Responsive neurostimulation as a treatment for super-refractory focal status epilepticus: a systematic review and case series.

OBJECTIVE: Super-refractory status epilepticus (SRSE) has high rates of morbidity and mortality. Few published studies have investigated neurostimulation treatment options in the setting of SRSE. This systematic literature review and series of 10 cases investigated the safety and efficacy of implanting and activating the responsive neurostimulation (RNS) system acutely during SRSE and discusses the rationale for lead placement and selection of stimulation parameters. METHODS: Through a literature search (of databases and American Epilepsy Society abstracts that were last searched on March 1, 2023) and direct contact with the manufacturer of the RNS system, 10 total cases were identified that utilized RNS acutely during SE (9 SRSE cases and 1 case of refractory SE [RSE]). Nine centers obtained IRB approval for retrospective chart review and completed data collection forms. A tenth case had published data from a case report that were referenced in this study. Data from the collection forms and the published case report were compiled in Excel. RESULTS: All 10 cases presented with focal SE: 9 with SRSE and 1 with RSE. Etiology varied from known lesion (focal cortical dysplasia in 7 cases and recurrent meningioma in 1) to unknown (2 cases, with 1 presenting with new-onset refractory focal SE [NORSE]). Seven of 10 cases exited SRSE after RNS placement and activation, with a time frame ranging from 1 to 27 days. Two patients died of complications due to ongoing SRSE. Another patient's SE never resolved but was subclinical. One of 10 cases had a device-related significant adverse event (trace hemorrhage), which did not require intervention. There was 1 reported recurrence of SE after discharge among the cases in which SRSE resolved up to the defined endpoint. CONCLUSIONS: This case series offers preliminary evidence that RNS is a safe and potentially effective treatment option for SRSE in patients with 1-2 well-defined seizure-onset zone(s) who meet the eligibility criteria for RNS. The unique features of RNS offer multiple benefits in the SRSE setting, including real-time electrocorticography to supplement scalp EEG for monitoring SRSE progress and response to treatment, as well as numerous stimulation options. Further research is indicated to investigate the optimal stimulation settings in this unique clinical scenario.

Mechanisms of Neurostimulation for Epilepsy.

This review discusses the use of neurostimulation therapies for epilepsy treatment, including vagal nerve stimulation, responsive neurostimulation, and deep brain stimulation. Different therapeutic strategies and their underlying mechanisms are explored, with a focus on optimizing parameters for seizure reduction. The review also highlights the paradigm shift toward a more diverse and multimodal approach to deep brain neuromodulation.

Epileptic Seizure Induced by Head-Up Tilt: A Case Series Study.

PURPOSE: Epilepsy and syncope can be difficult to distinguish, with misdiagnosis resulting in unnecessary or incorrect treatment and disability. Combined tilt-table and video EEG (vEEG) testing (tilt-vEEG) is infrequently used to parse these entities even at large centers. Because of the discovery of a rare case of epileptic seizure induced by head-up tilt (HUT) (no prior cases have been published), the authors sought to verify the rarity of this phenomenon. METHODS: An observational, retrospective case series study of all combined tilt-vEEG studies performed at Stanford Health Care over a 2-year period was performed. Studies were grouped into categories: (1) abnormal tilt and normal vEEG; (2) abnormal vEEG and normal tilt; (3) abnormal vEEG and abnormal tilt; (4) normal tilt and normal vEEG, with neurologic symptoms; and (5) normal tilt and normal vEEG without neurologic symptoms. RESULTS: Sixty-eight percent of patients had an abnormal study (categories A-C), with only 3% having both an abnormal tilt and an abnormal EEG (category C). Of these, one patient had a focal epileptic seizure induced by HUT. With HUT positioning, the patient stopped answering questions and vEEG showed a left temporal seizure; systolic blood pressure abruptly dropped to 89 mm Hg (64 mm Hg below baseline); heart rate did not change, but pacemaker showed increased firing (threshold: <60 bpm). CONCLUSIONS: Combined tilt-table and vEEG evaluation was able to identify a previously unreported scenario-head-up tilt provocation of an epileptic seizure-and improve treatment. Combined tilt and vEEG testing should be considered for episodes that persist despite treatment to confirm proper diagnosis.

The Effect of Epilepsy on Sleep Quality During Pregnancy and Postpartum.

