Neuromodulation for Drug-Resistant Epilepsy

Emerging Trends in Neuromodulation for Treatment of Drug-Resistant Epilepsy

• Epilepsy affects over 70 million people globally and a significant proportion is resistant to anti-epileptic drugs.

• Neuromodulation has emerged as a pivotal alternative in the management of drug-resistant epilepsy for patients who are not candidates for resection or ablation.

• Candidates for neuromodulation include those who have seizure foci involving the eloquent cortex, decline traditional surgical resection, have multifocal or generalized epilepsy, or have continued seizures despite resection/ablation.

• Trigeminal Nerve Stimulation (TNS) is a non-invasive, transcutaneous stimulation modality for medication-resistant epilepsy with strong evidence for safety and efficacy.

• Vagus Nerve Stimulation (VNS) has been shown to significantly reduce seizures in patients with drug-resistant epilepsy and recent advancements in VNS technology have allowed for the utilization of a closed loop stimulation approach using a heart rate-based seizure detection algorithm.

• Responsive Neurostimulation (RNS) is a closed-loop neuromodulation system that initiates stimulation in response to the detection of an epileptic event electrographically and has demonstrated a 75% median seizure reduction in patients with intractable focal onset epilepsy.

• Deep Brain Stimulation (DBS) has been shown to reduce seizures in patients with drug-resistant epilepsy and studies have highlighted the role of astrocyte activation in DBS by inducing local neuronal modulation.

• The SANTE trial demonstrated the safety and efficacy of DBS in the anterior nucleus of thalamus stimulation for epilepsy and demonstrated continued improvement of efficacy over time.

• The thalamus is a key subcortical structure implicated in the epilepsy network, making various nuclei desirable targets for neuromodulatory techniques.

• The etiology of refractory epilepsy is complex and the prevalence of epilepsy in the general population is estimated to be ∼0.5–1%, with 30% of these patients being resistant to medical therapy.

• TNS, VNS, RNS, and DBS are all viable options for refractory epilepsy with varying degrees of efficacy and safety.

• Neuromodulation techniques involve directly stimulating or impeding neuronal action potential conduction through various mechanisms, including chemical, mechanical, thermal, optogenetic, magnetic, and electrical manipulation, with electrical stimulation being the most widely used.Neuromodulatory Trends for Intractable Epilepsy: Thalamic Stimulation Targets

• Deep Brain Stimulation (DBS) was initially used as a diagnostic intervention to confirm target areas prior to lesioning.

• DBS is now a widely used therapeutic intervention for conditions such as essential tremor, Parkinson's disease, and pain.

• DBS has been approved by the FDA for patients with refractory partial-onset seizures, with and without generalization, who are 18 years of age or older.

• DBS is contraindicated in patients who are incapable of operating the neurostimulator, have significant psychiatric contraindications, or are medically frail and unable to undergo surgical implantation.

• The anti-epileptic mechanisms of DBS are largely unknown and complex, with proposed mechanisms including inhibition and activation of GABAergic neurons.

• The thalamus is a sensory relay center with widespread synaptic connectivity to many cortical regions and plays a role in the propagation of abnormal epileptiform activity.

• The anterior nucleus of the thalamus (ANT) is a key component of the Papez Circuit, whose role in seizure propagation has been extensively explored.

• Direct electrical stimulation of the thalamus allows for modulation of neural circuitry and ultimately interferes with seizure propagation.

• The centromedian nucleus (CM) is a desirable target for neuromodulation due to its connectivity with the anterior cingulate gyrus, which is part of the Papez Circuit and implicated in seizure propagation.

• The median pulvinar thalamic nucleus is a novel promising target for DBS in epilepsy patients.

• Responsive Neurostimulation (RNS) of the pulvinar was successful in treating posterior quadrant epilepsy.

• Combined open and closed loop DBS and RNS have been studied in rodent models and in a single case study in a patient, showing potential for future neuromodulatory systems.Neuromodulatory Trends for Intractable Epilepsy

• Neuromodulatory techniques have had significant success in treating epilepsy in patients who are refractory to medication or not suitable for traditional resective or ablative surgery.

