Responsive neurostimulation for focal motor status epilepticus.

No clear evidence-based treatment paradigm currently exists for refractory and super-refractory status epilepticus, which can result in significant mortality and morbidity. While patients are typically treated with antiepileptic drugs and anesthetics, neurosurgical neuromodulation techniques can also be considered. We present a novel case in which responsive neurostimulation was used to effectively treat a patient who had developed super-refractory status epilepticus, later consistent with epilepsia partialis continua, that was refractory to antiepileptic drugs, immunomodulatory therapies, and transcranial magnetic stimulation. This case demonstrates how regional therapy provided by responsive neurostimulation can be effective in treating super-refractory status epilepticus through neuromodulation of seizure networks.

Expert Perspective: Who May Benefit Most From the New Ultra Long-Term Subcutaneous EEG Monitoring?

Today's modalities for short-term monitoring of EEG are primarily meant for supporting clinical diagnosis of epilepsy or classifying seizures and interictal epileptiform discharges while long-term EEG adds the value of differential diagnosis investigation or pre-surgical evaluation. However, longitudinal epilepsy care relies on patient diaries, which is known to be unreliable for most patients and especially those with focal impaired awareness or nocturnal seizures. The subcutaneous ultra long-term EEG (ULT-EEG) systems alleviate those issue by enabling objective, continuous EEG monitoring for days, weeks, months, or years. Albeit a great advance in continuous EEG over extended periods, it comes with the caveat of limited spatial resolution of two channels. Therefore, the new subcutaneous EEG modality may be especially suited for a selected group of patients. We convened a panel of experienced epileptologists to consider the utility of a subcutaneous, two-channel ULT-EEG device with the goal of developing a consensus-based expert recommendation on selecting the optimal patient types for this investigative technique. The ideal patients to select for this type of monitoring would have focal impaired awareness seizures without predominant motor features and seizures with medium to high voltage patterns. As this technology matures and we learn more about its limitations and benefits we might find a wider array of use case scenarios as it is believed that the benefits for many patients are most likely to outweigh the risks and cost.

Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy.

OBJECTIVE: To prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years. METHODS: Adults treated with brain-responsive neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL with the Quality of Life in Epilepsy (QOLIE-89) inventory. RESULTS: Of 256 patients treated in the initial trials, 230 participated in the LTT. At 9 years, the median percent reduction in seizure frequency was 75% (p < 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency. We found that 18.4% (47 of 256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-up and an average seizure-free period of 3.2 years (range 1.04-9.6 years). Overall QOL and epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved (p < 0.05). There were no serious AEs related to stimulation, and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators (p < 0.05, 1-tailed χ2). CONCLUSIONS: Adjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS with improved QOL. Stimulation was well tolerated; implantation-related AEs were typical of other neurostimulation devices; and SUDEP rates were low. CLINICALTRIALSGOV IDENTIFIER: NCT00572195. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.

Responsive neurostimulation targeting anterior thalamic nucleus in generalized epilepsy.

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

Radiosurgery versus open surgery for mesial temporal lobe epilepsy: The randomized, controlled ROSE trial.

OBJECTIVE: To compare stereotactic radiosurgery (SRS) versus anterior temporal lobectomy (ATL) for patients with pharmacoresistant unilateral mesial temporal lobe epilepsy (MTLE). METHODS: This randomized, single-blinded, controlled trial recruited adults eligible for open surgery among 14 centers in the USA, UK, and India. Treatment was either SRS at 24 Gy to the 50% isodose targeting mesial structures, or standardized ATL. Outcomes were seizure remission (absence of disabling seizures between 25 and 36 months), verbal memory (VM), and quality of life (QOL) at 36-month follow-up. RESULTS: A total of 58 patients (31 in SRS, 27 in ATL) were treated. Sixteen (52%) SRS and 21 (78%) ATL patients achieved seizure remission (difference between ATL and SRS = 26%, upper 1-sided 95% confidence interval = 46%, P value at the 15% noninferiority margin = .82). Mean VM changes from baseline for 21 English-speaking, dominant-hemisphere patients did not differ between groups; consistent worsening occurred in 36% of SRS and 57% of ATL patients. QOL improved with seizure remission. Adverse events were anticipated cerebral edema and related symptoms for some SRS patients, and cerebritis, subdural hematoma, and others for ATL patients. SIGNIFICANCE: These data suggest that ATL has an advantage over SRS in terms of proportion of seizure remission, and both SRS and ATL appear to have effectiveness and reasonable safety as treatments for MTLE. SRS is an alternative to ATL for patients with contraindications for or with reluctance to undergo open surgery.

