Long-term evaluation of anterior thalamic deep brain stimulation for epilepsy in the European MORE registry.

OBJECTIVE: Short-term outcomes of deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) were reported for people with drug-resistant focal epilepsy (PwE). Because long-term data are still scarce, the Medtronic Registry for Epilepsy (MORE) evaluated clinical routine application of ANT-DBS. METHODS: In this multicenter registry, PwE with ANT-DBS were followed up for safety, efficacy, and battery longevity. Follow-up ended after 5 years or upon study closure. Clinical characteristics and stimulation settings were compared between PwE with no benefit, improvers, and responders, that is, PwE with average monthly seizure frequency reduction rates of ≥50%. RESULTS: Of 170 eligible PwE, 104, 62, and 49 completed the 3-, 4-, and 5-year follow-up, respectively. Most discontinuations (68%) were due to planned study closure as follow-up beyond 2 years was optional. The 5-year follow-up cohort had a median seizure frequency reduction from 16 per month at baseline to 7.9 per month at 5-year follow-up (p < .001), with most-pronounced effects on focal-to-bilateral tonic-clonic seizures (n = 15, 77% reduction, p = .008). At last follow-up (median 3.5 years), 41% (69/170) of PwE were responders. Unifocal epilepsy (p = .035) and a negative history of epilepsy surgery (p = .002) were associated with larger average monthly seizure frequency reductions. Stimulation settings did not differ between response groups. In 179 implanted PwE, DBS-related adverse events (AEs, n = 225) and serious AEs (n = 75) included deterioration in epilepsy or seizure frequency/severity/type (33; 14 serious), memory/cognitive impairment (29; 3 serious), and depression (13; 4 serious). Five deaths occurred (none were ANT-DBS related). Most AEs (76.3%) manifested within the first 2 years after implantation. Activa PC depletion (n = 37) occurred on average after 45 months. SIGNIFICANCE: MORE provides further evidence for the long-term application of ANT-DBS in clinical routine practice. Although clinical benefits increased over time, side effects occurred mainly during the first 2 years. Identified outcome modifiers can help inform PwE selection and management.

Burden of suspected epileptic seizures on emergency services: A population-based study.

BACKGROUND AND PURPOSE: Patients with acute epileptic seizures form a large patient group in emergency neurology. This study aims to determine the burden caused by suspected epileptic seizures at different steps in emergency care. METHODS: A retrospective, cross-sectional, population-based (>1,000,000 inhabitants), 4-year (2015-2018) study was conducted in an urban setting with a single dispatch centre, a university hospital-affiliated emergency medical service (EMS), and five emergency departments (EDs). The study covered all adult (≥16 years old) emergency neurology patients receiving medical attention due to suspected epileptic seizures from the EMS and EDs and during hospital admissions in the Helsinki metropolitan area. RESULTS: Epileptic seizures were suspected in 14,364 EMS calls, corresponding to 3.3% of all EMS calls during the study period. 9,112 (63.4%) cases were transported to hospital due to suspected epileptic seizures, and 3368 (23.4%) were discharged on the scene. 6969 individual patients had 11,493 seizure-related ED visits, accounting for 3.1% of neurology- and internal medicine-related ED visits and 4607 hospital admissions were needed with 3 days' median length of stay (IQR=4, Range 1-138). Male predominance was noticeable at all stages (EMS 64.7%, EDs 60.1%, hospital admissions 56.2%). The overall incidence was 333/100,000 inhabitants/year for seizure-related EMS calls, 266/100,000 inhabitants/year for ED visits and 107/100,000 inhabitants/year for hospital admissions. Total estimated costs were 6.8 million €/year, corresponding to 0.5% of all specialized healthcare costs in the study area. CONCLUSIONS: Patients with suspected epileptic seizures cause a significant burden on the health care system. Present-day epidemiological data are paramount when planning resource allocation in emergency services.

Impedance Characteristics of Stimulation Contacts in Deep Brain Stimulation of the Anterior Nucleus of the Thalamus and Its Relationship to Seizure Outcome in Patients With Refractory Epilepsy.

