Emerging approaches in neurostimulation for epilepsy.

PURPOSE OF REVIEW: Neurostimulation is a quickly growing treatment approach for epilepsy patients. We summarize recent approaches to provide a perspective on the future of neurostimulation. RECENT FINDINGS: Invasive stimulation for treatment of focal epilepsy includes vagus nerve stimulation, responsive neurostimulation of the cortex and deep brain stimulation of the anterior nucleus of the thalamus. A wide range of other targets have been considered, including centromedian, central lateral and pulvinar thalamic nuclei; medial septum, nucleus accumbens, subthalamic nucleus, cerebellum, fornicodorsocommissure and piriform cortex. Stimulation for generalized onset seizures and mixed epilepsies as well as increased efforts focusing on paediatric populations have emerged. Hardware with more permanently implanted lead options and sensing capabilities is emerging. A wider variety of programming approaches than typically used may improve patient outcomes. Finally, noninvasive brain stimulation with its favourable risk profile offers the potential to treat increasingly diverse epilepsy patients. SUMMARY: Neurostimulation for the treatment of epilepsy is surprisingly varied. Flexibility and reversibility of neurostimulation allows for rapid innovation. There remains a continued need for excitability biomarkers to guide treatment and innovation. Neurostimulation, a part of bioelectronic medicine, offers distinctive benefits as well as unique challenges.

Multimodal approach leads to seizure-freedom in a case of highly refractory drug-resistant focal epilepsy.

Drug-resistant, nonlesional, extratemporal lobe focal epilepsy can be difficult to treat and may require a high degree of multidisciplinary teamwork to localize the seizure onset zone for resective surgery. Here, we describe a patient with longstanding drug-resistant, nonlesional, extratemporal focal epilepsy with a high seizure burden who became seizure-free after prolonged evaluation and eventual left frontal cortical resection. Prior evaluations included magnetoencephalography, invasive video-EEG monitoring, and implantation of a responsive neurostimulation (RNS) device for ongoing intracranial stimulation. Highly sophisticated techniques were utilized including stereotactic localization of prior evaluations to guide repeat stereo-EEG (SEEG), electrical stimulation mapping, SEEG-guided radiofrequency ablation, and awake resection with language and motor mapping using a cognitive testing platform . Incorporating a wide array of data from multiple centers and evaluation time periods was necessary to optimize seizure control and minimize the risk of neurological deficits from surgery.

Practical considerations in epilepsy neurostimulation.

Neuromodulation is a key therapeutic tool for clinicians managing patients with drug-resistant epilepsy. Multiple devices are available with long-term follow-up and real-world experience. The aim of this review is to give a practical summary of available neuromodulation techniques to guide the selection of modalities, focusing on patient selection for devices, common approaches and techniques for initiation of programming, and outpatient management issues. Vagus nerve stimulation (VNS), deep brain stimulation of the anterior nucleus of the thalamus (DBS-ANT), and responsive neurostimulation (RNS) are all supported by randomized controlled trials that show safety and a significant impact on seizure reduction, as well as a suggestion of reduction in the risk of sudden unexplained death in epilepsy (SUDEP). Significant seizure reductions are observed after 3 months for DBS, RNS, and VNS in randomized controlled trials, and efficacy appears to improve with time out to 7 to 10 years of follow-up for all modalities, albeit in uncontrolled follow-up or retrospective studies. A significant number of patients experience seizure-free intervals of 6 months or more with all three modalities. Number and location of epileptogenic foci are important factors affecting efficacy, and together with comorbidities such as severe mood or sleep disorders, may influence the choice of modality. Programming has evolved-DBS is typically initiated at lower current/voltage than used in the pivotal trial, whereas target charge density is lower with RNS, however generalizable optimal parameters are yet to be defined. Noninvasive brain stimulation is an emerging stimulation modality, although it is currently not used widely. In summary, clinical practice has evolved from those established in pivotal trials. Guidance is now available for clinicians who wish to expand their approach, and choice of neuromodulation technique may be tailored to individual patients based on their epilepsy characteristics, risk tolerance, and preferences.

Speech-induced action myoclonus.

