Stereoelectroencephalography: a review of complications and outcomes in a new Australian centre.

BACKGROUND: Surgical management of refractory focal epilepsy requires preoperative localisation of the epileptogenic zone (EZ). To augment noninvasive studies, stereoelectroencephalography (SEEG) is being increasingly adopted as a form of intracranial monitoring. AIMS: This study aimed to determine the rate of complications for patients undergoing SEEG and to report the success of SEEG with regard to EZ detection and seizure outcome following definitive surgery. METHODS: A retrospective cohort design investigated all cases of SEEG at our institution. Surgical, anaesthetic and medical complications with subsequent epilepsy surgery and seizure outcome data were extracted from medical records. Multivariate logistic regression was used to investigate the relationship between both the number of electrodes per patient and the duration of SEEG recording with the rate of complications. RESULTS: Sixty-four patients with 66 implantations were included. Headache was the most common complication (n = 54, 82%). There were no major surgical or medical complications. Two anaesthetic complications occurred. EZ localisation was successful in 63 cases (95%). Curative intent surgery was performed in 39 patients (59%) and 23 patients achieved an Engel class I outcome (59% of those undergoing surgery). The number of electrodes and duration of recording were not associated with complications. CONCLUSIONS: No patients in our series experienced major surgical or medical complications and we have highlighted the challenges associated with neuroanaesthesia in SEEG. Our complication rates and seizure outcomes are equivalent to published literature indicating that this technique can be successfully established in newer centres using careful case selection. Standardised reporting of SEEG complications should be adopted.

Phase II randomised placebo-controlled trial of sodium selenate as a disease-modifying treatment in chronic drug-resistant temporal lobe epilepsy: the SeLECT study protocol.

INTRODUCTION: Epilepsy is one of the most common neurological conditions worldwide. Despite many antiseizure medications (ASMs) being available, up to one-third of patients do not achieve seizure control. Preclinical studies have shown treatment with sodium selenate to have a disease-modifying effect in a rat model of chronic temporal lobe epilepsy (TLE). AIM: This randomised placebo-controlled trial aims to evaluate the antiseizure and disease-modifying effects of sodium selenate in people with drug-resistant TLE. METHODS: This will be a randomised placebo-controlled trial of sodium selenate. One hundred and twenty-four adults with drug-resistant TLE and ≥4 countable seizures/month will be recruited. Outcomes of interest will be measured at baseline, week 26 and week 52 and include an 8-week seizure diary, 24-hour electroencephalogram and cognitive, neuropsychiatric and quality of life measures. Participants will then be randomised to receive a sustained release formulation of sodium selenate (initially 10 mg three times a day, increasing to 15 mg three times a day at week 4 if tolerated) or a matching placebo for 26 weeks. OUTCOMES: The primary outcome will be a consumer codesigned epilepsy-Desirability of Outcome Rank (DOOR), combining change in seizure frequency, adverse events, quality of life and ASM burden measures into a single outcome measure, compared between treatment arms over the whole 52-week period. Secondary outcomes will compare baseline measures to week 26 (antiseizure) and week 52 (disease modification). Exploratory measures will include biomarkers of treatment response. ETHICS AND DISSEMINATION: The study has been approved by the lead site, Alfred Hospital Ethics Committee (594/20). Each participant will provide written informed consent prior to any trial procedures. The results of the study will be presented at national and international conferences, published in peer-reviewed journals and disseminated through consumer organisations. CONCLUSION: This study will be the first disease-modification randomised controlled trial in patients with drug-resistant TLE. TRIAL REGISTRATION NUMBER: ANZCTR; ACTRN12623000446662.

The efficacy and tolerability of adjunctive brivaracetam for the treatment of adult epilepsy: An Australian multi-center retrospective real-world observational cohort study.

