Feasibility study of microburst VNS therapy in drug-resistant focal and generalized epilepsy.

BACKGROUND: Vagus nerve stimulation (VNS) at low frequencies (≤30 Hz) has been an established treatment for drug-resistant epilepsy (DRE) for over 25 years. OBJECTIVE: To examine the initial safety and efficacy performance of an investigational, high-frequency (≥250 Hz) VNS paradigm herein called "Microburst VNS" (µVNS). µVNS consists of short, high-frequency bursts of electrical pulses believed to preferentially modulate certain brain regions. METHODS: Thirty-three (33) participants were enrolled into an exploratory feasibility study, 21 with focal-onset seizures and 12 with generalized-onset seizures. Participants were titrated to a personalized target dose of µVNS using an investigational fMRI protocol. Participants were then followed for up to 12 months, with visits every 3 months, and monitored for side-effects at all time points. This study was registered as NCT03446664 on February 27th, 2018. RESULTS: The device was well-tolerated. Reported adverse events were consistent with typical low frequency VNS outcomes and tended to diminish in severity over time, including dysphonia, cough, dyspnea, and implant site pain. After 12 months of µVNS, the mean seizure frequency reduction for all seizures was 61.3% (median reduction: 70.4%; 90% CI of median: 48.9%-83.3%). The 12-month responder rate (≥50% reduction) was 63.3% (90% CI: 46.7%-77.9%) and the super-responder rate (≥80% reduction) was 40% (90% CI: 25.0%-56.6%). Participants with focal-onset seizures appeared to benefit similarly to participants with generalized-onset seizures (mean reduction in seizures at 12 months: 62.6% focal [n = 19], versus 59.0% generalized [n = 11]). CONCLUSION: Overall, µVNS appears to be safe and potentially a promising therapeutic alternative to traditional VNS. It merits further investigation in randomized controlled trials which will help determine the impact of investigational variables and which patients are most suitable for this novel therapy.

ASCEND: A randomized controlled trial of titration strategies for vagus nerve stimulation in drug-resistant epilepsy.

Vagus Nerve Stimulation (VNS) therapy is widely understood to provide clinically meaningful improvements in seizure control to patients with drug-resistant epilepsy, and has been a staple in the clinical armamentaria available to epileptologists for over 25 years. Despite the long history of evidence-based reviews by neurology professional societies, there is still evidence of a practice gap in VNS titration and dosing that aims to maximize clinical benefit. Recent retrospective analyses have strongly argued for a more consistent application of a population-wide target dose of VNS, and further argued the importance of quickly achieving this target dose to hasten the onset of clinical benefits; however, these analyses failed to provide evidence for practical implementation. Herein, we describe a randomized controlled trial assessing the impact of titrating VNS according to three different protocols to achieve the target dose of 1.5 mA at 500µsec, for a 20-Hz signal frequency. The study was registered as NCT02385526 on March 11, 2015. Sixty-two patients were randomized into treatment groups that followed different titration protocols. One protocol (Group A) was designed to align with currently accepted professional guidance for VNS titration and the manufacturer's labeling for VNS in epilepsy (Heck et al., 2002), while the other two protocols were derived from VNS applications in other therapeutic areas. Group A participants were most likely to achieve the target dose parameters in 12 weeks or less (81.8%), with a median time-until-achievement of the target dose of 8.1 weeks, while less than 60% of patients in other groups were able to achieve the same endpoint. Participants in all groups experienced low levels of transient tolerability concerns and adverse events, suggesting titration to the target dose in 12 weeks or less following the Group A protocol is generally acceptable to most patients. These findings indicate that patients receiving VNS for epilepsy can achieve the manufacturer-recommended dose range in 12 weeks or less. A wider implementation of the approach will likely improve the clinical impact of VNS on seizure control and prevent undertreatment.

COVID-19 Continuous-EEG Case Series: A Descriptive Study.

