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.

Using pre-surgical suspicion to guide insula implantation strategy.

Rationale: Insular epilepsy can be a challenging diagnosis due to overlapping semiology and scalp EEG findings with frontal, temporal, and parietal lobe epilepsies. Stereotactic electroencephalography (sEEG) provides an opportunity to better localize seizure onset. The possibility of improved localization is balanced by implantation risk in this vascularly rich anatomic region. We review both safety and pre-implantation factors involved in insular electrode placement across four years at an academic medical center. Methods: Presurgical data, operative reports, and invasive EEG summaries were retrospectively reviewed for patients undergoing invasive epilepsy monitoring on the insula from 2016 through 2019. EEG reports were reviewed to record the presence of insula ictal and interictal involvement. We recorded which presurgical findings suggested insular involvement (insula lesion on MRI, insula changes on PET/SPECT/scalp EEG, characteristic semiology, or history of failed anterior temporal lobectomy). The likelihood of pre-sEEG insular onset was categorized as low suspicion if no presurgical findings were present ("rule out"), moderate suspicion if one finding was present, and high suspicion if two or more findings were present. Results: 76 patients received 189 insular electrodes as part of their implantation strategy for 79 surgical cases. Seven patients (8.9%) had insular ictal onset. One clinically significant complication (left hemiparesis) occurred in a patient with moderate suspicion for insular onset. There were 38 low suspicion cases, 36 moderate suspicion cases, and 5 high suspicion cases for pre-sEEG insula ictal onset. Two low suspicion (5.3%), three moderate suspicion (8.6%), and two high suspicion (40%) cases had insular ictal onset. Conclusions: The insula can safely receive sEEG. Having two or more presurgical factors indicating insular onset is a strong, albeit incomplete, predictor of insular seizure onset. Using pre-implantation clinical findings can offer clinicians predictive value for targeting the insula during invasive EEG monitoring.

Beyond Resection: Neuromodulation and Minimally Invasive Epilepsy Surgery.

Epilepsy is a common neurological disease impacting both patients and healthcare systems. Approximately one third of patients have drug-resistant epilepsy (DRE) and are candidates for surgical options. However, only a small percentage undergo surgical treatment due to factors such as patient misconception/fear of surgery, healthcare disparities in epilepsy care, complex presurgical evaluation, primary care knowledge gap, and lack of systemic structures to allow effective coordination between referring physician and surgical epilepsy centers. Resective surgical treatments are superior to medication management for DRE patients in terms of seizure outcomes but may be less palatable to patients. There have been major advancements in minimally invasive surgeries (MIS) and neuromodulation techniques that may allay these concerns. Both epilepsy MIS and neuromodulation have shown promising seizure outcomes while minimizing complications. Minimally invasive methods include Laser Interstitial Thermal Therapy (LITT), RadioFrequency Ablation (RFA), Stereotactic RadioSurgery (SRS). Neuromodulation methods, which are more palliative, include Vagus Nerve Stimulation (VNS), Deep Brain Stimulation (DBS), and Responsive Neurostimulation System (RNS). This review will discuss the role of these techniques in varied epilepsy subtypes, their effectiveness in improving seizure control, and adverse outcomes.

Source-sink connectivity: a novel interictal EEG marker for seizure localization.