BACKGROUND: Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is an emerging form of adjunctive therapy in focal refractory epilepsy. Unlike conventional DBS targets, the ANT is both encapsulated by white matter layers and located immediately adjacent to the cerebrospinal fluid (CSF) space. Owing to the location of the ANT, implantation has most commonly been performed using a transventricular trajectory. Previous studies suggest different electrical conductivity between gray matter, white matter, and CSF. OBJECTIVES: In this study, we asked whether therapeutic impedance values from a fully implanted DBS device could be used to deduce the actual location of the active contact to optimize the stimulation site. Secondly, we tested whether impedance values correlate with patient outcomes. MATERIALS AND METHODS: A total of 16 patients with ANT-DBS for refractory epilepsy were evaluated in this prospective study. Therapeutic impedance values were recorded on regular outpatient clinic visits. Contact locations were analyzed using delayed contrast-enhanced postoperative computed tomography-3T magnetic resonance imaging short tau inversion recovery fusion images previously shown to demonstrate anatomical details around the ANT. RESULTS: Transventricularly implanted contacts immediately below the CSF surface showed overall lower and slightly decreasing impedances over time compared with higher and more stable impedances in contacts with deeper parenchymal location. Impedance values in transventricularly implanted contacts in the ANT were significantly lower than those in transventricularly implanted contacts outside the ANT or extraventricularly implanted contacts that were typically at the posterior/inferior/lateral border of the ANT. Increasing contact distance from the CSF surface was associated with a linear increase in therapeutic impedance. We also found that therapeutic impedance values were significantly lower in contacts with favorable therapy response than in nonresponding contacts. Finally, we observed a significant correlation between the left- and right-side averaged impedance and the reduction of the total number of seizures. CONCLUSIONS: Valuable information can be obtained from the noninvasive measurement of therapeutic impedances. The selection of active contacts to target stimulation to the anterior nucleus may be guided by therapeutic impedance measurements to optimize outcome.

Anti-epileptic drugs and prostate cancer-specific mortality compared to non-users of anti-epileptic drugs in the Finnish Randomized Study of Screening for Prostate Cancer.

BACKGROUND: Drugs with histone deacetylase inhibitory (HDACi) properties have shown to decrease prostate cancer (PCa) cell growth in vitro. METHODS: A cohort of 9261 PCa cases from the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) was used to evaluate prostate cancer-specific mortality in men using anti-epileptic drugs (AEDs). A national subscription database was used to obtain information on medication use. Cox regression with AED use as a time-dependent variable was used to analyse prostate cancer mortality in men using AEDs compared to non-users, and in men using HDACi AEDs compared to users of other AEDs. The analysis was adjusted for age, screening trial arm, PCa risk group, primary treatment of PCa, Charlson co-morbidity score and concomitant use of other drugs. RESULTS: The use of AEDs, in general, was associated with an increased risk of PCa death. The use of HDACi AEDs was not significantly associated with decreased PCa mortality compared to use of other AEDs (HR 0.61, 95% CI 0.31-1.23). CONCLUSIONS: AED usage is associated with elevated PCa mortality compared to non-users, likely reflecting the differences between men with epilepsy and those without. No benefit was observed from HDACi drugs compared to other AEDs.

Semiautomated classification of nocturnal seizures using video recordings.

OBJECTIVE: The objective of this study was to evaluate the accuracy of a semiautomated classification of nocturnal seizures using a hybrid system consisting of an artificial intelligence-based algorithm, which selects epochs with potential clinical relevance to be reviewed by human experts. METHODS: Consecutive patients with nocturnal motor seizures admitted for video-electroencephalographic long-term monitoring (LTM) were prospectively recruited. We determined the extent of data reduction by using the algorithm, and we evaluated the accuracy of seizure classification from the hybrid system compared with the gold standard of LTM. RESULTS: Forty consecutive patients (24 male; median age = 15 years) were analyzed. The algorithm reduced the duration of epochs to be reviewed to 14% of the total recording time (1874 h). There was a fair agreement beyond chance in seizure classification between the hybrid system and the gold standard (agreement coefficient = .33, 95% confidence interval = .20-.47). The hybrid system correctly identified all tonic-clonic and clonic seizures and 82% of focal motor seizures. However, there was low accuracy in identifying seizure types with more discrete or subtle motor phenomena. SIGNIFICANCE: Using a hybrid (algorithm-human) system for reviewing nocturnal video recordings significantly decreased the workload and provided accurate classification of major motor seizures (tonic-clonic, clonic, and focal motor seizures).