PURPOSE: Corona virus disease 2019 (COVID-19) refers to coronavirus disease secondary to SARS-CoV2 infection mainly affecting the human respiratory system. The SARS-CoV2 has been reported to have neurotropic and neuroinvasive features and neurological sequalae with wide range of reported neurological manifestations, including cerebrovascular disease, skeletal muscle injury, meningitis, encephalitis, and demyelination, as well as seizures and focal status epilepticus. In this case series, we analyzed the continuous video-EEGs of patients with COVID-19 infection to determine the presence of specific EEG features or epileptogenicity. METHODS: All continuous video-EEG tracings done on SARS-CoV2-positive patients during a 2-week period from April 5, 2020, to April 19, 2020, were reviewed. The demographics, clinical characteristics, imaging, and EEG features were analyzed and presented. RESULTS: Of 23 patients undergoing continuous video-EEG, 16 were COVID positive and were included. Continuous video-EEG monitoring was ordered for "altered mental status" in 11 of 16 patients and for "clinical seizure" in 5 of 16 patients. None of the patients had seizures or status epilepticus as a presenting symptom of COVID-19 infection. Instead, witnessed clinical seizures developed as results of COVID-19-related medical illness(es): anoxic brain injury, stroke/hemorrhage, lithium (Li) toxicity (because of kidney failure), hypertension, and renal disease. Three patients required therapeutic burst suppression because of focal nonconvulsive status epilepticus, status epilepticus/myoclonus secondary to anoxic injury from cardiac arrest, and one for sedation (and with concomitant EEG abnormalities secondary to Li toxicity). CONCLUSIONS: In this observational case series of 16 patients with COVID-19 who were monitored with continuous video-EEG, most patients experienced a nonspecific encephalopathy. Clinical seizures and electrographic status epilepticus were the second most commonly observed neurological problem.

A journey into the unknown: An ethnographic examination of drug-resistant epilepsy treatment and management in the United States.

Patients often recognize unmet needs that can improve patient-provider experiences in disease treatment management. These needs are rarely captured and may be hard to quantify in difficult-to-treat disease states such as drug-resistant epilepsy (DRE). To further understand challenges living with and managing DRE, a team of medical anthropologists conducted ethnographic field assessments with patients to qualitatively understand their experience with DRE across the United States. In addition, healthcare provider assessments were conducted in community clinics and Comprehensive Epilepsy Centers to further uncover patient-provider treatment gaps. We identified four distinct stages of the treatment and management journey defined by patients' perceived control over their epilepsy: Gripped in the Panic Zone, Diligently Tracking to Plan, Riding a Rollercoaster in the Dark, and Reframing Priorities to Redefine Treatment Success. We found that patients sought resources to streamline communication with their care team, enhanced education on treatment options beyond medications, and long-term resources to protect against a decline in control over managing their epilepsy once drug-resistant. Likewise, treatment management optimization strategies are provided to improve current DRE standard of care with respect to identified patient-provider gaps. These include the use of digital disease management tools, standardizing neuropsychiatrists into patients' initial care team, and introducing surgical and non-pharmacological treatment options upon epilepsy and DRE diagnoses, respectively. This ethnographic study uncovers numerous patient-provider gaps, thereby presenting a conceptual framework to advance DRE treatment. Further Incentivization from professional societies and healthcare systems to support standardization of the treatment optimization strategies provided herein into clinical practice is needed.

Primary payer status in patients with seizures: A nationwide study during 1997-2014 in the United States.

OBJECTIVE: In countries where health coverage is not universal, there is ample evidence of disparities in healthcare, often associated with insurance. People with seizures, similar to those living with any complicated chronic medical comorbidity, need further health-related attention to improve their quality-of-life outcomes. METHODS: We conducted a retrospective cohort study of the National Inpatient Sample (NIS) component of the Healthcare Cost and Utilization Project (HCUP) national database between 1997-2014. The analysis focused on the mortality rate, and patients with a principal admission diagnosis of seizure at the time of discharge were identified. Primary Payer Status (PPS) included Medicare, Medicaid, private, and uninsured. Multivariate linear regression modeling was conducted to examine the contribution of the predictive variables to in-hospital mortality. RESULTS: Between 1997-2014, 4,594,213 seizure-related discharges was recorded. The overall mean patient age was 41.69 ± 0.98 years, and 58.1 % were female. The average age during this period decreased significantly in Medicare, increased substantially in uninsured, without significant change in Medicaid and private. Patients in Medicare had the highest length of stay (LOS) (4.49 ± 0.29 days), and uninsured (2.79 ± 0.15) had the least. Over time, there was a significant increase in the number of seizure discharges in Medicare, Medicaid, and private insurance. However, there was a significant decrease in in-hospital mortality in Medicare, Medicaid, and private, with the most prominent decline in Medicare. Risk-adjusted for age, gender, LOS, illness severity, and time, regression results showed Medicare has a significantly higher association with less in-hospital mortality compared with other insurances. CONCLUSIONS: Our study showed a significant increase in the number of seizure diagnoses at discharge in Medicare, Medicaid, and private in the United States between 1997-2014; however, there was a decrease in the in-hospital mortality rate across all insurance payers. Uninsured patients had the highest mortality rate after Medicare without risk justification. Risk-stratified models confirmed Medicare was significantly associated with a less in-hospital mortality rate.