• Modulation of various thalamic nuclei, through open and closed loop systems, is an effective and safe option for these patients.

• Open loop anterior thalamic nucleus (ANT) stimulation is the most established target for epilepsy.

• Concurrent stimulation of multiple thalamic nuclei on seizure frequency is not well studied.

• Closed loop stimulation carries a lower burden of stimulation, fewer stimulation related side effects, fewer cognitive and mood disruptions, and records chronic ambulatory EEG data.

• Closed loop stimulation is useful in measuring seizure burden in response to changes in antiepileptic medications, behavior modification, and in characterizing neurobehavioral spells.

• Open loop stimulation lacks the capability to personalize therapy.

• Closed loop stimulation has the ability to provide a more personalized approach to care by configuring stimulation in response to the patient’s specific needs and epileptic activity.

• Treatment decision making should be guided by patient specific factors.

• Closed loop stimulation is limited by our current insufficient understanding of optimal stimulation parameters and electrode selection, which prevents maximal efficacy.

• Future larger scale studies are needed to draw substantial conclusions on the effects of stimulation of more than one thalamic nucleus on seizure control.

• Neuromodulatory techniques have the potential to significantly improve the quality of life for patients with medically resistant epilepsy.Neuromodulatory Trends for Intractable Epilepsy

• Stimulation and neuromodulation are effective treatment options for epilepsy.

• Vagus nerve stimulation (VNS) is a commonly used method for epilepsy treatment.

• Long-term treatment with VNS has been shown to reduce seizure frequency.

• Closed-loop VNS is a newer technology that may improve efficacy and reduce side effects.

• Trigeminal nerve stimulation (TNS) is a promising alternative to VNS.

• TNS has been shown to reduce seizure frequency in some patients with refractory epilepsy.

• Deep brain stimulation (DBS) of the thalamus is another option for epilepsy treatment.

• DBS of the anterior nucleus of the thalamus (ANT) has been shown to reduce seizure frequency in some patients.

• DBS of the centromedian nucleus (CM) and medial pulvinar (MP) are newer targets for epilepsy treatment.

• Responsive neurostimulation (RNS) is a newer technology that detects and responds to seizure activity in real-time.

• RNS has been shown to reduce seizure frequency in some patients with refractory epilepsy.

• Further research is needed to fully understand the mechanisms and efficacy of these neuromodulatory treatments for epilepsy.

Emerging Trends in Neuromodulation for Treatment of Drug-Resistant Epilepsy

• Epilepsy affects over 70 million people globally and a significant proportion is resistant to anti-epileptic drugs.

• Neuromodulation has emerged as a pivotal alternative in the management of drug-resistant epilepsy for patients who are not candidates for resection or ablation.

• Candidates for neuromodulation include those who have seizure foci involving the eloquent cortex, decline traditional surgical resection, have multifocal or generalized epilepsy, or have continued seizures despite resection/ablation.

• Trigeminal Nerve Stimulation (TNS) is a non-invasive, transcutaneous stimulation modality for medication-resistant epilepsy with strong evidence for safety and efficacy.

• Vagus Nerve Stimulation (VNS) has been shown to significantly reduce seizures in patients with drug-resistant epilepsy and recent advancements in VNS technology have allowed for the utilization of a closed loop stimulation approach using a heart rate-based seizure detection algorithm.

• Responsive Neurostimulation (RNS) is a closed-loop neuromodulation system that initiates stimulation in response to the detection of an epileptic event electrographically and has demonstrated a 75% median seizure reduction in patients with intractable focal onset epilepsy.

• Deep Brain Stimulation (DBS) has been shown to reduce seizures in patients with drug-resistant epilepsy and studies have highlighted the role of astrocyte activation in DBS by inducing local neuronal modulation.

• The SANTE trial demonstrated the safety and efficacy of DBS in the anterior nucleus of thalamus stimulation for epilepsy and demonstrated continued improvement of efficacy over time.