High-mobility group box 1 as a predictive biomarker for drug-resistant epilepsy: A proof-of-concept study.

Currently no sensitive and specific biomarkers exist to predict drug-resistant epilepsy. We determined whether blood levels of high-mobility group box 1 (HMGB1), a mediator of neuroinflammation implicated in drug-resistant epilepsies, identifies patients with drug-resistant seizures. Patients with drug-resistant epilepsy express significantly higher levels of blood HMGB1 than those with drug-responsive, well-controlled seizures and healthy controls. No correlation existed between blood HMGB1 levels and total pretreatment seizure count or days since last seizure at new epilepsy diagnosis, indicating that blood HMGB1 does not solely reflect ongoing seizures. HMGB1 distinguishes with high specificity and selectivity drug-resistant versus drug-responsive patients. This protein therefore has potential clinical utility to act as a biomarker for predicting response to therapy, which should be addressed in prospective clinical studies.

Norwegian population-based study of long-term effects, safety, and predictors of response of vagus nerve stimulation treatment in drug-resistant epilepsy: The NORPulse study.

OBJECTIVE: This study was undertaken to evaluate the efficacy of vagus nerve stimulation (VNS) over time, and to determine which patient groups derive the most benefit. METHODS: Long-term outcomes are reported in 436 epilepsy patients from a VNS quality registry (52.8% adults, 47.2% children), with a median follow-up of 75 months. Patients were stratified according to evolution of response into constant responders, fluctuating responders, and nonresponders. The effect was evaluated at 6, 12, 24, 36, and 60 months. Multivariate regression analysis was used to identify predictors of response. RESULTS: The cumulative probability of ≥50% seizure reduction was 60%; however, 15% of patients showed a fluctuating course. Of those becoming responders, 89.5% (230/257) did so within 2 years. A steady increase in effect was observed among constant responders, with 48.7% (19/39) of those becoming seizure-free and 29.3% (39/133) with ≥75% seizure reduction achieving these effects within 2-5 years. Some effect (25%-<50%) at 6 months was a positive predictor of becoming a responder (odds ratio [OR] = 10.18, p < .0001) and having ≥75% reduction at 2 years (OR = 3.34, p = .03). Patients without intellectual disability had ORs of 3.34 and 3.11 of having ≥75% reduction at 2 and 5 years, respectively, and an OR of 6.22 of being seizure-free at last observation. Patients with unchanged antiseizure medication over the observation period showed better responder rates at 2 (63.0% vs. 43.1%, p = .002) and 5 years (63.4% vs. 46.3%, p = .031) than patients whose antiseizure medication was modified. Responder rates were higher for posttraumatic (70.6%, p = .048) and poststroke epilepsies (75.0%, p = .05) than other etiologies (46.5%). SIGNIFICANCE: Our data indicate that the effect of VNS increases over time and that there are important clinical decision points at 6 and 24 months for evaluating and adjusting the treatment. There should be better selection of candidates, as certain patient groups and epilepsy etiologies respond more favorably.

Treatment outcomes in women with idiopathic generalized epilepsy.

OBJECTIVES: To evaluate the changes in prescription patterns in the treatment of idiopathic generalized epilepsy (IGE) due to updated treatment recommendations and to assess seizure outcomes of valproate compared to other antiseizure medications (ASMs), with emphasis on women with epilepsy (WWE). MATERIALS AND METHODS: Records of IGE patients treated at Tampere University Hospital between 1 January 2009 and 31 December 2018 were retrospectively inspected. Data were analysed for two subgroups based on age and sex. Seizure control with reference to the efficacy of different ASMs and their combinations was examined for each subgroup. RESULTS: The study compiled 263 subjects (166 females and 97 males). Of all patients, 72.6% remained seizure free. There was no difference in seizure control between sexes (OR 1.25, p = .48). Males used valproate more often than females while females used lamotrigine and levetiracetam more often than males. Lamotrigine and levetiracetam were used especially as monotherapy in WWE, and mostly as part of combination therapy in males. Valproate alternatives were found as effective as valproate when used in monotherapy in adults. Valproate remained the most used ASM in the paediatric subgroup. CONCLUSIONS: The use of valproate has decreased in daily clinical use with the simultaneous increased use of alternative ASMs compared to our previous study. Decreasing use of valproate in WWE did not increase the risk of seizure recurrence; therefore, valproate alternatives could be considered as first-line ASMs for WWE. Overall, IGE patients demonstrated good clinical outcomes with valproate or other broad-spectrum ASMs as monotherapy.