Good for sewage treatment and good for agriculture: Algal based compost and biochar.

In this study we test a novel approach to closing the anthropogenic nutrient cycle, by using the freshwater macroalga, Oedogonium intermedium, to recover dissolved nitrogen (N) and phosphorous (P) from municipal wastewater. We then convert this cultivated algae into two types of soil ameliorant; compost and biochar. To produce compost, algae was combined with sugarcane bagasse and left to mature for 10 weeks, and to produce biochar, algae was processed through slow pyrolysis at 450 °C. The mature compost had a total N and P content of 2.5% and 0.6%, which was 2- to 4-times lower than the algal biochar, which had a total N and P content of 5.5% and 2.5% respectively. Composting stabilized the N and P recovered from wastewater, with 80% of the initial N and >99% of the initial P retained in the mature compost. In contrast, only 29% of the initial N and 62% of the initial P was retained in the biochar. When the mature compost was added to a low fertility soil it significantly increased the production of sweet corn (Zea mays). Treatments receiving 50 and 100% compost produced 4-9 times more corn biomass than when synthetic fertilizer alone was added to the low fertility soil. When biochar was applied in conjunction with compost there was an additional 15% increase in corn productivity, most likely due to the ability of the biochar to bind labile N and P and prevent its loss from the soil. This study demonstrates a unique model for recovering N and P from municipal wastewater and recycling these nutrients into the agricultural industry. This could be an ideal model for regional areas where agriculture and water treatment facilities are co-located and could ultimately reduce the reliance of agriculture on finite mineral sources of P.

Brain-responsive neurostimulation in patients with medically intractable seizures arising from eloquent and other neocortical areas.

OBJECTIVE: Evaluate the seizure-reduction response and safety of brain-responsive stimulation in adults with medically intractable partial-onset seizures of neocortical origin. METHODS: Patients with partial seizures of neocortical origin were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. Additional analyses considered safety and seizure reduction according to lobe and functional area (e.g., eloquent cortex) of seizure onset. RESULTS: There were 126 patients with seizures of neocortical onset. The average follow-up was 6.1 implant years. The median percent seizure reduction was 70% in patients with frontal and parietal seizure onsets, 58% in those with temporal neocortical onsets, and 51% in those with multilobar onsets (last observation carried forward [LOCF] analysis). Twenty-six percent of patients experienced at least one seizure-free period of 6 months or longer and 14% experienced at least one seizure-free period of 1 year or longer. Patients with lesions on magnetic resonance imaging (MRI; 77% reduction, LOCF) and those with normal MRI findings (45% reduction, LOCF) benefitted, although the treatment response was more robust in patients with an MRI lesion (p = 0.02, generalized estimating equation [GEE]). There were no differences in the seizure reduction in patients with and without prior epilepsy surgery or vagus nerve stimulation. Stimulation parameters used for treatment did not cause acute or chronic neurologic deficits, even in eloquent cortical areas. The rates of infection (0.017 per patient implant year) and perioperative hemorrhage (0.8%) were not greater than with other neurostimulation devices. SIGNIFICANCE: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including adults with seizures of neocortical onset, and those with onsets from eloquent cortex.

Brain-responsive neurostimulation in patients with medically intractable mesial temporal lobe epilepsy.