• The thalamus is a key subcortical structure implicated in the epilepsy network, making various nuclei desirable targets for neuromodulatory techniques.

• The etiology of refractory epilepsy is complex and the prevalence of epilepsy in the general population is estimated to be ∼0.5–1%, with 30% of these patients being resistant to medical therapy.

• TNS, VNS, RNS, and DBS are all viable options for refractory epilepsy with varying degrees of efficacy and safety.

• Neuromodulation techniques involve directly stimulating or impeding neuronal action potential conduction through various mechanisms, including chemical, mechanical, thermal, optogenetic, magnetic, and electrical manipulation, with electrical stimulation being the most widely used.Neuromodulatory Trends for Intractable Epilepsy: Thalamic Stimulation Targets

• Deep Brain Stimulation (DBS) was initially used as a diagnostic intervention to confirm target areas prior to lesioning.

• DBS is now a widely used therapeutic intervention for conditions such as essential tremor, Parkinson's disease, and pain.

• DBS has been approved by the FDA for patients with refractory partial-onset seizures, with and without generalization, who are 18 years of age or older.

• DBS is contraindicated in patients who are incapable of operating the neurostimulator, have significant psychiatric contraindications, or are medically frail and unable to undergo surgical implantation.

• The anti-epileptic mechanisms of DBS are largely unknown and complex, with proposed mechanisms including inhibition and activation of GABAergic neurons.

• The thalamus is a sensory relay center with widespread synaptic connectivity to many cortical regions and plays a role in the propagation of abnormal epileptiform activity.

• The anterior nucleus of the thalamus (ANT) is a key component of the Papez Circuit, whose role in seizure propagation has been extensively explored.

• Direct electrical stimulation of the thalamus allows for modulation of neural circuitry and ultimately interferes with seizure propagation.

• The centromedian nucleus (CM) is a desirable target for neuromodulation due to its connectivity with the anterior cingulate gyrus, which is part of the Papez Circuit and implicated in seizure propagation.

• The median pulvinar thalamic nucleus is a novel promising target for DBS in epilepsy patients.

• Responsive Neurostimulation (RNS) of the pulvinar was successful in treating posterior quadrant epilepsy.

• Combined open and closed loop DBS and RNS have been studied in rodent models and in a single case study in a patient, showing potential for future neuromodulatory systems.Neuromodulatory Trends for Intractable Epilepsy

• Neuromodulatory techniques have had significant success in treating epilepsy in patients who are refractory to medication or not suitable for traditional resective or ablative surgery.

• Modulation of various thalamic nuclei, through open and closed loop systems, is an effective and safe option for these patients.

• Open loop anterior thalamic nucleus (ANT) stimulation is the most established target for epilepsy.

• Concurrent stimulation of multiple thalamic nuclei on seizure frequency is not well studied.

• Closed loop stimulation carries a lower burden of stimulation, fewer stimulation related side effects, fewer cognitive and mood disruptions, and records chronic ambulatory EEG data.

• Closed loop stimulation is useful in measuring seizure burden in response to changes in antiepileptic medications, behavior modification, and in characterizing neurobehavioral spells.

• Open loop stimulation lacks the capability to personalize therapy.

• Closed loop stimulation has the ability to provide a more personalized approach to care by configuring stimulation in response to the patient’s specific needs and epileptic activity.

• Treatment decision making should be guided by patient specific factors.

• Closed loop stimulation is limited by our current insufficient understanding of optimal stimulation parameters and electrode selection, which prevents maximal efficacy.

• Future larger scale studies are needed to draw substantial conclusions on the effects of stimulation of more than one thalamic nucleus on seizure control.

• Neuromodulatory techniques have the potential to significantly improve the quality of life for patients with medically resistant epilepsy.Neuromodulatory Trends for Intractable Epilepsy

• Stimulation and neuromodulation are effective treatment options for epilepsy.

• Vagus nerve stimulation (VNS) is a commonly used method for epilepsy treatment.