Clinical utility of a video/audio-based epilepsy monitoring system Nelli.

OBJECTIVE: The aim of this study was to evaluate the clinical utility of a semi-automated hybrid video/audio-based epilepsy monitoring system (Nelli®) in a home setting. METHODS: In this retrospective study, 104 consecutive patients underwent Nelli-registration for an average of 29 days at their home. The seizure-related data obtained from the registration were assessed to investigate the utility of the Nelli-registration regarding clinical decision-making. RESULTS: Of 104 patients, Nelli® hybrid system was able to recognize clinically relevant events in 83 (80%) patients: epileptic seizures in 67 (65%) and nonepileptic events in 16 (15%). A total of 2767 epileptic seizures of different seizure types were captured and identified. These seizures included not only tonic-clonic seizures but also other complex or simple motor seizures. For the outcomes regarding clinical decision-making, a need for a new therapeutic intervention was recognized in 54 (51.9%) patients based on the number and severity of seizures captured by Nelli-registration. In 12 (11.5%) patients, the need to change the treatment plan was excluded because no evidence of suspected epileptic seizures was found. Nelli-registration aided in confirming the therapeutic efficacy of modifications of antiseizure medications (ASMs) or neuromodulation therapies in 13 (12.5%) patients. Nelli-registration enabled to determine the change in seizure classification and facilitated to reach clear diagnostic conclusions in 11 (10.6%) patients. In 14 (13.5%) patients, there was no change in clinical outcome, as Nelli-registration was unable to infer any clinical decision either due to inconclusive results or lack of typical events. Seizures detected during Nelli-registration aided in decision-making for therapeutic interventions in 71 (68%) patients. Altogether, 44 (42%) patients had adjustment of ASMs, and in 9 (9%) patients, Nelli-registrations led to the change in the settings of vagus nerve stimulation (VNS) or deep brain stimulation (DBS) treatment. Additionally, 18 (17%) patients were referred to presurgical evaluation or established a baseline seizure frequency before surgical implantation for neuromodulation treatment with VNS or DBS, while 33 (32%) patients had no change in therapy. Nine patients (8.7%) were referred to video-EEG monitoring (VEM), as Nelli-recorded events highlighted the need for presurgical evaluation in 6 patients or further diagnostic evaluation in 3 patients. CONCLUSION: This study confirms the clinical utility of the video/audio monitoring system Nelli® in home settings. Home monitoring with Nelli® hybrid system provides a new alternative for the assessment of frequency and type of epileptic seizures as well as for a recognition of nonepileptic events. Thus, Nelli-registration can facilitate the optimization of seizure monitoring and management in clinical practice, complementing existing methods such as VEM and ambulatory EEG recordings.

Antiepileptic drugs and prostate cancer risk in the Finnish Randomized Study of Screening for Prostate Cancer.

Antiepileptic drugs (AEDs) with histone deacetylase (HDAC) inhibitor properties decrease prostate cancer (PCa) cell proliferation in vitro. A population-based cohort of 78 615 men was used to evaluate the risk of PCa among users of AEDs. Study population was linked to the Finnish national prescription database to obtain information on individual medication reimbursements in 1996 to 2015. Cox regression with antiepileptic medication use as a time-dependent variable was used to analyze PCa risk overall, and low, medium and high-risk PCa separately. The analysis was adjusted for age, screening trial arm, and other drugs in use, including statins, antidiabetic drugs, antihypertensive drugs, aspirin, and nonsteroidal anti-inflammatory drugs. Compared to the nonusers of AEDs, overall PCa risk was decreased among AED users (hazard ratio [HR] = 0.86, 95% confidence interval [CI] = 0.76-0.96). A similar PCa risk decrease was observed among users of HDACi AEDs (HR = 0.87, 95% CI = 0.76-1.01), but no risk difference was found when comparing HDACi AED users to users of other AEDs (HR = 0.98, 95% CI = 0.76-1.27). Our study showed a decrease in overall PCa risk among men using AEDs compared to nonusers. The risk associations were similar for HDAC inhibitors as for AEDs in general.