OBJECTIVE: Assess the efficacy and tolerability of add-on therapy brivaracetam (BRV) in adult patients with epilepsy in a real-world setting. METHODS: This multi-center retrospective observational cohort study examined all adult patients who commenced on BRV at 11 Australian epilepsy centers between 2017 and 2020. Primary outcomes were seizure response (≥50% reduction in frequency) and seizure freedom 12 months post BRV commencement, and tolerability. We report three approaches to missing data (complete case analysis, CCA; last observation carried forward, LOCF; and intention to treat, ITT). Secondary outcomes included the durability of early BRV response and continuous seizure freedom from BRV initiation. Subgroup analysis examined patients with focal and generalized epilepsy and patients with refractory (≥4 prior ASMs) and highly refractory (≥7 prior ASMs) epilepsy. Outcomes were also assessed at 'personalized' seizure outcome time points based on baseline seizure frequency. RESULTS: Baseline and follow-up data were available for 228 patients. The mean age was 41.5 years (IQR 30, 50). Most had focal epilepsy (188/228, 82.5%). Median number of previous ASMs was 4 (2, 7), and concomitant ASMs 2 (2, 3). Twelve-month responder rate was: 46.3% using CCA (95% CI 34.0, 58.9); 39.5% using LOCF (33.1, 46.1); and 15.4% using ITT (10.9, 20.7). Twelve-month seizure freedom was: 23.9% using CCA (14.3, 35.9); 24.6% using LOCF (19.1, 30.7); and 7.9% using ITT (4.7, 12.1). The most frequent adverse effects were sedation or cognitive slowing (33/228, 14.5%), irritability or aggression (16/228, 7.0%), and low mood (14/228, 6.1%). Outcomes were similar using continuous outcome definitions and 'personalized' outcome assessment time points. Early responses were highly durable, with 3-month response maintained at all subsequent time points at 83%, and seizure freedom maintained at 85%. Outcomes were similar in focal (n = 187) and generalizsed (n = 25) subgroups. Outcomes were similar in refractory patients (n = 129), but lower in the highly refractory group (n = 62), however improvement with BRV was still observed with 12-month seizure freedom of 8.3% using CCA (1.0, 27), 6.5% using LOCF (1.8, 15.7); and 3.2% using ITT (0.4, 11.2). CONCLUSIONS: Meaningful real-world responder and seizure freedom rates can be still observed in a refractory epilepsy population. Brivaracetam response can occur early and appears to be maintained with minimal later relapse. The results should be interpreted with caution given the retrospective nature of the study and the quantities of missing data at later time points.

Potential new roles for glycogen in epilepsy.

Seizures often originate in epileptogenic foci. Between seizures (interictally), these foci and some of the surrounding tissue often show low signals with 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) in many epileptic patients, even when there are no radiologically detectable structural abnormalities. Low FDG-PET signals are thought to reflect glucose hypometabolism. Here, we review knowledge about metabolism of glucose and glycogen and oxidative stress in people with epilepsy and in acute and chronic rodent seizure models. Interictal brain glucose levels are normal and do not cause apparent glucose hypometabolism, which remains unexplained. During seizures, high amounts of fuel are needed to satisfy increased energy demands. Astrocytes consume glycogen as an additional emergency fuel to supplement glucose during high metabolic demand, such as during brain stimulation, stress, and seizures. In rodents, brain glycogen levels drop during induced seizures and increase to higher levels thereafter. Interictally, in people with epilepsy and in chronic epilepsy models, normal glucose but high glycogen levels have been found in the presumed brain areas involved in seizure generation. We present our new hypothesis that as an adaptive response to repeated episodes of high metabolic demand, high interictal glycogen levels in epileptogenic brain areas are used to support energy metabolism and potentially interictal neuronal activity. Glycogenolysis, which can be triggered by stress or oxidative stress, leads to decreased utilization of plasma glucose in epileptogenic brain areas, resulting in low FDG signals that are related to functional changes underlying seizure onset and propagation. This is (partially) reversible after successful surgery. Last, we propose that potential interictal glycogen depletion in epileptogenic and surrounding areas may cause energy shortages in astrocytes, which may impair potassium buffering and contribute to seizure generation. Based on these hypotheses, auxiliary fuels or treatments that support glycogen metabolism may be useful to treat epilepsy.

High-fidelity dendritic sodium spike generation in human layer 2/3 neocortical pyramidal neurons.