Evolution of the Vagus Nerve Stimulation (VNS) Therapy System Technology for Drug-Resistant Epilepsy.

The vagus nerve stimulation (VNS) Therapy® System is the first FDA-approved medical device therapy for the treatment of drug-resistant epilepsy. Over the past two decades, the technology has evolved through multiple iterations resulting in software-related updates and implantable lead and generator hardware improvements. Healthcare providers today commonly encounter a range of single- and dual-pin generators (models 100, 101, 102, 102R, 103, 104, 105, 106, 1000) and related programming systems (models 250, 3000), all of which have their own subtle, but practical differences. It can therefore be a daunting task to go through the manuals of these implant models for comparison, some of which are not readily available. In this review, we highlight the technological evolution of the VNS Therapy System with respect to device approval milestones and provide a comparison of conventional open-loop vs. the latest closed-loop generator models. Battery longevity projections and an in-depth examination of stimulation mode interactions are also presented to further differentiate amongst generator models.

A case of ictal burst-suppression.

"Burst-suppression" pattern consists of complete attenuation of background between bursts of mixed frequencies, variable morphology and waveforms. It is a subgroup of periodic patterns seen in severe cerebral damage, anesthesia or prematurity. Here, we present a 46-year-old woman with post-anoxic encephalopathy on cooling protocol with two electrographically similar patterns of burst-suppression (one with a clinical ictal correlate of isolated eye movements), as well as three electroclinical seizures. The literature on rare clinical phenomenon of isolated eye movements associated with burst-suppression is reviewed, with the conclusion that the presented case suggests an ictal origin.

Mobile Software as a Medical Device (SaMD) for the Treatment of Epilepsy: Development of Digital Therapeutics Comprising Behavioral and Music-Based Interventions for Neurological Disorders.

Digital health technologies for people with epilepsy (PWE) include internet-based resources and mobile apps for seizure management. Since non-pharmacological interventions, such as listening to specific Mozart's compositions, cognitive therapy, psychosocial and educational interventions were shown to reduce epileptic seizures, these modalities can be integrated into mobile software and delivered by mobile medical apps as digital therapeutics. Herein, we describe: (1) a survey study among PWE about preferences to use mobile software for seizure control, (2) a rationale for developing digital therapies for epilepsy, (3) creation of proof-of-concept mobile software intended for use as an adjunct digital therapeutic to reduce seizures, and (4) broader applications of digital therapeutics for the treatment of epilepsy and other chronic disorders. A questionnaire was used to survey PWE with respect to preferred features in a mobile app for seizure control. Results from the survey suggested that over 90% of responders would be interested in using a mobile app to manage their seizures, while 75% were interested in listening to specific music that can reduce seizures. To define digital therapeutic for the treatment of epilepsy, we designed and created a proof-of-concept mobile software providing digital content intended to reduce seizures. The rationale for all components of such digital therapeutic is described. The resulting web-based app delivered a combination of epilepsy self-care, behavioral interventions, medication reminders and the antiseizure music, such as the Mozart's sonata K.448. To improve long-term patient engagement, integration of mobile medical app with music and multimedia streaming via smartphones, tablets and computers is also discussed. This work aims toward development and regulatory clearance of software as medical device (SaMD) for seizure control, yielding the adjunct digital therapeutic for epilepsy, and subsequently a drug-device combination product together with specific antiseizure medications. Mobile medical apps, music, therapeutic video games and their combinations with prescription medications present new opportunities to integrate pharmacological and non-pharmacological interventions for PWE, as well as those living with other chronic disorders, including depression and pain.

Non ictal onset zone: A window to ictal dynamics.

The focal and network concepts of epilepsy present different aspects of electroclinical phenomenon of seizures. Here, we present a 23-year-old man undergoing surgical evaluation with left fronto-temporal electrocorticography (ECoG) and microelectrode-array (MEA) in the middle temporal gyrus (MTG). We compare action-potential (AP) and local field potentials (LFP) recorded from MEA with ECoG. Seizure onset in the mesial-temporal lobe was characterized by changes in the pattern of AP-firing without clear changes in LFP or ECoG in MTG. This suggests simultaneous analysis of neuronal activity in differing spatial scales and frequency ranges provide complementary insights into how focal and network neurophysiological activity contribute to ictal activity.