BACKGROUND: Speech-induced action myoclonus may occur as a component of a generalized myoclonus syndrome. However, it may also present in isolation, or with a paucity of other findings, and be diagnostically challenging. OBJECTIVES: To report a retrospective case series of restricted speech-induced action myoclonus. METHODS: We reviewed cases of speech-induced action myoclonus evaluated at Mayo Clinic Rochester from 1989 to 2020. We eliminated cases where a more generalized myoclonic disorder was also present. Clinical, imaging, and electrophysiologic data were extracted. RESULTS: Four cases were identified in which speech-induced action myoclonus of craniofacial muscles was the predominant clinical presentation. All described cranial muscle twitching induced by speaking, and two cases also reported speech interruptions. Diagnosis was confirmed by expert speech pathologists in all cases. Diagnostic aids included modulation with different speech tasks and speaking rates, and surface electrophysiology which confirmed craniofacial myoclonus induced by speaking tasks (three cases). Previous misdiagnosis included functional, dystonic, neuromuscular junction pathology, or hemifacial spasm. Two cases had isolated speech-induced myoclonus, and the other two had coexistent upper limb tremor. Potential etiologic factors were identified in three cases - medication (2), epilepsy (1) - while in one patient no cause was identified. One patient partially improved with anti-myoclonic medication and speech therapy. CONCLUSIONS: Speech-induced action myoclonus may occur in isolation and is frequently misdiagnosed. Diagnostic aids include modulation with different speech tasks and speaking rates, and surface electrophysiology.

Markov modelling of treatment response in a 30-year cohort study of newly diagnosed epilepsy.

People with epilepsy have variable and dynamic trajectories in response to antiseizure medications. Accurately modelling long-term treatment response will aid prognostication at the individual level and health resource planning at the societal level. Unfortunately, a robust model is lacking. We aimed to develop a Markov model to predict the probability of future seizure-freedom based on current seizure state and number of antiseizure medication regimens trialled. We included 1795 people with newly diagnosed epilepsy who attended a specialist clinic in Glasgow, Scotland, between July 1982 and October 2012. They were followed up until October 2014 or death. We developed a simple Markov model, based on current seizure state only, and a more detailed model, based on both current seizure state and number of antiseizure medication regimens trialled. Sensitivity analyses were performed for the regimen-based states model to examine the effect of regimen changes due to adverse effects. The model was externally validated in a separate cohort of 455 newly diagnosis epilepsy patients seen in Perth, Australia, between May 1999 and May 2016. Our models suggested that once seizure-freedom was achieved, it was likely to persist, regardless of the number of antiseizure medications trialled to reach that point. The likelihood of achieving long-term seizure-freedom was highest with the first antiseizure medication regimen, at approximately 50%. The chance of achieving seizure-freedom fell with subsequent regimens. Fluctuations between seizure-free and not seizure-free states were highest earlier on but decreased with chronicity of epilepsy. Seizure-freedom/recurrence risk tables were constructed with these probability data, similar to cardiovascular risk tables. Sensitivity analyses showed that the general trends and conclusions from the base model were maintained despite perturbing the model and input data with regimen changes due to adverse effects. Quantitative comparison with the external validation cohort showed excellent consistency at Year 1, good at Year 3 and moderate at Year 5. Quantitative models, as used in this study, can provide pertinent clinical insights that are not apparent from simple statistical analysis alone. Attaining seizure freedom at any time in a patient's epilepsy journey will confer durable benefit. Seizure-freedom risk tables may be used to individualize the prediction of future seizure control trajectory.

The effect of weight reduction surgery on the efficacy and tolerability of epilepsy pharmacotherapy.

BACKGROUND: Bariatric surgery is an increasingly utilized procedure among patients with obesity-related medical complications. The impact of bariatric surgery on seizure frequency and antiseizure drug (ASD) levels are not well described. METHODS: We conducted a retrospective chart review of adult patients with a history of epilepsy or seizures undergoing bariatric surgery for morbid obesity from September 1997-September 2019. The median follow-up was 60 months [range 9-220 months]. RESULTS: Forty-six patients with a history of seizures were identified (38 female); 44 patients had recurrent and unprovoked seizures. Seventeen sets of pre- and post-surgery drug concentrations from 14 patients were reviewed. The median age at surgery was 44 years (range, 19-68). Thirty-three patients were prescribed ASDs at the time of bariatric surgery (median 1 drug [range, 1-3]). Laparoscopic Roux-en-Y was performed in 40 patients, and sleeve gastrectomy in 6 patients. Median pre-surgery weight was 120.75 kg (range, 71-230) and BMI 44.4 kg/m2 (range, 34-77.6). Six months following surgery the median weight was 89.5 kg (range, 58.2-202) and BMI 34.2 kg/m2 (range, 24.5-61.9). Nine patients (19.6%) had a worsening of seizure control on long-term follow-up (median 60, range 9-220 months) following bariatric surgery, including five (10.8%) who suffered seizures within 6 months of bariatric surgery. Five patients developed ASD-associated side effects following bariatric surgery including irritability in two patients (levetiracetam and phenytoin) and one patient each suffering from somnolence (phenytoin), hyperammonemic encephalopathy (sodium valproate), and nausea and vomiting (carbamazepine). Subtherapeutic post-surgery drug concentrations were identified in 5 patients and supratherapeutic concentrations in one patient. In the initial 6 months following surgery, ASD doses were increased in five patients and reduced in five. CONCLUSIONS: The majority of patients with epilepsy who undergo bariatric surgery have no change in seizure frequency. However, a significant minority of patients may experience medication side effects or an increase in seizure tendency due to the impact of bariatric surgery on ASD drug absorption and metabolism leading. Pre- and post-surgical serum concentrations should be measured in patients with seizures or epilepsy receiving ASDs.