Dendritic spikes function as cardinal components of rodent neocortical circuit computations. Recently, the biophysical properties of human pyramidal neurons (PNs) have been reported to be divergent, raising the question of whether dendritic spikes have homologous roles in the human neocortex. To directly address this, we made electrical recordings from the soma and apical dendrites of human and rat layer 2/3 PNs of the temporal cortex. In both species, dendritic excitatory input led to the initiation of sodium-channel-mediated dendritic spikes. Dendritic sodium spikes could be generated across a wide input range, exhibited a similar frequency range of activation, and forward-propagated with high-fidelity to implement stereotyped computations in human and rat PNs. However, the physical expansion and complexification of the apical dendritic trees of human PNs allowed the enriched expression of dendritic spike generation. The computational capacity of human PNs is therefore enhanced by the widespread implementation of a conserved dendritic integration mechanism.

Effect of immunotherapy on intracranial EEG in patients with seronegative autoimmune-associated epilepsy

Objective: Immunity is increasingly implicated in the aetiology of certain types of epilepsy, however, the clinical and EEG features in such cases remain poorly defined. We present stereo-electroencephalography (SEEG) findings in patients who were thought to have autoantibody-mediated epilepsy on the basis of clinical improvement after administration of immunotherapy (IT). Methods: All patients undergoing SEEG implantation in our service were reviewed and those receiving immunotherapy, either before, during, or after SEEG evaluation, were identified. Response to immunotherapy was defined as greater than 50% seizure reduction. We compared the clinical features and SEEG findings between those who responded to immunotherapy and those who did not. Results: Sixty-two cases underwent SEEG evaluation. Of these, 11 received immunotherapy and three cases demonstrated a positive clinical benefit. The three responsive patients had multifocal seizure onset, repetitive spiking interictally and ictally, perisylvian semiology, seizure onset in the posterior perisylvian regions, and normal neuroimaging. Significance: Seronegative immunotherapy responders exist in epilepsy populations, therefore the diagnosis of autoimmune-associated epilepsy should be considered before proceeding to epilepsy surgery. Possible features of an electroclinical syndrome associated with autoimmunity may include multifocal seizure onset, perisylvian involvement, and normal neuroimaging.

Impact of the first wave of COVID-19 on stroke admissions across three tertiary hospitals in Brisbane.

BACKGROUND: COVID-19 has caused a global shift in healthcare-seeking behaviour; however, presentation rates with serious conditions, such as stroke in low COVID-19-prevalence cities, has received less attention. AIMS: To determine if there was a significant reduction in stroke admissions, delivery of acute reperfusion therapies, or increased delays to presentation during the first wave of the COVID-19 pandemic. METHODS: A multicentre, retrospective, observational cohort study was performed across three tertiary hospitals in Brisbane, Australia. Cases were identified using ICD-10 codes and then individually reviewed for eligibility using prespecified inclusion and exclusion criteria. All metrics were compared over 3 months from 1 March to 31 May 2020 with two corresponding 3-month periods in 2018 and 2019. RESULTS: There was a mean of 2.15 (95% CI 1.87-2.48) stroke admissions per day in the examined pandemic months compared with 2.13 (95% CI 1.85-2.45) and 2.26 (95% CI 1.97-2.59) in March to May 2018 and 2019 respectively, with no significant difference found (P = 0.81). There was also no difference in rates of intravenous thrombolysis (P = 0.82), endovascular thrombectomy (P = 0.93) and time from last known well to presentation (P = 0.54). Conversely, daily emergency department presentations (including non-stroke presentations) significantly reduced (P < 0.0001). CONCLUSIONS: During the early months of the COVID-19 pandemic there was no significant reduction in stroke presentations, use of acute reperfusion therapies or delays to presentation, despite a reduction in ED presentations for any cause. Our results differ from the global experience, with possible explanations, including differences in public health messaging and healthcare infrastructure.

Autoimmune-Associated Seizures.