Automatic Vagus Nerve Stimulation Triggered by Ictal Tachycardia: Clinical Outcomes and Device Performance--The U.S. E-37 Trial.

OBJECTIVES: The Automatic Stimulation Mode (AutoStim) feature of the Model 106 Vagus Nerve Stimulation (VNS) Therapy System stimulates the left vagus nerve on detecting tachycardia. This study evaluates performance, safety of the AutoStim feature during a 3-5-day Epilepsy Monitoring Unit (EMU) stay and long- term clinical outcomes of the device stimulating in all modes. MATERIALS AND METHODS: The E-37 protocol (NCT01846741) was a prospective, unblinded, U.S. multisite study of the AspireSR(®) in subjects with drug-resistant partial onset seizures and history of ictal tachycardia. VNS Normal and Magnet Modes stimulation were present at all times except during the EMU stay. Outpatient visits at 3, 6, and 12 months tracked seizure frequency, severity, quality of life, and adverse events. RESULTS: Twenty implanted subjects (ages 21-69) experienced 89 seizures in the EMU. 28/38 (73.7%) of complex partial and secondarily generalized seizures exhibited ≥20% increase in heart rate change. 31/89 (34.8%) of seizures were treated by Automatic Stimulation on detection; 19/31 (61.3%) seizures ended during the stimulation with a median time from stimulation onset to seizure end of 35 sec. Mean duty cycle at six-months increased from 11% to 16%. At 12 months, quality of life and seizure severity scores improved, and responder rate was 50%. Common adverse events were dysphonia (n = 7), convulsion (n = 6), and oropharyngeal pain (n = 3). CONCLUSIONS: The Model 106 performed as intended in the study population, was well tolerated and associated with clinical improvement from baseline. The study design did not allow determination of which factors were responsible for improvements.

Termination patterns of complex partial seizures: An intracranial EEG study.

PURPOSE: While seizure onset patterns have been the subject of many reports, there have been few studies of seizure termination. In this study we report the incidence of synchronous and asynchronous termination patterns of partial seizures recorded with intracranial arrays. METHODS: Data were collected from patients with intractable complex partial seizures undergoing presurgical evaluations with intracranial electrodes. Patients with seizures originating from mesial temporal and neocortical regions were grouped into three groups based on patterns of seizure termination: synchronous only (So), asynchronous only (Ao), or mixed (S/A, with both synchronous and asynchronous termination patterns). RESULTS: 88% of the patients in the MT group had seizures with a synchronous pattern of termination exclusively (38%) or mixed (50%). 82% of the NC group had seizures with synchronous pattern of termination exclusively (52%) or mixed (30%). In the NC group, there was a significant difference of the range of seizure durations between So and Ao groups, with Ao exhibiting higher variability. Seizures with synchronous termination had low variability in both groups. CONCLUSIONS: Synchronous seizure termination is a common pattern for complex partials seizures of both mesial temporal or neocortical onset. This may reflect stereotyped network behavior or dynamics at the seizure focus.

Auditory synesthesias.

Synesthesia is experienced when sensory stimulation of one sensory modality (the inducer) elicits an involuntary or automatic sensation in another sensory modality or different aspect of the same sensory modality (the concurrent). Auditory synesthesias (AS) occur when auditory stimuli trigger a variety of concurrents, or when non-auditory sensory stimulations trigger auditory synesthetic perception. The AS are divided into three types: developmental, acquired, and induced. Developmental AS are not a neurologic disorder but a different way of experiencing one's environment. They are involuntary and highly consistent experiences throughout one's life. Acquired AS have been reported in association with neurologic diseases that cause deafferentation of anterior optic pathways, with pathologic lesions affecting the central nervous system (CNS) outside of the optic pathways, as well as non-lesional cases associated with migraine, and epilepsy. It also has been reported with mood disorders as well as a single idiopathic case. Induced AS has been reported in experimental and postsurgical blindfolding, as well as intake of hallucinogenics or psychedelics. In this chapter the three different types of synesthesia, their characteristics, and phenomologic differences, as well as their possible neural mechanisms are discussed.

Therapeutic hypothermia for status epilepticus: A report, historical perspective, and review.