OBJECTIVE: Evaluate the seizure-reduction response and safety of mesial temporal lobe (MTL) brain-responsive stimulation in adults with medically intractable partial-onset seizures of mesial temporal lobe origin. METHODS: Subjects with mesial temporal lobe epilepsy (MTLE) were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. RESULTS: There were 111 subjects with MTLE; 72% of subjects had bilateral MTL onsets and 28% had unilateral onsets. Subjects had one to four leads placed; only two leads could be connected to the device. Seventy-six subjects had depth leads only, 29 had both depth and strip leads, and 6 had only strip leads. The mean follow-up was 6.1 ± (standard deviation) 2.2 years. The median percent seizure reduction was 70% (last observation carried forward). Twenty-nine percent of subjects experienced at least one seizure-free period of 6 months or longer, and 15% experienced at least one seizure-free period of 1 year or longer. There was no difference in seizure reduction in subjects with and without mesial temporal sclerosis (MTS), bilateral MTL onsets, prior resection, prior intracranial monitoring, and prior vagus nerve stimulation. In addition, seizure reduction was not dependent on the location of depth leads relative to the hippocampus. The most frequent serious device-related adverse event was soft tissue implant-site infection (overall rate, including events categorized as device-related, uncertain, or not device-related: 0.03 per implant year, which is not greater than with other neurostimulation devices). SIGNIFICANCE: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including patients with unilateral or bilateral MTLE who are not candidates for temporal lobectomy or who have failed a prior MTL resection.

Slow pyrolysis enhances the recovery and reuse of phosphorus and reduces metal leaching from biosolids.

In this study, biochar is produced from biosolids with and without alum at a range of temperatures and simulated oxidative aging of the biochars is conducted to quantify the long-term leaching of P and metals. While biosolids containing alum had negligible amounts of plant-available P, after pyrolysis >90% of the P became immediately available for plant growth. When biosolids with no alum were converted into biochar there was a small increase in the availability of P but a larger pool was available after oxidation. Both of the biosolids leached significant amounts of metals after oxidation. In contrast, the biochars had a very low available metal content and this did not increase with oxidation, demonstrating a stable metal content. Pyrolysis is an effective waste management strategy for biosolids that can simultaneously reduce the leaching of metals and increase the efficiency of recycling of P for beneficial re-use.

Removing constraints on the biomass production of freshwater macroalgae by manipulating water exchange to manage nutrient flux.

Freshwater macroalgae represent a largely overlooked group of phototrophic organisms that could play an important role within an industrial ecology context in both utilising waste nutrients and water and supplying biomass for animal feeds and renewable chemicals and fuels. This study used water from the intensive aquaculture of freshwater fish (Barramundi) to examine how the biomass production rate and protein content of the freshwater macroalga Oedogonium responds to increasing the flux of nutrients and carbon, by either increasing water exchange rates or through the addition of supplementary nitrogen and CO2. Biomass production rates were highest at low flow rates (0.1-1 vol.day-1) using raw pond water. The addition of CO2 to cultures increased biomass production rates by between 2 and 25% with this effect strongest at low water exchange rates. Paradoxically, the addition of nitrogen to cultures decreased productivity, especially at low water exchange rates. The optimal culture of Oedogonium occurred at flow rates of between 0.5-1 vol.day-1, where uptake rates peaked at 1.09 g.m-2.day-1 for nitrogen and 0.13 g.m-2.day-1 for phosphorous. At these flow rates Oedogonium biomass had uptake efficiencies of 75.2% for nitrogen and 22.1% for phosphorous. In this study a nitrogen flux of 1.45 g.m-2.day-1 and a phosphorous flux of 0.6 g.m-2.day-1 was the minimum required to maintain the growth of Oedogonium at 16-17 g DW.m-2.day-1 and a crude protein content of 25%. A simple model of minimum inputs shows that for every gram of dry weight biomass production (g DW.m-2.day-1), Oedogonium requires 0.09 g.m-2.day-1 of nitrogen and 0.04 g.m-2.day-1 of phosphorous to maintain growth without nutrient limitation whilst simultaneously maintaining a high-nutrient uptake rate and efficiency. As such the integrated culture of freshwater macroalgae with aquaculture for the purposes of nutrient recovery is a feasible solution for the bioremediation of wastewater and the supply of a protein resource.

Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: final results of the RNS System Pivotal trial.