Over 15 million epilepsy patients worldwide have drug-resistant epilepsy. Successful surgery is a standard of care treatment but can only be achieved through complete resection or disconnection of the epileptogenic zone, the brain region(s) where seizures originate. Surgical success rates vary between 20% and 80%, because no clinically validated biological markers of the epileptogenic zone exist. Localizing the epileptogenic zone is a costly and time-consuming process, which often requires days to weeks of intracranial EEG (iEEG) monitoring. Clinicians visually inspect iEEG data to identify abnormal activity on individual channels occurring immediately before seizures or spikes that occur interictally (i.e. between seizures). In the end, the clinical standard mainly relies on a small proportion of the iEEG data captured to assist in epileptogenic zone localization (minutes of seizure data versus days of recordings), missing opportunities to leverage these largely ignored interictal data to better diagnose and treat patients. IEEG offers a unique opportunity to observe epileptic cortical network dynamics but waiting for seizures increases patient risks associated with invasive monitoring. In this study, we aimed to leverage interictal iEEG data by developing a new network-based interictal iEEG marker of the epileptogenic zone. We hypothesized that when a patient is not clinically seizing, it is because the epileptogenic zone is inhibited by other regions. We developed an algorithm that identifies two groups of nodes from the interictal iEEG network: those that are continuously inhibiting a set of neighbouring nodes ('sources') and the inhibited nodes themselves ('sinks'). Specifically, patient-specific dynamical network models were estimated from minutes of iEEG and their connectivity properties revealed top sources and sinks in the network, with each node being quantified by source-sink metrics. We validated the algorithm in a retrospective analysis of 65 patients. The source-sink metrics identified epileptogenic regions with 73% accuracy and clinicians agreed with the algorithm in 93% of seizure-free patients. The algorithm was further validated by using the metrics of the annotated epileptogenic zone to predict surgical outcomes. The source-sink metrics predicted outcomes with an accuracy of 79% compared to an accuracy of 43% for clinicians' predictions (surgical success rate of this dataset). In failed outcomes, we identified brain regions with high metrics that were untreated. When compared with high frequency oscillations, the most commonly proposed interictal iEEG feature for epileptogenic zone localization, source-sink metrics outperformed in predictive power (by a factor of 1.2), suggesting they may be an interictal iEEG fingerprint of the epileptogenic zone.

sEEG for expansion of a surgical epilepsy program: Safety and efficacy in 152 consecutive cases.

OBJECTIVE: Stereoelectroencephalography (sEEG) is an intracranial encephalography method of expanding use. The need for increased epilepsy surgery access has led to the consideration of sEEG adoption by new or expanding surgical epilepsy programs. Data regarding safety and efficacy are uncommon outside of high-volume, well-established centers, which may be less applicable to newer or low-volume centers. The objective of this study was to add to the sEEG outcomes in the literature from the perspective of a rapidly expanding center. METHODS: A retrospective chart review of consecutive sEEG cases from January 2016 to December 2019 was performed. Data extraction included demographic data, surgical data, and outcome data, which pertinently examined surgical method, progression to therapeutic procedure, clinically significant adverse events, and Engel outcomes. RESULTS: One hundred and fifty-two sEEG procedures were performed on 131 patients. Procedures averaged 10.5 electrodes for a total of 1603 electrodes. The majority (84%) of patients progressed to a therapeutic procedure. Six clinically significant complications occurred: three retained electrodes, two hemorrhages, and one failure to complete investigation. Only one complication resulted in a permanent deficit. Engel 1 outcome was achieved in 63.3% of patients reaching one-year follow-up after a curative procedure. SIGNIFICANCE: New or expanding epilepsy surgery centers can appropriately consider the use of sEEG. The complication rate is low and the majority of patients progress to therapeutic surgery. Procedural safety, progression to therapeutic intervention, and Engel outcomes are comparable to cohorts from long-established epilepsy surgery programs.

Efficacy and tolerability of olive oil-based ketogenic diet in children with drug-resistant epilepsy: A single center experience from Turkey.

PURPOSE: Ketogenic diet (KD) is an effective non-pharmacological treatment for drug-resistant epilepsy. The aim of this study was to investigate the efficacy, tolerability and complications of olive oil-based KD in epileptic children. METHOD: In this single-center, prospective study, patients were followed up at 1, 3, 6 and 12 months after KD initiation. Initially, blood ketone levels were measured daily, and as needed thereafter to maintain the levels between 4 and 5 mmol/L. Patient demographics, seizure frequency, serum biochemistry, abdominal ultrasonography and adverse effects were recorded. Efficacy of KD was defined as ≥50% seizure reduction. RESULTS: A total of 389 patients with drug-resistant epilepsy receiving KD from 2012 to 2016 were included. One hundred patients (25.7%) stopped the diet for different reasons in the first year, and 369, 314, 225 and 160 patients have been receiving KD treatment for 1, 3, 6 and 12 months, respectively. At 1, 3, 6 and 12th months, 65.8% (243/369), 74.7% (235/314), 70.6% (159/225) and 83.1% (133/160) of the patients were responders, respectively. None of the children had an increased seizure-frequency. Hyperlipidemia (50.8%), selenium deficiency (26.9%), constipation (26.2%), sleep disturbances (20.0%), nephrolithiasis (3.0%), hyperuricemia (3.0) and hepatic side effects (2.6%) were the most common complications of KD. Previous adrenocorticotropic hormone (ACTH) use due to epileptic encephalopathy and presence of constipation at baseline or during KD treatment were found the predictors of treatment efficacy. CONCLUSION: KD is an effective and well-tolerated treatment option for patients with drug-resistant epilepsy. Previous history of ACTH use and constipation during KD treatment are important factors that affect the efficacy of KD treatment.