Response to first antiseizure medication in patients diagnosed with epilepsy.

OBJECTIVES: To investigate the interaction among the efficacy, tolerability and overall effectiveness of the first antiseizure medication in patients 16 years or older with newly diagnosed epilepsy. MATERIALS AND METHODS: The study included 584 patients who were referred to the Tampere University Hospital between 1 January 1995 and 31 December 2005 and were diagnosed with epilepsy. All individuals were retrospectively followed up until 31 December 2006, until reaching at least one year of seizure freedom, or until death if before the cut-off date. RESULTS: Overall, after thorough validation of the epilepsy diagnosis 459 patients comprised the study cohort; among these patients, 73% of males and 60% of females became seizure-free for at least one year with the first antiseizure medication. The seizure freedom rate for focal epilepsy was 67%. There was no significant difference in focal epilepsy to achieve seizure freedom between oxcarbazepine, carbamazepine or valproic acid. The seizure freedom rate among patients above 60 years of age was 67%. For patients with structural and unknown aetiology, seizure freedom rates were 61.5% and 75.3%, respectively. Additionally, epileptiform activity on EEG in patients with focal epilepsy decreased odds of seizure freedom in adjusted logistic regression models (OR 0.55, p=0.036). CONCLUSIONS: This study provides a more positive prediction of seizure freedom compared with previous studies with the onset of epilepsy at 16 years or older with an overall estimation that two-thirds of patients with new-onset epilepsy obtain seizure freedom with the first antiseizure medication.

EpiTrack is a feasible tool for assessing attention and executive functions in patients with refractory epilepsy.

OBJECTIVE: The purpose of this cross-sectional retrospective study was to utilize EpiTrack to assess cognitive performance within the domain of attention and executive functions in patients with refractory epilepsy in consideration for treatment interventions either with antiepileptic drug (AED) changes and/or neuromodulation therapies. We also aimed to identify the relevant clinical and treatment factors possibly affecting EpiTrack performance. METHODS: The patient group consisted of 95 consecutive refractory epilepsy patients who were evaluated with EpiTrack. Based on their EpiTrack performance, the patients could be categorized as cognitively unimpaired, mildly, or severely impaired. The patients were also divided into three groups based on the planned treatment modification: AED group (n = 38) with only AED treatment, vagal nerve stimulation (VNS) group (n = 40) and deep-brain stimulation (DBS) group (n = 17). However, the effect of planned interventions was not the subject of this study. We retrospectively reviewed the medical records for detailed clinical characterization. RESULTS: EpiTrack performance was severely impaired in 48 (50.5%), mildly impaired in 22 (23.2%) and unimpaired in 25 (26.3%) of the patients. The DBS group had significantly lower EpiTrack scores (mean (SD) and median, 25.5 (4.81) and 27.0, respectively) compared to the AED group (28.6 (6.2) and 30.0, respectively, p = 0.049). Sixty-three (66.3%) of the whole study population had more than 2 AEDs. When comparing EpiTrack scores between patient groups based on the number of AEDs administered, there was a trend toward better performance in EpiTrack with 2 AEDs as compared to 3-4 AEDs. CONCLUSIONS: Deficits in attention and executive functions were frequent among patients with refractory epilepsy. Deficits were evident in all three treatment groups being most severe in the DBS group reflecting the patient selection. Furthermore, the effect of AED burden on executive functions was remarkable since two thirds of the patients had more than two AEDs and the deficits were more prominent among those with a higher AED burden. These results highlight the benefits of a feasible screening tool such as EpiTrack for assessing attention and executive functions when optimizing the treatment effects of neurostimulation therapies on cognition, and when evaluating the impacts of the AED burden.

A new era in electroencephalographic monitoring? Subscalp devices for ultra-long-term recordings.