PURPOSE OF REVIEW: This article focuses on the seizure manifestations and presentations of autoimmune-associated epilepsy and acute symptomatic seizures in autoimmune encephalitis. It discusses the specificity of the various central nervous system autoantibodies and clarifies when their presence can be considered indicative of an immune etiology. Finally, current recommendations regarding patient selection for autoimmune antibody evaluation are reviewed, and an approach to immunotherapy is provided. RECENT FINDINGS: Although autoimmune seizures are caused by a heterogeneous group of autoantibodies, key features reported in the literature should alert clinicians to the possible diagnosis. In particular, seizure characteristics including frequency, timing, duration, and symptomatology can provide vital clues to help differentiate autoimmune-associated seizures from other causes of epilepsy. Diagnostic certainty also requires an understanding and integration of the spectrum of clinical and paraclinical presentations, and several scoring systems have been developed that may be useful to aid the identification of autoimmune seizures. SUMMARY: Seizures due to autoimmune etiology are increasingly encountered in clinical practice. It is critical that clinicians recognize immune seizure etiologies early in their course given they are often responsive to immunotherapy but are usually resistant to antiseizure medications. Currently, however, it is unfortunately not uncommon for autoimmune-associated seizure disorders to remain undiagnosed, resulting in missed opportunities to administer effective therapies. Efforts to better understand autoimmune seizure manifestations and treatment strategies are ongoing.

What déjà vu and the "dreamy state" tell us about episodic memory networks.

Illusions of inappropriate familiarity with the current experience or hallucinatory recall of memories are reported in temporal lobe seizures. Pathophysiological hypotheses have been proposed, involving temporal limbic regions (Hughlings-Jackson), temporal neocortex ("interpretive cortex", Penfield), or both (Bancaud). Recent data acquired from presurgical investigations using intracerebral electrode recordings, demonstrate a critical role for the sub- and para-hippocampal cortices. From this, a novel hypothesis of cortico-limbic networks emerged: déjà-vu results from an abnormal synchronization between rhinal cortices and hippocampus, and reminiscences ("dreamy state") from activation of the associational function of the hippocampus in re-assembling elements of the past experience networks. "Experiential" phenomena are better scrutinized during direct cortical stimulation than during spontaneous occurrence, because it allows precise spatiotemporal correlations to be made between the illusion/hallucination and the electrical discharge features and localization. Therefore, we present a summary of the stimulation data published since Penfield's seminal studies, review the anatomical and physiological correlations of stimulation findings, and question their functional significance. We reappraise the distinct and coactive roles of the various regions involved in perception-memory processes including the hippocampus, rhinal cortices, temporal neocortex and constituent elements of the ventral stream. Additionally, we draw insights from what is known about the perception-cognition continuum underlying the construction of episodic memories. Finally, we compare the results from cortical stimulation in the epileptogenic zone with the use of stimulation for memory enhancement and explore what this reveals about the mechanisms of stimulation.

Discerning the Role of Autoimmunity and Autoantibodies in Epilepsy: A Review.

Importance: The literature on neural autoantibody positivity in epilepsy has expanded over the last decade, with an increased interest among clinicians in identifying potentially treatable causes of otherwise refractory seizures. Observations: Prior studies have reported a wide range of neural autoantibody positivity rates among various epilepsy populations, with the highest frequency reported in individuals with focal epilepsy of unknown cause and new-onset seizures. The antibodies in some cases are of uncertain significance, and their presence can cause conundrums regarding therapy. Conclusions and Relevance: There is likely some role for neural autoantibody assessment in patients with unexplained epilepsy who lack clear evidence of autoimmune encephalitis, but the clinical implications of such testing remain unclear owing to limitations in previous published studies. A framework for study design to bridge the current gaps in knowledge on autoimmune-associated epilepsy is proposed.

Cytokines as a marker of central nervous system autoantibody associated epilepsy.