Preliminary Evidence for Limbic-Frontal Hyperexcitability in Psychogenic Nonepileptic Seizure Patients.

OBJECTIVES: The goal of the current pilot project was to probe the resting-state magnetoencephalography (MEG) in individuals with psychogenic nonepileptic seizures (PNES) and ascertain if there is evidence for frontal temporal cortical hyperexcitability, as evidenced by increased focal coherence in these regions. METHODS: Six patients with PNES and without any evidence of epilepsy were included. Nine healthy control (HC) subjects (age matched as a group) were also included. Subjects underwent 10 minutes of eyes open and 10 minutes of eyes closed MEG recording without any specific cognitive tasks (ie, resting state). RESULTS: Analysis shows posterior-occipital alpha power to be decreased but fronto-temporal delta/theta power increased in people with PNES compared with HC subjects. Analyses of mean interregional functional connectivity of 54 brain regions, patients with PNES tended to have reduced mean coherence in extra-fronto-temporal regions (ex-FTRs) while increased mean coherence in fronto-temporal regions (FTRs) compared with HC. Furthermore, all 6 patients with PNES had their highest coherence structure within the FTRs. This is in contrast to the HC subjects where only 3 of the 9 subjects had their highest coherence value structure in the FTRs (χ2 = 6.67, P = .010). CONCLUSIONS: The above findings are consistent with a disbalance between frontotemporal and posterior brain regions in this population with possible increased excitability in the FTRs. The data support the need for further investigations of the pathophysiology of PNES. The identification of a biomarker for PNES would not only provide for more informed therapeutic approaches, but it could also eliminate the stigma associated with the diagnosis of PNES.

Unexpected Aphasia following Right Temporal Lobectomy as Treatment of Recurrent Super-Refractory Status Epilepticus.

BACKGROUND: Super-refractory status epilepticus (SRSE) is a critical neurological condition with a high mortality rate. There are only limited data to direct the treatment in SRSE, and surgery has been reported to successfully stop SRSE. We present a case of recurrent SRSE treated with urgent right temporal lobectomy in a right-handed woman which potentially saved her life but resulted in crossed sensory aphasia. CASE DESCRIPTION: A 61-year-old woman with a recent episode of prolonged focal SRSE due to right frontotemporal meningioma and hyperkalemia was admitted for recurrence of seizures that evolved to SRSE despite aggressive treatment with multiple fosphenytoin antiepileptic drugs (AEDs) and anesthetics. The patient underwent a right temporal lobectomy to remove the encephalomalacic and gliotic tissue around the meningioma that had been resected during a previous admission. Postoperatively the patient had a protracted course with modest improvement after stepwise reduction in her AEDs; however, her recovery unveiled a severe crossed aphasia. CONCLUSION: Resective surgery is an effective treatment option in the treatment of SRSE, although the recovery period can be protracted. Crossed aphasia after right temporal lobectomy should be considered in patients where it is not possible to complete a presurgical evaluation of higher cortical functions.

Postictal ammonia as a biomarker for electrographic convulsive seizures: A prospective study.

OBJECTIVE: Transient hyperammonemia (THA) was reported to follow generalized convulsions without sufficient evidence to confirm the epileptic nature of those events. We aimed to determine if postictal THA can differentiate between different types of events as confirmed electroencephalographically using video-electroencephalography (vEEG) monitoring. METHODS: In our prospective cohort, we screened all consented adults (>18 years) admitted to the epilepsy monitoring unit. Ammonia was checked at baseline, within 60 min of the event (for all patients) and 24 h after event (whenever possible). Patients were grouped into generalized convulsive seizures (GCS), psychogenic nonepileptic seizures with convulsions (PNES-C), or focal seizures (FS) based on vEEG. Data were analyzed using descriptive statistics and parametric/nonparametric methods. RESULTS: Of 78 patients enrolled, 13 had GCS, 8 had FS, and 9 had PNES-C. The groups were different with regard to gender (p = 0.04) and baseline ammonia (p = 0.02), but not age. The change in ammonia postictally from baseline was significantly different among the three groups (p = 0.004). The area under the receiver operator characteristic (ROC) curve for postictal ammonia to distinguish GCS from other groups was 0.88 (95% confidence interval [CI] 0.69-0.96) suggesting ammonia to be a good test differentiating epileptic GCS from other events. An ammonia level of ≥80 µmol/L correctly classified 80% of our patients (sensitivity 53.9%, specificity 100%). SIGNIFICANCE: Our results provide objective evidence for the association between THA and GCS seizures utilizing vEEG monitoring, and a basis for future studies to determine the role of postictal ammonia as an inexpensive diagnostic test to diagnose GCS.