Inaccurate subjective seizure counting poses treatment and diagnostic challenges and thus suboptimal quality in epilepsy management. The limitations of existing hospital- and home-based monitoring solutions are motivating the development of minimally invasive, subscalp, implantable electroencephalography (EEG) systems with accompanying cloud-based software. This new generation of ultra-long-term brain monitoring systems is setting expectations for a sea change in the field of clinical epilepsy. From definitive diagnoses and reliable seizure logs to treatment optimization and presurgical seizure foci localization, the clinical need for continuous monitoring of brain electrophysiological activity in epilepsy patients is evident. This paper presents the converging solutions developed independently by researchers and organizations working at the forefront of next generation EEG monitoring. The immediate value of these devices is discussed as well as the potential drivers and hurdles to adoption. Additionally, this paper discusses what the expected value of ultra-long-term EEG data might be in the future with respect to alarms for especially focal seizures, seizure forecasting, and treatment personalization.

Chronically reduced IL-10 plasma levels are associated with hippocampal sclerosis in temporal lobe epilepsy patients.

BACKGROUND: Increasing evidence supports the role of soluble inflammatory mediators in the pathogenesis of refractory temporal lobe epilepsy (TLE). Hippocampal sclerosis (HS) is a well-described pathohistological abnormality in TLE. The association of proinflammatory cytokines with epileptic disease profiles is well established; however, the potential significance of circulating interleukin 10 (IL-10), particularly in TLE-associated HS, is still poorly understood. Therefore, taking into consideration the neuroprotective and anticonvulsive effects of IL-10, we performed this study to examine the role of the plasma levels of IL-10 in patients with TLE with HS (TLE + HS), TLE without HS (TLE-HS) and with other types of epilepsy. METHODS: This study included 270 patients with refractory epilepsy who were classified into four groups: i) 34 patients with TLE + HS, ii) 105 patients with TLE-HS, iii) 95 patients with extra-TLE (XLE) and iv) 36 patients with idiopathic generalized epilepsy (IGE). The plasma IL-10 levels were quantified using a commercially available enzyme-linked immunosorbent assay (ELISA). RESULTS: IL-10 levels were significantly lower in TLE + HS than in TLE-HS (p = 0.013). In a subgroup of TLE-HS patients who had seizures 1 month before sampling, patients with seizures had significantly higher IL-10 levels than patients who were seizure-free (p = 0.039). Among a small group (n = 15) of non-refractory TLE-HS patients, IL-10 levels showed a moderate negative correlation with the duration of epilepsy (r = - 0.585, p = 0.023). CONCLUSIONS: This study demonstrated that chronically reduced levels of plasma IL-10 were associated with HS in TLE patients, suggesting that there was an inadequate systemic anti-inflammatory immune response. These results could provide new biological insights into the pathophysiology of HS in TLE. We also found that the production of IL-10 could be affected by the seizure frequency and declined concomitantly with increased disease durations. Therefore, the measurement of plasma IL-10 may have diagnostic value as a biomarker for stratifying TLE + HS from other epilepsy types or as a marker of disease progression towards a progressive form of epilepsy.

Circadian distribution of autostimulations in rVNS therapy in patients with refractory focal epilepsy.

BACKGROUND: Responsive vagus nerve stimulation (rVNS) utilizes an electrocardiograph (ECG)-based algorithm to detect rapid sympathetic activations associated with the onset of a seizure. Abrupt sympathetic activation may also be associated with nocturnal arousals between sleep cycles or transitioning from sleep to wakefulness, a period in which many patients with epilepsy experience seizures. Because of circadian changes in autonomic function, we hypothesized that the autostimulation feature might also behave in a circadian fashion. OBJECTIVE: The aim of this study was to assess the circadian rhythmicity of autostimulations in rVNS treatment in patients with drug-resistant epilepsy (DRE). MATERIALS AND METHODS: We performed a retrospective follow-up study of 30 patients with DRE treated with rVNS including 17 new implantations and 13 battery replacements at a single center in Finland. After initiation of autostimulation mode, the exact rVNS stimulation parameters and the timestamps of all individual autostimulations delivered were registered. A clustered autostimulation was defined as any autostimulation that occurred within the duration of the therapeutic cycle during the therapy "OFF" time compared with both the previous autostimulation and the following autostimulation. RESULTS: Autostimulations and especially autostimulation clusters show a higher probability of occurring in the morning and less at night. This trend appeared to follow the circadian rhythm of cortisol concentration. CONCLUSIONS: Early morning peaks of autostimulations at low thresholds may reflect awakening-induced activation of the cardiovascular system, which is associated with a shift towards the dominance of the sympathetic branch of the autonomic nervous system. Cortisol release occurs in parallel driven by wakening-induced activation of the hypothalamic-pituitary-adrenal axis, which is fine-tuned by direct sympathetic input to the adrenal gland. This is of interest considering the known sympathetic hyperactivity in patients with epilepsy.