OBJECTIVE: To demonstrate the safety and effectiveness of responsive stimulation at the seizure focus as an adjunctive therapy to reduce the frequency of seizures in adults with medically intractable partial onset seizures arising from one or two seizure foci. METHODS: Randomized multicenter double-blinded controlled trial of responsive focal cortical stimulation (RNS System). Subjects with medically intractable partial onset seizures from one or two foci were implanted, and 1 month postimplant were randomized 1:1 to active or sham stimulation. After the fifth postimplant month, all subjects received responsive stimulation in an open label period (OLP) to complete 2 years of postimplant follow-up. RESULTS: All 191 subjects were randomized. The percent change in seizures at the end of the blinded period was -37.9% in the active and -17.3% in the sham stimulation group (p = 0.012, Generalized Estimating Equations). The median percent reduction in seizures in the OLP was 44% at 1 year and 53% at 2 years, which represents a progressive and significant improvement with time (p < 0.0001). The serious adverse event rate was not different between subjects receiving active and sham stimulation. Adverse events were consistent with the known risks of an implanted medical device, seizures, and of other epilepsy treatments. There were no adverse effects on neuropsychological function or mood. SIGNIFICANCE: Responsive stimulation to the seizure focus reduced the frequency of partial-onset seizures acutely, showed improving seizure reduction over time, was well tolerated, and was acceptably safe. The RNS System provides an additional treatment option for patients with medically intractable partial-onset seizures.

Development of new treatment approaches for epilepsy: unmet needs and opportunities.

A working group was created to address clinical "gaps to care" as well as opportunities for development of new treatment approaches for epilepsy. The working group primarily comprised clinicians, trialists, and pharmacologists. The group identified a need for better animal models for both efficacy and tolerability, and noted that animal models for potential disease-modifying or antiepileptogenic effect should mirror conditions in human trials. For antiseizure drugs (ASDs), current animal models have not been validated with respect to their relationship to efficacy in common epilepsy syndromes. The group performed an "expert opinion" survey of perceived efficacy of the available ASDs, and identified a specific unmet need for ASDs to treat tonic-atonic and myoclonic seizures. No correlation has as yet been demonstrated between animal models of tolerability and adverse effects (AEs), versus tolerability in humans. There is a clear opportunity for improved therapies in relation to dose-related AEs. The group identified common and rare epilepsy syndromes that could represent opportunities for clinical trials. They identified opportunities for antiepileptogenic (AEG) therapies in both adults and children, acknowledging that the presence of a biomarker would substantially improve the chances of a successful trial. However, the group acknowledged that disease-modifying therapies (given after the first seizure or after the development of epilepsy) would be easier to study than AEG therapies.

Epilepsy biomarkers.

A biomarker is defined as an objectively measured characteristic of a normal or pathologic biologic process. Identification and proper validation of biomarkers of epileptogenesis (the development of epilepsy) and ictogenesis (the propensity to generate spontaneous seizures) might predict the development of an epilepsy condition; identify the presence and severity of tissue capable of generating spontaneous seizures; measure progression after the condition is established; and determine pharmacoresistance. Such biomarkers could be used to create animal models for more cost-effective screening of potential antiepileptogenic and antiseizure drugs and devices, and to reduce the cost of clinical trials by enriching the trial population, and acting as surrogate markers to shorten trial duration. The objectives of the biomarker subgroup for the London Workshop were to define approaches for identifying possible biomarkers for these purposes. Research to identify reliable biomarkers may also reveal underlying mechanisms that could serve as therapeutic targets for the development of new antiepileptogenic and antiseizure compounds.

Finding a better drug for epilepsy: preclinical screening strategies and experimental trial design.

The antiepileptic drugs (AEDs) introduced during the past two decades have provided several benefits: they offered new treatment options for symptomatic treatment of seizures, improved ease of use and tolerability, and lowered risk for hypersensitivity reactions and detrimental drug-drug interactions. These drugs, however, neither attenuated the problem of drug-refractory epilepsy nor proved capable of preventing or curing the disease. Therefore, new preclinical screening strategies are needed to identify AEDs that target these unmet medical needs. New therapies may derive from novel targets identified on the basis of existing hypotheses for drug-refractory epilepsy and the biology of epileptogenesis; from research on genetics, transcriptomics, and epigenetics; and from mechanisms relevant for other therapy areas. Novel targets should be explored using new preclinical screening strategies, and new technologies should be used to develop medium- to high-throughput screening models. In vivo testing of novel drugs should be performed in models mimicking relevant aspects of drug refractory epilepsy and/or epileptogenesis. To minimize the high attrition rate associated with drug development, which arises mainly from a failure to demonstrate sufficient clinical efficacy of new treatments, it is important to define integrated strategies for preclinical screening and experimental trial design. An important tool will be the discovery and implementation of relevant biomarkers that will facilitate a continuum of proof-of-concept approaches during early clinical testing to rapidly confirm or reject preclinical findings, and thereby lower the risk of the overall development effort. In this review, we overview some of the issues related to these topics and provide examples of new approaches that we hope will be more successful than those used in the past.