The effect of olive oil-based ketogenic diet on serum lipid levels in epileptic children.

Ketogenic diet (KD) is one of the most effective therapies for intractable epilepsy. Olive oil is rich in monounsaturated fatty acids and antioxidant molecules and has some beneficial effects on lipid profile, inflammation and oxidant status. The aim of this study was to evaluate the serum lipid levels of children who were receiving olive oil-based KD for intractable seizures at least 1 year. 121 patients (mean age 7.45 ± 4.21 years, 57 girls) were enrolled. At baseline and post-treatment 1, 3, 6, and 12 months body mass index-SDS, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol and triglyceride levels were measured. Repeated measure ANOVA with post hoc Bonferroni correction was used for data analysis. The mean duration of KD was 15.4 ± 4.1 months. Mean total cholesterol, LDL-cholesterol and triglyceride levels were significantly higher at 1st, 3rd, 6th and 12th months of the KD treatment, compared to pre-treatment levels (p = 0.001), but showed no difference among during-treatment measurements. Mean body mass index-SDS and HDL-cholesterol levels were not different among the baseline and follow-up time points (p = 0.113 and p = 0.067, respectively). No child in this study discontinued the KD because of dyslipidemia. Even if rich in olive oil, high-fat KD causes significant increase in LDL-cholesterol and triglyceride levels. More studies are needed to determine the effect of KD on serum lipids in children using different fat sources in the diet.

Intravenous anesthesia in treatment of nonconvulsive status epilepticus: Characteristics and outcomes.

OBJECTIVE: To determine factors associated with continuous anesthetic drug (IVAD) use in nonconvulsive status epilepticus (NCSE). METHODS: Retrospective cohort study of patients who met clinical and EEG criteria of NCSE from 2009 to 2014 at a tertiary academic medical center. Patients were categorized according to IVAD use. Outcome variables were response to treatment and in-hospital death. We used descriptive analyses for baseline characteristics and outcome variable differences among patients who did and did not receive IVAD. RESULTS: Forty-three patients had a total of 45 NCSE episodes. IVAD was used in 69% of the episodes. Patients treated with IVAD were younger (53.1 ± 14.1 vs 64.1 ± 13.3, p = 0.019). The episodes treated with IVAD occurred more frequently in patients with an acute neurologic pathology (58% vs 21%, p = 0.024) and those presenting in a coma (39% vs 7%, p = 0.030). NCSE resolved in 74% of the patients who received IVAD. Duration of NCSE did not differ significantly by treatment group. There were total 13 in-hospital deaths: ten in IVAD users vs three in the no-IVAD group (p > 0.05). Only one in-hospital death appeared to be a direct consequence of IVAD use. Mortality was more common among episodes that were not treated according to the published status epilepticus treatment guidelines compared to the episodes where guidelines were followed. CONCLUSION: Our findings showed that factors such as younger age, acute neurologic pathology and coma at presentation were associated with IVAD use in patients with NCSE. These factors should be controlled in the future outcome and effectiveness studies to determine the effect of IVAD use on outcome of NCSE.

The Short-Term Effects of Ketogenic Diet on Cardiac Ventricular Functions in Epileptic Children.