Frequency of Automatic Stimulations in Responsive Vagal Nerve Stimulation in Patients With Refractory Epilepsy.

BACKGROUND: In vagal nerve stimulation (VNS) therapy, the release of VNS model 106 (AspireSR) allowed for responsive VNS (rVNS). rVNS utilizes a cardiac-based seizure detection algorithm to detect seizure-induced tachycardia to trigger additional stimulation. There are some studies suggesting clinical benefits of rVNS over traditional VNS, but the performance and significance of autostimulation mode in clinical practice are poorly understood. OBJECTIVES: To assess the effect of initiation of rVNS therapy and altered stimulation settings on the number of daily stimulations and energy consumption in VNS therapy and to compare autostimulation performance in different epilepsy types. MATERIALS AND METHODS: Retrospective follow-up of 30 patients with drug-resistant epilepsy treated with rVNS including 17 new implantations and 13 battery replaces at a single center in Finland. Our data consist of 208 different stimulation periods, that is, episodes with defined stimulation settings and both autostimulation and total stimulation performance-related data along with clinical follow-up. RESULTS: The variation in autostimulation frequency was highly dependent on the duration of the OFF-time and autostimulation threshold (p < 0.05). There was a large additional effect of autostimulation mode on therapy time and energy consumption with longer OFF-times, but a minor effect with shorter OFF-times. Significantly more autostimulations were triggered in the temporal lobe and multifocal epilepsies than in extratemporal lobe epilepsies. CONCLUSIONS: The initiation of autostimulation mode in VNS therapy increased the total number of stimulations. Shortening the OFF-time leads to a decreased number and share of automatic activations. Epilepsy type may affect autostimulation activity.

Autostimulation in Vagus Nerve Stimulator Treatment: Modulating Neuromodulation.

OBJECTIVES: Until now, the vagus nerve stimulation (VNS) treatment in epilepsy has consisted of two different modes: normal and magnet stimulation. A new vagus nerve stimulator model (106 AspireSR®, LivaNova, Houston, TX, USA) also allows automatic stimulation (AutoStim). The purpose of this study is to examine the effect of autostimulation on seizure frequencies together with energy consumption. MATERIALS AND METHODS: The study material consisted of 14 patients whose former stimulator model (102/103) was replaced with model 106. We calculated the theoretical charge (Q) in Coulombs for one day in both of those groups. We evaluated the follow-up data of the patients' seizure counts, with a mean follow-up time of 18.1 months (SD 8.1). RESULTS: The total charge, "VNS dose," was reduced with model 106 in comparison with models 102 or 103 (p = 0.001, Mann-Whitney test). The average charge (Qtotal ) for one day with AutoStim was 142.56 mC; without AutoStim, it was 321.09 mC. We were able to assess seizure diaries in 11 out of 14 patients. Four patients (36%) had >50% seizure reduction and two patients (18%) experienced a reduction in seizure severity with VNS with autostimulation. Five patients (46%) remained unchanged. In three out of four patients with improved seizure control, the duty cycle was maintained at the original level. The patients whose duty cycle was modified for a more prolonged OFF-time had unchanged seizure frequencies. CONCLUSION: VNS with AutoStim achieves maintenance of prior-established seizure control with markedly less energy consumption and can also improve seizure control as compared to former stimulator model.

Successful management of super-refractory status epilepticus with thalamic deep brain stimulation.

Super-refractory status epilepticus is a condition characterized by recurrence of status epilepticus despite use of deep general anesthesia, and it has high morbidity and mortality rates. We report a case of a 17-year-old boy with a prolonged super-refractory status epilepticus that eventually resolved after commencing deep brain stimulation of the centromedian nucleus of the thalamus. Later attempt to reduce stimulation parameters resulted in immediate relapse of status epilepticus, suggesting a pivotal role of deep brain stimulation in the treatment response. Deep brain stimulation may be a treatment option in super-refractory status epilepticus when other treatment options have failed. ANN NEUROL 2017;81:142-146.