Management of epilepsy in drug-resistant patients.

Epilepsy affects > 2 million people in the United States, making it one of the most common neurobiological conditions. Typically, epilepsy is treated with one of several available antiepileptic drugs and patients are able to experience freedom from seizures with minimal side effects. However, there are some patients who do not respond to treatment and require the use of multiple drug combinations or surgical intervention. Although there are few studies supporting its use, multi-drug regimens have been known to be helpful for patients, although clinicians should monitor patients for adverse side effects. Vagus nerve stimulation is the only US Food and Drug Administration-approved surgical neurostimulation therapy for epilepsy, and patients' conditions often progress for many years before epilepsy surgery options are considered. Lastly, due to the chronic nature of epilepsy, clinicians should be aware of the presence of comorbid psychiatric conditions as well. This supplement is Part One in the "Case in Point: Evidence-Based Insights for Epilepsy Management" series. In this Expert Review Supplement, Andrew J. Cole, MD, FRCPC, outlines a case of a patient with drug resistant epilepsy, and Brien J. Smith, MD, outlines the best practices for the case patient including discussion on defining drug resistance in patients as well as the benefits and risks of available and emerging drug and surgical treatments.

Commentary: physical approaches for the treatment of epilepsy: electrical and magnetic stimulation and cooling.

Physical approaches for the treatment of epilepsy currently under study or development include electrical or magnetic brain stimulators and cooling devices, each of which may be implanted or applied externally. Some devices may stimulate peripheral structures, whereas others may be implanted directly into the brain. Stimulation may be delivered chronically, intermittently, or in response to either manual activation or computer-based detection of events of interest. Physical approaches may therefore ultimately be appropriate for seizure prophylaxis by causing a modification of the underlying substrate, presumably with a reduction in the intrinsic excitability of cerebral structures, or for seizure termination, by interfering with the spontaneous discharge of pathological neuronal networks. Clinical trials of device-based therapies are difficult due to ethical issues surrounding device implantation, problems with blinding, potential carryover effects that may occur in crossover designs if substrate modification occurs, and subject heterogeneity. Unresolved issues in the development of physical treatments include optimization of stimulation parameters, identification of the optimal volume of brain to be stimulated, development of adequate power supplies to stimulate the necessary areas, and a determination that stimulation itself does not promote epileptogenesis or adverse long-term effects on normal brain function.

Effects of noninvasive transcutaneous electrical stimulation via concentric ring electrodes on pilocarpine-induced status epilepticus in rats.

PURPOSE: The aim of this pilot study was to investigate the antiepileptic effects of a novel noninvasive stimulation technique, transcutaneous electrical stimulation (TcES) via scalp concentric ring electrodes, on pilocarpine-induced status epilepticus (SE) in rats. METHODS: Five minutes after the onset of SE, TcES was administered to the experimental rat via bipolar concentric ring electrode at the CZ location. Symmetrical, biphasic, charge-balanced, constant current, isolated pulses were applied via a custom-made stimulator. TcES parameters ranged from 200-750 Hz, 200 or 300 mus pulse duration, and 50 or 60 mA, applied for 1 min, started with the least intense parameter set and progressively increased. RESULTS: TcES attenuated electrographic seizure activity and halted the progression of behavioral seizures. Interruption of seizure activity outlasted the period of stimulation and appeared to be long-lasting. TcES treatment significantly extended the life and enhanced the survival of rats after SE. CONCLUSIONS: Noninvasive TcES, applied 5 min after SE onset via novel concentric ring electrodes on the scalp, reduced, or abolished electrographic and behavioral seizure activity in pilocarpine-induced SE in rats. These findings suggest that TcES may have a role in the treatment of SE.