials; assumed risk 136 per 1000, corresponding risk 126 to 445 per 1000) but may be effective in achieving at least 50% reduction in seizure frequency (55.3% in control group versus 73.7% in intervention group, RR 1.32, 95% CI 1.05 to 1.66, 2 trials; assumed risk 556 per 1000, corresponding risk 583 to 923 per 1000) and better QOL after treatment (QOLIE-31 score mean 172.6 points in the control group versus 184.64 points in the intervention group, MD 12.04 points, 95% CI 4.05 to 20.03 points, 1 trial). Compared with antiepileptic drugs, catgut implantation at acupoints plus antiepileptic drugs was not effective in achieving seizure freedom (13% in control group versus 19.6% in intervention group, RR 1.51, 95% CI 0.93 to 2.43, 4 trials; assumed risk 127 per 1000, corresponding risk 118 to 309 per 1000) but may be effective in achieving at least 50% reduction in seizure frequency (63.1% in control group versus 82% in intervention group, RR 1.42, 95% CI 1.07 to 1.89, 5 trials; assumed risk 444 per 1000, corresponding risk 475 to 840 per 1000) and better QOL after treatment (QOLIE-31 score (higher score indicated worse quality of life) mean 53.21 points in the control group versus 45.67 points in the intervention group, MD -7.54 points, 95% CI -14.47 to -0.61 points, 1 trial). Compared with valproate, catgut implantation may be effective in achieving seizure freedom (8% in control group versus 19.7% in intervention group, RR 2.82, 95% CI 1.61 to 4.94, 4 trials; assumed risk 82 per 1000, corresponding risk 132 to 406 per 1000) and better QOL after treatment (QOLIE-31 score (higher score indicated better quality of life) mean 172.6 points in the control group versus 191.33 points in the intervention group, MD 18.73 points, 95% CI 11.10 to 26.36 points, 1 trial) but not at least 50% reduction in seizure frequency (65.6% in control group versus 91.7% in intervention group, RR 1.31, 95% CI 0.94 to 1.84, 4 trials; assumed risk 721 per 1000, corresponding risk 677 to 1000 per 1000). Acupuncture did not have excess adverse events compared to control treatment in the included trials. AUTHORS' CONCLUSIONS: Available RCTs are small, heterogeneous and have high risk of bias. The current evidence does not support acupuncture for treating epilepsy.

Role of reflexology and antiepileptic drugs in managing intractable epilepsy--a randomized controlled trial.

BACKGROUND: This report is based on the results of a randomized parallel controlled trial conducted to determine the efficacy of reflexology therapy in managing intractable epilepsy. METHODS: Subjects who failed epilepsy surgery or were not candidates for epilepsy surgery or were non-responders of antiepileptic drugs (AEDs) took part in this study. The trial was completed by 77 subjects randomly assigned to 2 arms: control (AEDs) and reflexology (AEDs + reflexology therapy). The hypothesis was that hand reflexology therapy could produce results similar to those of vagus nerve stimulation, and foot reflexology therapy could maintain homeostasis in the functional status of individual body parts. Reflexology therapy was applied by family members. The follow-up period was 1.5 years. Quality of life in epilepsy patients was assessed with the QOLIE-31 instrument. RESULTS: In the reflexology group, the median baseline seizure frequency decreased from 9.5 (range 2-120) to 2 (range 0-110) with statistical significance (p < 0.001). In the control arm, the decrease was less than 25% with a baseline value of 16 (range 2-150). The pretherapy QOLIE-31 scores in the control group and the reflexology group were 41.05 ± 7 and 43.6 ± 8, respectively. Posttherapy data were 49.07 ± 6 and 65.4 ± 9, respectively (p < 0.002). The reflexology method allowed detection of knee pain in 85% of the reflexology group patients (p < 0.001), and 85.3% of patients derived 81% relief from it (p < 0.001). 4 reflexology group patients reported nausea/vomiting (n = 1), change in voice (n = 2), and hoarseness (n = 1). CONCLUSION: Reflexology therapy together with AEDs may help reducing seizure frequency and improving quality of life in individuals with epilepsy.