Refractory status epilepticus is a disease associated with high morbidity and mortality, which does not always respond to standard treatments, and when they fail, alternative modalities become crucial. Therapeutic hypothermia slows nerve conduction in vitro, and has been shown to abort seizures in animal models. Therapeutic hypothermia has been experimentally used in humans since 1963 for a variety of intracranial pathologies. More recently there have been multiple reports demonstrating the effectiveness of therapeutic hypothermia in treating refractory status epilepticus. We report a case of super-refractory status epilepticus successfully treated with therapeutic hypothermia, complimented by a historical and literature review of this modality. While there is limited evidence, and some risks associated with therapeutic hypothermia, it should be considered as a reasonable and potentially effective treatment option for refractory status epilepticus.

Update on once-daily zonisamide monotherapy in partial seizures.

Zonisamide is an antiepileptic drug that is structurally different from other antiepileptic agents. Its long half-life, once-daily dosing, lack of induction of hepatic enzymes, and broad spectrum of action makes it a suitable candidate for monotherapy. It has been approved as monotherapy for partial onset epilepsy in Japan and South Korea for more than a decade, and was recently approved as monotherapy in Europe. In the USA, it is only approved by the US Food and Drug Administration for adjunctive treatment of partial onset epilepsy. In this paper, we briefly review the literature on zonisamide monotherapy in partial onset epilepsy with regard to its efficacy, safety, tolerability, and long-term side effects, including a recent noninferiority trial in comparison with extended-release carbamazepine. While European regulatory agencies use noninferiority trials for approval of monotherapy, such a trial design does not meet the current regulatory requirements for approval as monotherapy in the USA.

Lacosamide treatment of juvenile myoclonic epilepsy.

Juvenile myoclonic epilepsy is the most common form of idiopathic generalized epilepsy with onset at puberty or late teenage years. About 80-90% of patients with juvenile myoclonic epilepsy respond to appropriate antiepileptic treatment and achieve seizure freedom, and about 15% of patients become intractable. Valproic acid, levetiracetam, lamotrigine, topiramate and zonisamide are used as first line or adjunctive therapy of this disorder. Lacosamide is approved for adjunctive treatment of partial onset epilepsies. The role of lacosamide in treatment of idiopathic generalized epilepsy including juvenile myoclonic epilepsy is unknown. We present three patients with classic clinical and electrographic features of juvenile myoclonic epilepsy that were maintained on lacosamide (one on monotherapy and two as adjuvant therapy). There were no special pharmacodynamic actions causing exacerbation or worsening of myoclonic jerks or generalized seizures in these three patients. In conclusion, although, the data from our three patients' suggest that lacosamide may be effective in the treatment of juvenile myoclonic epilepsy, larger studies are needed to explore efficacy and role of lacosamide in the treatment of this disorder.

Neurophysiological investigation of idiopathic acquired auditory-visual synesthesia.

We present a case of acquired auditory-visual synesthesia and its neurophysiological investigation in a healthy 42-year-old woman. She started experiencing persistent positive and intermittent negative visual phenomena at age 37 followed by auditory-visual synesthesia. Her neurophysiological investigation included video-EEG, fMRI, and MEG. Auditory stimuli (700 Hz, 50 ms duration, 0.5 s ISI) were presented binaurally at 60 db above the hearing threshold in a dark room. The patient had bilateral symmetrical auditory-evoked neuromagnetic responses followed by an occipital-evoked field 16.3 ms later. The activation of occipital cortex following auditory stimuli may represent recruitment of existing cross-modal sensory pathways.

EEG findings in an adult with severe case of alobar holoprosencephaly.

Holoprosencephaly is a category of congenital brain malformation that is frequently associated with epilepsy. Epileptic spasms and partial seizures are reported with a variety of electrographic ictal and interictal EEG findings. We report a case of severe alobar holoprosencephaly with cortical tissue limited to inferior-anterior-frontal areas and a thin mantle over the posterior areas, and no appreciable connective fibers to the subcortical structures. Interictal EEG consisted mainly of 2-3 Hz irregular delta activity during wakefulness and sleep. Clinical seizures had two different semiologies: (1) epileptic spasms lasting 0.5s during state change and (2) prolonged tonic spasms lasting 5-8s followed by appendicular clonic activity, abnormal nystagmoid eye movements and eye flutter lasting 5-8s. Preceding the epileptic spasms, there was 1-2s of electrodecrement in the EEG. During prolonged tonic spasms there was also electrodecrement in the EEG. No other electrographic activity was seen. Due to lack of any appreciable connecting fibers between cortical and subcortical structures, these findings suggest an increase in brain stem excitability with inefficient (or lack of) cortical modulation as a possible underlying mechanism for epileptic spasms in this patient.