Reversible psychiatric adverse effects related to deep brain stimulation of the anterior thalamus in patients with refractory epilepsy.

OBJECTIVE: Anterior nucleus of thalamus (ANT) deep brain stimulation (DBS) is becoming a more common treatment for drug-resistant epilepsy. Epilepsy and depression display a bidirectional association. Anterior nucleus of thalamus has connections to anterior cingulate cortex and orbitomedial prefrontal cortex, hence, a possible role in emotional and executive functions, and thus, ANT DBS might exert psychiatric adverse effects. Our aim was to evaluate previous and current psychiatric symptoms in patients with epilepsy undergoing ANT DBS surgery and assess the predictability of psychiatric adverse effects. Programming-related psychiatric adverse effects are also reported. METHOD: Twenty-two patients with ANT DBS for retractable epilepsy were examined, and a psychiatric evaluation of depressive and other psychiatric symptoms was performed with Montgomery and Åsberg Depression Rating Scale (MADRS), Beck Depression Inventory (BDI), and Symptom Checklist prior to surgery, concentrating on former and current psychiatric symptoms and medications. The follow-up visit was one year after surgery. RESULTS: At the group level, no changes on mood were observed during ANT DBS treatment. Two patients with former histories of depression experienced sudden depressive symptoms related to DBS programming settings; these were quickly alleviated after changing the stimulation parameters. In addition, two patients with no previous histories of psychosis gradually developed clear paranoid and anxiety symptoms that also relieved slowly after changing the programming settings. CONCLUSION: The majority of our ANT DBS patients did not experience psychiatric adverse effects. Certain DBS parameters might predispose to sudden depressive or slowly manifesting paranoid symptoms that are reversible via programming changes.

Causal Evidence from Humans for the Role of Mediodorsal Nucleus of the Thalamus in Working Memory.

The mediodorsal nucleus of the thalamus (MD), with its extensive connections to the lateral pFC, has been implicated in human working memory and executive functions. However, this understanding is based solely on indirect evidence from human lesion and imaging studies and animal studies. Direct, causal evidence from humans is missing. To obtain direct evidence for MD's role in humans, we studied patients treated with deep brain stimulation (DBS) for refractory epilepsy. This treatment is thought to prevent the generalization of a seizure by disrupting the functioning of the patient's anterior nuclei of the thalamus (ANT) with high-frequency electric stimulation. This structure is located superior and anterior to MD, and when the DBS lead is implanted in ANT, tip contacts of the lead typically penetrate through ANT into the adjoining MD. To study the role of MD in human executive functions and working memory, we periodically disrupted and recovered MD's function with high-frequency electric stimulation using DBS contacts reaching MD while participants performed a cognitive task engaging several aspects of executive functions. We hypothesized that the efficacy of executive functions, specifically working memory, is impaired when the functioning of MD is perturbed by high-frequency stimulation. Eight participants treated with ANT-DBS for refractory epilepsy performed a computer-based test of executive functions while DBS was repeatedly switched ON and OFF at MD and at the control location (ANT). In comparison to stimulation of the control location, when MD was stimulated, participants committed 2.26 times more errors in general (total errors; OR = 2.26, 95% CI [1.69, 3.01]) and 2.86 times more working memory-related errors specifically (incorrect button presses; OR = 2.88, CI [1.95, 4.24]). Similarly, participants committed 1.81 more errors in general ( OR = 1.81, CI [1.45, 2.24]) and 2.08 times more working memory-related errors ( OR = 2.08, CI [1.57, 2.75]) in comparison to no stimulation condition. "Total errors" is a composite score consisting of basic error types and was mostly driven by working memory-related errors. The facts that MD and a control location, ANT, are only few millimeters away from each other and that their stimulation produces very different results highlight the location-specific effect of DBS rather than regionally unspecific general effect. In conclusion, disrupting and recovering MD's function with high-frequency electric stimulation modulated participants' online working memory performance providing causal, in vivo evidence from humans for the role of MD in human working memory.