Anatomically dependent anticonvulsant properties of temporally-coded electrical stimulation.

In the PTZ animal model of epilepsy, electrical stimulation applied to the amygdaloid complex may result in either pro-convulsive or anticonvulsant effect, depending on the temporal pattern used (i.e. periodic-PS and non-periodic-NPS electrical stimulation). Our hypothesis is that the anatomical target is a determinant factor for the differential effect of temporally-coded patterns on seizure outcome. The threshold dose of PTZ to elicit forelimb clonus and generalized tonic-clonic seizure behavior was measured. The effect of amygdaloid complex PS on forelimb clonus threshold showed a pro-convulsive effect while NPS was anticonvulsant. NPS also significantly increased generalized tonic-clonic threshold; while PS, although at lower threshold levels, did not present statistical significance. Thalamus stimulation did not affect forelimb clonus threshold and showed similar anticonvulsant profiles for both PS and NPS on generalized tonic-clonic threshold. In summary, the anatomical target is a determinant factor on whether temporally-coded ES differentially modulates seizure outcome.

Power spectral frequency and coherence abnormalities in patients with intractable epilepsy and their usefulness in long-term remediation of seizures using neurofeedback.

Medically intractable seizures appear to be highly correlated with focal slow activity (delta or theta). They also correlate highly with decreases in the coherence of theta. Normalization of focal slowing and of decreased theta coherence will probably be the neurofeedback approaches most likely to decrease or eliminate seizures in future cases. Neurofeedback has been used for over 35 years to reduce the incidence and severity of seizures. With power training to decrease theta and increase the sensorimotor rhythm (12-15 Hz), an average of 82% of patients experienced a significant reduction in seizure frequency, and occasional remissions were seen. Recent improvements using QEEG to guide neurofeedback training have made it possible to eliminate seizures in most patients, even those with intractable seizures. Following our previous study in 2005, we report an additional 25 patients so treated. We also report an analysis of the frequency of QEEG abnormalities in this patient group. All of the intractable epileptic patients had one or more slow foci (excessive theta or delta compared with the normal database). One third had a relative deficiency of beta power. One fourth had a deficiency of absolute delta. Eighteen percent had excessive absolute alpha power, 18% had deficient absolute alpha power, 18% percent had excessive absolute beta power, and 18% percent had deficient absolute beta power. Hypocoherence of theta was found in 75%, and decreases in alpha coherence were noted in 42%. Hypocoherence of beta was found in 50%, and hypocoherence of delta was found in 25%. Increases in alpha coherence were noted in 33%. Seventeen percent had no coherence abnormalities. When most of the power and coherence abnormalities were normalized with neurofeedback training, all the patients became seizure-free; 76% no longer required an anticonvulsant for seizure control.

Right-sided vagus nerve stimulation in humans: an effective therapy?

Vagus nerve stimulation (VNS) is an additive treatment option for refractory epilepsy. The electrode is placed on the cervical trunk of the left vagus nerve. In patients who are not suitable for left-sided vagus nerve stimulation (L-VNS) right-sided vagus nerve stimulation (R-VNS) may be as effective. In animal models epilepsy is sufficiently suppressed by R-VNS. In a 16 years old boy suffering from medically refractory psychomotoric seizures with secondary generalisation, L-VNS reduced the frequency of generalized seizures. A deep wound infection required the removal of the system eight weeks later. Cicatrisation did not allow preparation of the left vagus nerve, therefore we implanted R-VNS with sufficient seizure suppression. However, compared to L-VNS, the effect occurred months later and cardiac symptoms were induced by stimulation of the right vagus nerve. R-VNS seems to be an effective and alternative therapy in selected patients responding to L-VNS where a left-sided reimplantation is not possible. Placement and adjustment of the device should be performed under ECG control. Further studies are necessary to compare the efficacy of L-VNS and R-VNS.