OBJECTIVE: This study seeks to understand how sleep is affected in pregnant women with epilepsy (WWE) relative to healthy pregnant women during pregnancy and postpartum and to non-pregnant WWE during comparative time periods. BACKGROUND: Sleep impacts maternal health and mood during pregnancy. Maternal sleep disturbances are related to poor fetal growth and increased fetal deaths. Epilepsy is the most common neurologic condition in pregnancy. Sleep disruption can worsen epileptic seizures. The interplay between epilepsy, pregnancy, and sleep is poorly understood. DESIGN: /Methods: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is an NIH-funded, prospective, observational, multicenter study, enrolling women from December 2012 through January 2016. Sleep quality was assessed utilizing the average Pittsburgh Sleep Quality Index collected during pregnancy; postpartum; or analogous time periods. Sleep scores range from 0 to 21 with higher scores indicating worse sleep quality; scores > 5 are associated with poor sleep quality. RESULTS: Of 351 pregnant WWE, 105 healthy pregnant women, and 109 non-pregnant WWE enrolled in MONEAD, data from 241 pregnant WWE, 74 healthy pregnant women, and 84 non-pregnant WWE were analyzed. Pregnant WWE had worse sleep (higher mean sleep score) during pregnancy compared to healthy pregnant women in unadjusted analysis (p=0.006), but no longer significant in adjusted analysis (p=0.062), pregnant WWE (least square mean sleep score (95% CI) = 5.8 (5.5, 6.1)) vs. healthy pregnant women (5.1 (4.6, 5.7)). During postpartum, pregnant WWE (5.6 (5.4, 5.9)) had similarly impaired sleep compared to healthy pregnant women (5.7 (5.2, 6.2); adjusted p=0.838). Sleep was significantly worse in pregnant WWE vs non-pregnant WWE (for comparable time period) in pregnancy and postpartum in unadjusted and adjusted analyses. Adjusted scores for pregnant WWE in pregnancy (5.7 (5.4, 6.0)) and postpartum (5.7 (5.4, 6.0)) compared to non-pregnant WWE (4.7 (4.2, 5.3); p=0.002) and (4.1 (3.6, 4.7); p<0.001), respectively. Sleep quality between pregnancy and postpartum varied only in healthy pregnant women (change in mean score = 0.8 (0.2, 1.3); p=0.01), whose sleep was worse in postpartum. CONCLUSIONS: Pregnant WWE had worse sleep during pregnancy and postpartum than non-pregnant WWE during comparable periods in the adjusted analysis.The study is registered at clinicaltrials.gov as NCT01730170.

Duration of postictal impaired awareness after bilateral tonic-clonic seizures: EEG and patient characteristics.

OBJECTIVE: Ictal and postictal phenomena that may impact the duration of postictal impaired awareness have not been well studied. Postictal unresponsiveness invariably occurs following bilateral tonic-clonic seizures (BTCS). Bilateral tonic-clonic seizures are a major risk factor for sudden unexpected death in epilepsy (SUDEP). We quantify the effects of seizure characteristics on postictal recovery of awareness following BTCS. Factors include: the total seizure duration, the duration of the tonic phase of a BTCS, presence of postictal generalized EEG suppression (PGES), duration of postictal tonic electromyographic discharge, peri-ictal respiratory dysfunction, patient age, duration of epilepsy, and gender. METHODS: Fifty-eight patients admitted to the epilepsy monitoring unit with BTCS were studied. Forty-one had unilateral onset temporal seizures. The remainder had bitemporal onsets, extratemporal onsets, undetermined onsets, or were generalized at onset. Following the first BTCS, time to initial recovery of awareness and its possible association with patient and seizure characteristics as well as peri-ictal respiratory dysfunction were evaluated. The presence or absence of postictal agitation was noted. RESULTS: The severity of respiratory dysfunction and seizure characteristics were not associated with time to initial recovery of awareness. A shorter time to recovery of awareness was significantly associated with a younger age (p = 0.007). Postictal agitation was more common in males (p = 0.023). SIGNIFICANCE: Focal seizures may impair awareness by active inhibition of subcortical arousal mechanisms. Focal seizures progressing to bilateral tonic-clonic seizures (BTCS) result in further widespread cerebral dysfunction impacting postictal awareness. MRI studies show accelerated brain aging in patients with temporal lobe epilepsy. Our findings suggest that patient age, as a surrogate marker for the lifetime burden of seizures, results in a progressive worsening in time to recovery after BTCS by an increasing negative impact on networks involved in arousal.

Epileptogenic network of focal epilepsies mapped with cortico-cortical evoked potentials.

OBJECTIVE: The goal of this study was to investigate the spatial extent and functional organization of the epileptogenic network through cortico-cortical evoked potentials (CCEPs) in patients being evaluated with intracranial stereoelectroencephalography. METHODS: We retrospectively included 25 patients. We divided the recorded sites into three regions: epileptogenic zone (EZ); propagation zone (PZ); and noninvolved zone (NIZ). The root mean square of the amplitudes was calculated to reconstruct effective connectivity network. We also analyzed the N1/N2 amplitudes to explore the responsiveness influenced by epileptogenicity. Prognostic analysis was performed by comparing intra-region and inter-region connectivity between seizure-free and non-seizure-free groups. RESULTS: Our results confirmed that stimulation of the EZ caused the strongest responses on other sites within and outside the EZ. Moreover, we found a hierarchical connectivity pattern showing the highest connectivity strength within EZ, and decreasing connectivity gradient from EZ, PZ to NIZ. Prognostic analysis indicated a stronger intra-EZ connection in the seizure-free group. CONCLUSION: The EZ showed highest excitability and dominantly influenced other regions. Quantitative CCEPs can be useful in mapping epileptic networks and predicting surgical outcome. SIGNIFICANCE: The generated computational connectivity model may enhance our understanding of epileptogenic networks and provide useful information for surgical planning and prognosis prediction.