OBJECTIVE: Autoantibodies to central nervous system (CNS) antigens are increasingly identified in patients with epilepsy. Alterations in cytokines and chemokines have also been demonstrated in epilepsy, but this has not been explored in subjects with autoantibodies. If antibody positive and antibody negative subjects show a difference in immune activation, as measured by cytokine levels, this could improve diagnostic and therapeutic approaches, and provide insights into the underlying pathophysiology. We aimed to evaluate serum and CSF cytokines and chemokines in patients with and without autoantibody positivity to identify any differences between the two groups. METHODS: We studied participants who had undergone serum and CSF testing for CNS autoantibodies, as part of their clinical evaluation. Cases were classified as antibody positive or antibody negative for comparison. Stored CSF and sera were analysed for cytokine and chemokine concentrations. RESULTS: 25 participants underwent testing. 8 were antibody positive, 17 were antibody negative. Significant elevations in the mean concentration of IL-13 and RANTES in CSF were found in the antibody positive cases and significant elevation of CSF VEGF was found in the antibody negative cases. Significant elevations in the mean concentrations of serum TNFß, INFγ, bNGF, IL-8, and IL-12 were seen in the antibody negative group, and there was poor correlation between the majority of serum and CSF concentrations. SIGNIFICANCE: Measurement of cytokines and chemokines such as IL-13 and RANTES could be useful in diagnosis of autoimmune associated epilepsy. Such markers might also guide targeted immunotherapy to improve seizure control and provide insights into the underlying pathophysiology of epilepsy associated with CNS autoantibodies.

Intracranial EEG recording in autoimmune epilepsy dataset.

The appearance of seizures in autoimmune epilepsy on intracranial recordings has not been previously demonstrated. The following data shows a multifocal epilepsy in a patient with seronegative autoimmune epilepsy (reported here; "Electroclinical Insights into Autoimmune Epilepsy", Gillinder, 2019). Independent seizures were seen to arise from 5 separate foci. These all began with slow repetitive spiking in a highly restricted area. Only after many minutes would this activity spread to other regions. Despite arising from different locations, all foci affected the posterior insula resulting in clinical symptoms.

Automatic detection of the epileptogenic zone: An application of the fingerprint of epilepsy.

BACKGROUND: The successful delineation of the epileptogenic zone in epilepsy monitoring is crucial for achieving seizure freedom after epilepsy surgery. NEW METHOD: We aim to improve epileptogenic zone localization by utilizing a computer-assisted tool for the automated grading of the seizure activity recorded in various locations for 20 patients undergoing stereo electroencephalography. Their epileptic seizures were processed to extract two potential biomarkers. The concentration of these biomarkers from within each patient's implantation were then graded to identify their epileptogenic zone and were compared to the clinical assessment. RESULTS: Our technique was capable of ranking the clinically defined epileptogenic zone with high accuracy, above 95%, with a true to false positive ratio of 1:1.52, and was effective with both temporal and extra-temporal onset epilepsies. COMPARISON WITH EXISTING METHOD: We compared our method to two other groups performing localization using similar biomarkers. Our classification metrics, sensitivity and precision together were comparable to both groups and our overall accuracy from a larger population was also higher then both. CONCLUSIONS: Our method is highly accurate, automated and non-parametric providing clinicians another tool that can be used to help identify the epileptogenic zone in patients undergoing the stereo electroencephalography procedure for epilepsy monitoring.

Short burst Clobazam dosing at discharge from VEEG evaluation reduces re-presentation with seizures.

PURPOSE: Recurrent seizures and status epilepticus after medication reduction for inpatient Video Electroencephalograph (VEEG) monitoring is a well-known complication of this investigation. In the literature this is reported to occur at a rate of approximately 3-7%. We review the use of short burst Clobazam dosing on discharge from the Epilepsy monitoring unit (EMU) to determine if this might reduce rates of representation with seizures. METHODS: We performed a retrospective review of all cases admitted to the EMU. Their medication reduction, number of seizures, seizure severity and demographics were collected. Representations to hospital were considered if they occurred within 14 days of discharge from the unit. RESULTS: 264 cases were included, and 146 patients received 5 days of Clobazam 10 mg PO BD upon discharge after VEEG and 118 did not. There were significantly fewer patients re-presenting to hospital for seizures in the 14 days following discharge in those who were administered short-burst Clobazam compared to those who were not (0% and 4.23% respectively). There was also a trend towards fewer re-admissions for non-seizure indications including mental health issues or non-epileptic seizures and AED side effects. There were no definite adverse reactions to Clobazam recorded. CONCLUSION: Short burst Clobazam appears to be a safe and effective means to reduce representation with seizures after medication reduction during VEEG recording. This obviously benefits patients but it may also be a cost-effective means to reduce unnecessary health expenditure.