Alternating hemiparesis in the context of hemolytic uremic syndrome and COVID-19 positivity.

Hemiparesis has been reported in hemolytic uremic syndrome (HUS), however electrophysiological findings associated with this syndrome have not been well-characterized, and alternating hemiparesis presentations have not been reported. We present detailed electrophysiological and clinical findings in a case of alternating hemiparesis corresponding to alternating focal contralateral delta slowing on prolonged EEG monitoring in a case of HUS with COVID-19 positivity. A 24-year-old woman was admitted with bloody diarrhea, acute kidney injury, and focal seizures initially presumed due to Escherichia coli 0157:H7 Shiga-like toxin-related hemolytic uremic syndrome (ST-HUS). After admission, the patient tested positive for COVID-19. Continuous EEG monitoring revealed diffuse polymorphic delta slowing. Around 24 hours into the admission, the delta slowing became focal in the right hemisphere and was associated with a left hemiparesis. Around three days later, the clinical and EEG pattern reversed, showing left hemisphere slowing and an associated right hemiparesis. Additionally, 14 Hz positive spikes were observed throughout the recording period. Neuroimaging, including CT and MRI, was negative for acute ischemia throughout. The patient subsequently recovered over several days with no residual neurologic abnormalities.

A quantitative analysis of branching, growth cone turning, and directed growth in zebrafish retinotectal axon guidance.

The topographic projection from the eye to the tectum (amphibians and fish)/superior colliculus (birds and mammals) is a paradigm model system for studying mechanisms of neural wiring development. It has previously been proposed that retinal ganglion cell axons use distinct guidance strategies in fish vs. mammals, with direct guidance to the tectal target zone in the former and overshoot followed by biased branching toward the target zone in the latter. Here we visualized individual retinal ganglion cell axons as they grew over the tectum in zebrafish for periods of 10-21 hours and analyzed these results using an array of quantitative measures. We found that, although axons were generally guided directly toward their targets, this occurred without growth cone turning. Instead, axons branched dynamically and profusely throughout pathfinding, and successive branches oriented growth cone extension toward a target zone in a stepwise manner. These data suggest that the guidance strategies used between fish and mammals may be less distinct than previously thought.

A simple model can unify a broad range of phenomena in retinotectal map development.

A paradigm model system for studying the development of patterned connections in the nervous system is the topographic map formed by retinal axons in the optic tectum/superior colliculus. Starting in the 1970s, a series of computational models have been proposed to explain map development in both normal conditions, and perturbed conditions where the retina and/or tectum/superior colliculus are altered. This stands in contrast to more recent models that have often been simpler than older ones, and tend to address more limited data sets, but include more recent genetic manipulations. The original exploration of many of the early models was one-dimensional and limited by the computational resources of the time. This leaves open the ability of these early models to explain both map development in two dimensions, and the genetic manipulation data that have only appeared more recently. In this article, we show that a two-dimensional and updated version of the XBAM model (eXtended Branch Arrow Model), first proposed in 1982, reproduces a range of surgical map manipulations not yet demonstrated by more modern models. A systematic exploration of the parameter space of this model in two dimensions also reveals richer behavior than that apparent from the original one-dimensional versions. Furthermore, we show that including a specific type of axon-axon interaction can account for the map collapse recently observed when particular receptor levels are genetically manipulated in a subset of retinal ganglion cells. Together these results demonstrate that balancing multiple influences on map development seems to be necessary to explain many biological phenomena in retinotectal map formation, and suggest important constraints on the underlying biological variables.

Theoretical models of neural circuit development.

Proper wiring up of the nervous system is critical to the development of organisms capable of complex and adaptable behaviors. Besides the many experimental advances in determining the cellular and molecular machinery that carries out this remarkable task precisely and robustly, theoretical approaches have also proven to be useful tools in analyzing this machinery. A quantitative understanding of these processes can allow us to make predictions, test hypotheses, and appraise established concepts in a new light. Three areas that have been fruitful in this regard are axon guidance, retinotectal mapping, and activity-dependent development. This chapter reviews some of the contributions made by mathematical modeling in these areas, illustrated by important examples of models in each section. For axon guidance, we discuss models of how growth cones respond to their environment, and how this environment can place constraints on growth cone behavior. Retinotectal mapping looks at computational models for how topography can be generated in populations of neurons based on molecular gradients and other mechanisms such as competition. In activity-dependent development, we discuss theoretical approaches largely based on Hebbian synaptic plasticity rules, and how they can generate maps in the visual cortex very similar to those seen in vivo. We show how theoretical approaches have substantially contributed to the advancement of developmental neuroscience, and discuss future directions for mathematical modeling in the field.