Status epilepticus and other EEG findings in patients with COVID-19: A case series.

PURPOSE: Neurological manifestations of COVID-19 infection include impaired consciousness, strokes, and seizures. Limited reports describing EEG abnormalities in patients with COVID-19 have been published. These articles reported nonspecific encephalopathic patterns, epileptiform discharges, and rarely seizures. Our primary aim was to assess EEG abnormalities in patients with COVID-19 and evaluate for epileptiform activity or seizures. METHODS: We identified five critically ill adult patients with COVID-19 who underwent EEG monitoring. All patients had Ceribell™ rapid response EEG initially and two continued with conventional long-term video EEG. RESULTS: All 5 patients had encephalopathy and 3 also had seizure-like movements, thus prompting EEG monitoring. EEGs all showed nonspecific markers of encephalopathy including diffuse slowing and generalized rhythmic delta activity. Two also had epileptiform discharges reaching 2-3 Hz at times, with one patient in nonconvulsive status epilepticus and the other developing clinical status epilepticus with myoclonic movements. EEG and clinical symptoms improved with anti-seizure medications. CONCLUSION: Status epilepticus was present in 2 out of our cohort of 5 critically ill patients who underwent EEG monitoring. These findings highlight the importance of EEG monitoring in high-risk patients with COVID-19 and encephalopathy. EEG recordings in such patients can identify pathological patterns that will benefit from treatment with anti-seizure medications.

Long-lasting hyperpolarization underlies seizure reduction by low frequency deep brain electrical stimulation.

Mesial temporal lobe epilepsy (MTLE) is a common medically refractory neurological disease. Deep brain electrical stimulation (DBS) of grey matter has been used for MTLE with limited success. However, stimulation of a white matter tract connecting the hippocampi, the ventral hippocampal commissure (VHC), with low frequencies that simulate interictal discharges has shown promising results, with seizure reduction greater than 98% in bilateral hippocampi during stimulation and greater than 50% seizure reduction in bilateral hippocampi after treatment. A major hurdle to the implementation and optimization of this treatment is that the mechanisms of seizure reduction by low frequency electrical stimulation (LFS) are not known. The goal of this study is to understand how commissural fibre tract stimulation reduces bilateral hippocampal epileptic activity in an in vitro slice preparation containing bilateral hippocampi connected by the VHC. It is our hypothesis that electrical stimuli induce hyperpolarization lasting hundreds of milliseconds following each pulse which reduces spontaneous epileptic activity during each inter-stimulus interval (ISI). Stimulus-induced long-lasting-hyperpolarization (LLH) can be mediated by GABA(B) inhibitory post-synaptic potentials (IPSPs) or slow after-hyperpolarization (sAHP). To test the role of LLH in effective bilateral seizure reduction by fibre tract stimulation, we measured stimulus-induced hyperpolarization during LFS of the VHC using electrophysiology techniques. Antagonism of the GABA(B) IPSP and/or sAHP diminished stimulus-induced hyperpolarization concurrently with LFS efficacy (greater than 50% reduction). Blocking both the GABA(B) IPSP and sAHP simultaneously eliminated the effect of electrical stimulation on seizure reduction entirely. These data show that LFS of the VHC is an effective protocol for bilateral hippocampal seizure reduction and that its efficacy relies on the induction of long-lasting hyperpolarization mediated through GABA(B) IPSPs and sAHP. Based on this study, optimization of the timing of LFS and LFS-induced-LLH may lead to improved outcomes from DBS treatments for human epilepsy.

Fiber tract stimulation can reduce epileptiform activity in an in-vitro bilateral hippocampal slice preparation.

Mesial temporal lobe epilepsy (MTLE) is a common medically refractory neurological disease that has been treated with electrical stimulation of gray matter with limited success. However, stimulation of a white matter tract connecting the hippocampi could maximize treatment efficacy and extent. We tested low-frequency stimulation (LFS) of a novel target that enables simultaneous targeting of bilateral hippocampi: the ventral hippocampal commissure (VHC) with a novel in-vitro slice preparation containing bilateral hippocampi connected by the VHC. The goal of this study is to understand the role of hippocampal interplay in seizure propagation and reduction by commissural fiber tract stimulation. LFS is applied to the VHC as extracellular and intracellular recording techniques are combined with signal processing to estimate several metrics of epilepsy including: (1) total time occupied by seizure activity (%); (2) seizure duration (s); (3) seizures per minute (#); and (4) power in the ictal (V(2)Hz(-1)); as well as (5) interictal spectra (V(2)Hz(-1)). Bilateral epileptiform activity in this preparation is highly correlated between hippocampi. Application of LFS to the VHC reduces all metrics of epilepsy during treatment in an amplitude and frequency dependent manner. This study lends several insights into the mechanisms of bilateral seizure reduction by LFS of the VHC, including that depolarization blocking, LTD/LTP and GABA(A) are not involved. Importantly, enhanced post-stimulation 1-Hz spiking correlates with long-lasting seizure reduction and both are heightened by targeting bilateral hippocampi via the VHC. Therefore, stimulating bilateral hippocampi via a single electrode in the VHC may provide an effective MTLE treatment.