Electroclinical insights into autoimmune epilepsy.

PURPOSE: Chronic autoimmune epilepsy is an increasingly recognised entity however its clinical and electrographic features remain poorly understood. We present a case undergoing diagnostic Stereo-electroencephalography implantation that was found to have a multifocal perisylvian epilepsy with unique electrographic features and is now seizure free with immunotherapy. METHODS: The patient had antibody negative refractory perisylvian epilepsy and underwent implantation of the perisylvian-temporal networks. Immunomodulatory treatment was administered during SEEG. RESULTS: SEEG demonstrated a multifocal perisylvian epilepsy with strong involvement of the posterior insula. There was almost continuous spiking seen interictally from multiple foci within the right hemisphere and independent seizures were generated from 5 locations. After treatment with intravenous methylprednisone and immunoglobulin during SEEG, spiking and seizures terminated while still off anti-seizure medications. The patient remains seizure free on immunotherapy. CONCLUSION: This case highlights the importance of considering autoimmunity in the differential diagnosis of refractory epilepsy, especially perisylvian epilepsy. It also highlights the need to define a clinical phenotype associated with autoantibodies in epilepsy, as there are likely many cases who are not positive for one of the commercially available tests. This case also provides insights into the possible features of an electroclinical syndrome associated with autoimmunity.

EEG findings in NMDA encephalitis - A systematic review.

PURPOSE: The clinical utility of EEG in cases of NMDA encephalitis is broad with many findings indicating not just epileptiform activity but also encephalopathy and potentially providing insights into pathophysiologic mechanisms of disease. We aimed to determine the frequency of different abnormalities described on EEG and their association with outcome in patients affected by NMDARE through a systematic review of all cases published. METHOD: A systematic literature review of PubMed and Embase of all published cases of anti-NMDA receptor encephalitis with EEG results, was performed from inception to January 2018. RESULTS: A total of 446 cases of anti-NMDA receptor encephalitis with reported EEG findings were identified. 373 EEGs were abnormal, and this strongly correlated with ICU admission and time to recovery (p = 0.014 and 0.04 respectively). ICU admission and recovery were also correlated with delta range abnormalities including extreme delta brush (p = 0.007 and 0.03). Electrographic seizures correlated strongly with clinical seizures (p < 0.0001), however only 39 cases had EEG seizures captured, while there were 294 cases with clinical seizures. CONCLUSIONS: EEG is useful in the clinical management and prognostication of cases on NMDA encephalitis. This is particularly true of certain findings which portend a higher likelihood of ICU admission or poorer outcome and this may assist in the decision to pursue more aggressive treatment options.

Refractory epilepsy secondary to anti-GAD encephalitis treated with DBS post SEEG evaluation: a novel case report based on stimulation findings.

We report a case of medically refractory anti-GAD encephalitis which was treated with deep brain stimulation (DBS) after seizure termination was achieved using cortical stimulation during stereo-electroencephalography (SEEG) evaluation. The patient underwent bilateral SEEG implantation and cortical stimulation. Upon stimulation, mimicking the intrinsic seizures (at 1 Hz), it was possible to induce seizures with typical semiology, on multiple attempts. Stimulation during these seizures with high frequency (50 Hz) resulted in complete termination of the seizure. DBS was inserted after the SEEG evaluation, targeting the bilateral anterior nucleus of the thalamus. There was a sustained reduction in seizure frequency and severity 12 months post insertion. There were also improvements in quality of life. To the best of our knowledge, this is the only case reported in which DBS was successfully used to treat refractory epilepsy in a patient with seizures that were proven to be responsive to electrical stimulation during SEEG recording.