• Long-term treatment with VNS has been shown to reduce seizure frequency.

• Closed-loop VNS is a newer technology that may improve efficacy and reduce side effects.

• Trigeminal nerve stimulation (TNS) is a promising alternative to VNS.

• TNS has been shown to reduce seizure frequency in some patients with refractory epilepsy.

• Deep brain stimulation (DBS) of the thalamus is another option for epilepsy treatment.

• DBS of the anterior nucleus of the thalamus (ANT) has been shown to reduce seizure frequency in some patients.

• DBS of the centromedian nucleus (CM) and medial pulvinar (MP) are newer targets for epilepsy treatment.

• Responsive neurostimulation (RNS) is a newer technology that detects and responds to seizure activity in real-time.

• RNS has been shown to reduce seizure frequency in some patients with refractory epilepsy.

• Further research is needed to fully understand the mechanisms and efficacy of these neuromodulatory treatments for epilepsy.

Emerging Trends in Neuromodulation for Treatment of Drug-Resistant Epilepsy

• Epilepsy affects over 70 million people globally and a significant proportion is resistant to anti-epileptic drugs.

• Neuromodulation has emerged as a pivotal alternative in the management of drug-resistant epilepsy for patients who are not candidates for resection or ablation.

• Candidates for neuromodulation include those who have seizure foci involving the eloquent cortex, decline traditional surgical resection, have multifocal or generalized epilepsy, or have continued seizures despite resection/ablation.

• Trigeminal Nerve Stimulation (TNS) is a non-invasive, transcutaneous stimulation modality for medication-resistant epilepsy with strong evidence for safety and efficacy.

• Vagus Nerve Stimulation (VNS) has been shown to significantly reduce seizures in patients with drug-resistant epilepsy and recent advancements in VNS technology have allowed for the utilization of a closed loop stimulation approach using a heart rate-based seizure detection algorithm.

• Responsive Neurostimulation (RNS) is a closed-loop neuromodulation system that initiates stimulation in response to the detection of an epileptic event electrographically and has demonstrated a 75% median seizure reduction in patients with intractable focal onset epilepsy.

• Deep Brain Stimulation (DBS) has been shown to reduce seizures in patients with drug-resistant epilepsy and studies have highlighted the role of astrocyte activation in DBS by inducing local neuronal modulation.

• The SANTE trial demonstrated the safety and efficacy of DBS in the anterior nucleus of thalamus stimulation for epilepsy and demonstrated continued improvement of efficacy over time.

• The thalamus is a key subcortical structure implicated in the epilepsy network, making various nuclei desirable targets for neuromodulatory techniques.

• The etiology of refractory epilepsy is complex and the prevalence of epilepsy in the general population is estimated to be ∼0.5–1%, with 30% of these patients being resistant to medical therapy.

• TNS, VNS, RNS, and DBS are all viable options for refractory epilepsy with varying degrees of efficacy and safety.

• Neuromodulation techniques involve directly stimulating or impeding neuronal action potential conduction through various mechanisms, including chemical, mechanical, thermal, optogenetic, magnetic, and electrical manipulation, with electrical stimulation being the most widely used.Neuromodulatory Trends for Intractable Epilepsy: Thalamic Stimulation Targets

• Deep Brain Stimulation (DBS) was initially used as a diagnostic intervention to confirm target areas prior to lesioning.

• DBS is now a widely used therapeutic intervention for conditions such as essential tremor, Parkinson's disease, and pain.

• DBS has been approved by the FDA for patients with refractory partial-onset seizures, with and without generalization, who are 18 years of age or older.

• DBS is contraindicated in patients who are incapable of operating the neurostimulator, have significant psychiatric contraindications, or are medically frail and unable to undergo surgical implantation.

• The anti-epileptic mechanisms of DBS are largely unknown and complex, with proposed mechanisms including inhibition and activation of GABAergic neurons.

• The thalamus is a sensory relay center with widespread synaptic connectivity to many cortical regions and plays a role in the propagation of abnormal epileptiform activity.