Is vagus nerve stimulation a treatment option for patients with drug-resistant idiopathic generalized epilepsy?

BACKGROUND: The value of vagus nerve stimulation (VNS) for treating patients with drug-resistant idiopathic generalized epilepsy (IGE) is not well documented. PATIENTS AND METHODS: Twelve patients (2 males, 10 females) with a mean age of 31 years (11-48 years) and with drug-resistant IGE had VNS implanted in the period 1995-2006. All had generalized seizures documented by video-electroencephalogram. Mean follow-up period was 23 months (9-54 months). RESULTS: There was a total seizure reduction of 61% (P = 0.0002). There was 62% reduction of generalized tonic-clonic seizures (P = 0.0020), 58% of absences (P = 0.0003) and 40% of myoclonic seizures (P = 0.0156). Eight patients were considered responders (>50% seizure reduction); two of these patients became seizure-free. Five out of seven patients with juvenile myoclonic epilepsy were responders. At the last follow-up visit, the patients had reduced the anti-epileptic drug (AED) usage from an average of 2.3 to 1.7 AED per patient (P = 0.0625). Two patients are currently being treated with VNS therapy only. Nine patients reported side effects, which were mostly mild and tended to diminish over time. CONCLUSION: Our results indicate that adjunctive VNS therapy is a favourable treatment option for patients with drug-resistant IGE. Rapid cycling seems worth trying in some of the non-responders.

Brain-type natriuretic peptide release and seizure activity during vagal nerve stimulation.

Vagus nerve stimulation (VNS) has emerged as an effective adjunctive therapy for medically refractory epilepsy when surgery is inadvisable. N-terminal brain-type natriuretic peptide (NT-proBNP) is a potent natriuretic, diuretic, and vasodilatative compound first discovered in the human brain but mainly synthesized in the myocardium. The monitoring of VNS effectiveness in reducing seizure frequency or the detection of possible cardiac adverse effects would be helped by a reliable biochemical marker, which has not been available thus far. We report a four-year-old boy with drug-resistant idiopathic generalized epilepsy whose NT-proBNP levels increased during VNS and seizures.

Neuromodulation of the centromedian thalamic nuclei in the treatment of generalized seizures and the improvement of the quality of life in patients with Lennox-Gastaut syndrome.

PURPOSE: Our aim was to evaluate the efficacy of ESCM (electrical stimulation of the centromedian thalamic nucleus) in treatment of generalized seizures of the Lennox-Gastaut syndrome (LGS) and improvement of patient disability. METHODS: Thirteen patients with LGS were studied. They had severe generalized tonic-clonic seizures (GTC) and atypical absences (AA). All patients had at least a 6-month baseline before bilateral electrode implantation to the centromedian (CM) nuclei of the thalamus to undergo therapeutic ESCM. Once implanted, electrodes were temporally externalized through a retromastoid point for electrophysiologic confirmation of their placement. After target confirmation, stimulation parameters were set. Patients came for follow-up assessment of seizures and neurophysiologic tests every 3 months during an 18-month period of time; AED therapy was not modified. RESULTS: The surgical procedure as well as electrical stimulation was well tolerated by all patients. No side effects occurred with the therapeutic stimulation parameters used, and patients were not aware of device activation. Two patients were explanted because of repeated and multiple skin erosions that could not be controlled by plastic surgery procedures. Overall seizure reduction was 80%. The three patients with poorest outcomes for seizure control did not improve their ability scale score. In contrast, the two patients rendered seizure free are living a normal life at present. The remaining eight patients experienced progressive improvement, from being totally disabled to becoming independent in five cases and partially dependent in two. Patients with adequate electrode placement had a seizure reduction >87%. To consider that an electrode is correctly placed, both stereotactic placement and neurophysiologic responses are taken into account. CONCLUSIONS: ESCM provides a nonlesional, neuromodulatory method with improvement in seizure outcome and in the abilities of patients with severe LGS.