OBJECTIVE: Our primary aim was to determine the short-term effects of a ketogenic diet on cardiac ventricular function in patients with refractory epilepsy. METHODS: Thirty-eight drug-resistant epileptic patients who were treated with a ketogenic diet were enrolled in this prospective study. Echocardiography was performed on all patients before beginning the ketogenic diet and after the sixth month of therapy. Two-dimensional, M-mode, color flow, spectral Doppler, and pulsed-wave tissue Doppler imaging measurements were performed on all patients. RESULTS: The median age of the 32 patients was 45.5 months, and 22 (57.8%) of them were male. Body weight, height, and body mass index increased significantly at the sixth month of therapy when compared with baseline values (P < 0.05). Baseline variables assessed by conventional M-mode echocardiography showed no significant difference at month 6 (P > 0.05). Doppler flow indices of mitral annulus and tricuspid annulus velocity of patients at baseline and month 6 showed no significant differences (P > 0.05). Tricuspid annular E/A ratio was lower at month 6 (P < 0.05). Although mitral annulus tissue Doppler imaging studies showed no significant difference (P > 0.05), there was a decrease in Ea velocity and Ea/Aa ratio gathered from tricuspid annulus at month 6 compared with baseline (P < 0.05). CONCLUSION: A 6-month duration ketogenic diet does not impair left ventricular functions in children with refractory epilepsy; however, it may be associated with a right ventricular diastolic dysfunction.

The Short-Term Effect of Ketogenic Diet on Carotid Intima-Media Thickness and Elastic Properties of the Carotid Artery and the Aorta in Epileptic Children.

The aim of this prospective study is to investigate the effect of a 6-month-long ketogenic diet on carotid intima-media thickness, carotid artery, and aortic vascular functions. Thirty-eight drug-resistant epileptic patients who were being treated with ketogenic diet were enrolled. Fasting total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, total cholesterol, and glucose concentrations were measured and echocardiography was performed in all patients before the beginning of ketogenic diet and at the sixth month of treatment. The body weight, height, body mass index, serum levels of triglyceride, total cholesterol, and low-density lipoprotein increased significantly at month 6 when compared to baseline values (P < .05). Carotid intima-media thickness, elastic properties of the aorta, and carotid artery did not change at the sixth month of therapy compared to baseline values. A 6-month-long ketogenic diet has no effect on carotid intima-media thickness and elastic properties of the carotid artery and the aorta.

Contingent negative variation is associated with cognitive dysfunction and secondary progressive disease course in multiple sclerosis.

BACKGROUND AND PURPOSE: The relationship between contingent negative variation (CNV), which is an event-related potential, and cognition in multiple sclerosis (MS) has not been examined previously. The primary objective of the present study was thus to determine the association between CNV and cognition in a sample of MS patients. METHODS: The subjects of this study comprised 66 MS patients [50 with relapsing-remitting MS (RRMS) and 16 with secondary progressive MS (SPMS)] and 40 matched healthy volunteers. A neuropsychological battery was administered to all of the subjects; CNV recordings were made from the Cz, Fz, and Pz electrodes, and the amplitude and area under the curve (AUC) were measured at each electrode. RESULTS: RRMS patients exhibited CNVs with lower amplitudes and smaller AUCs than the controls at Pz. SPMS patients exhibited CNVs with lower amplitudes and smaller AUCs than the controls, and CNVs with a smaller amplitude than the RRMS patients at both Cz and Pz. After correcting for multiple comparisons, a lower CNV amplitude at Pz was significantly associated with worse performance on measures of speed of information processing, verbal fluency, verbal learning, and verbal recall. CONCLUSIONS: CNV may serve as a marker for disease progression and cognitive dysfunction in MS. Further studies with larger samples and wider electrode coverage are required to fully assess the value of CNV in these areas.

Consumption of polyphenol plants may slow aging and associated diseases.

Slowing aging is a widely shared goal. Plant-derived polyphenols, which are found in commonly consumed food plants such as tea, cocoa, blueberry and grape, have been proposed to have many health benefits, including slowing aging. In-vivo studies have demonstrated the lifespan-extending ability of six polyphenol-containing plants. These include five widely consumed foods (tea, blueberry, cocoa, apple, pomegranate) and a flower commonly used as a folk medicine (betony). These and multiple other plant polyphenols have been shown to have beneficial effects on aging-associated changes across a variety of organisms from worm and fly to rodent and human.

Putaminal cavernous angioma presenting with hemichorea.

We report on a 63-year-old man presenting with hemichorea on his right side. Magnetic resonance imaging revealed a left putaminal cavernoma. To our knowledge this is the first report of such a case caused by contralateral putaminal cavernous angioma.