• The anterior nucleus of the thalamus (ANT) is a key component of the Papez Circuit, whose role in seizure propagation has been extensively explored.

• Direct electrical stimulation of the thalamus allows for modulation of neural circuitry and ultimately interferes with seizure propagation.

• The centromedian nucleus (CM) is a desirable target for neuromodulation due to its connectivity with the anterior cingulate gyrus, which is part of the Papez Circuit and implicated in seizure propagation.

• The median pulvinar thalamic nucleus is a novel promising target for DBS in epilepsy patients.

• Responsive Neurostimulation (RNS) of the pulvinar was successful in treating posterior quadrant epilepsy.

• Combined open and closed loop DBS and RNS have been studied in rodent models and in a single case study in a patient, showing potential for future neuromodulatory systems.Neuromodulatory Trends for Intractable Epilepsy

• Neuromodulatory techniques have had significant success in treating epilepsy in patients who are refractory to medication or not suitable for traditional resective or ablative surgery.

• Modulation of various thalamic nuclei, through open and closed loop systems, is an effective and safe option for these patients.

• Open loop anterior thalamic nucleus (ANT) stimulation is the most established target for epilepsy.

• Concurrent stimulation of multiple thalamic nuclei on seizure frequency is not well studied.

• Closed loop stimulation carries a lower burden of stimulation, fewer stimulation related side effects, fewer cognitive and mood disruptions, and records chronic ambulatory EEG data.

• Closed loop stimulation is useful in measuring seizure burden in response to changes in antiepileptic medications, behavior modification, and in characterizing neurobehavioral spells.

• Open loop stimulation lacks the capability to personalize therapy.

• Closed loop stimulation has the ability to provide a more personalized approach to care by configuring stimulation in response to the patient’s specific needs and epileptic activity.

• Treatment decision making should be guided by patient specific factors.

• Closed loop stimulation is limited by our current insufficient understanding of optimal stimulation parameters and electrode selection, which prevents maximal efficacy.

• Future larger scale studies are needed to draw substantial conclusions on the effects of stimulation of more than one thalamic nucleus on seizure control.

• Neuromodulatory techniques have the potential to significantly improve the quality of life for patients with medically resistant epilepsy.Neuromodulatory Trends for Intractable Epilepsy

• Stimulation and neuromodulation are effective treatment options for epilepsy.

• Vagus nerve stimulation (VNS) is a commonly used method for epilepsy treatment.

• Long-term treatment with VNS has been shown to reduce seizure frequency.

• Closed-loop VNS is a newer technology that may improve efficacy and reduce side effects.

• Trigeminal nerve stimulation (TNS) is a promising alternative to VNS.

• TNS has been shown to reduce seizure frequency in some patients with refractory epilepsy.

• Deep brain stimulation (DBS) of the thalamus is another option for epilepsy treatment.

• DBS of the anterior nucleus of the thalamus (ANT) has been shown to reduce seizure frequency in some patients.

• DBS of the centromedian nucleus (CM) and medial pulvinar (MP) are newer targets for epilepsy treatment.

• Responsive neurostimulation (RNS) is a newer technology that detects and responds to seizure activity in real-time.

• RNS has been shown to reduce seizure frequency in some patients with refractory epilepsy.

• Further research is needed to fully understand the mechanisms and efficacy of these neuromodulatory treatments for epilepsy.

Emerging Trends in Neuromodulation for Treatment of Drug-Resistant Epilepsy

• Epilepsy affects over 70 million people globally and a significant proportion is resistant to anti-epileptic drugs.

• Neuromodulation has emerged as a pivotal alternative in the management of drug-resistant epilepsy for patients who are not candidates for resection or ablation.

• Candidates for neuromodulation include those who have seizure foci involving the eloquent cortex, decline traditional surgical resection, have multifocal or generalized epilepsy, or have continued seizures despite resection/ablation.

• Trigeminal Nerve Stimulation (TNS) is a non-invasive, transcutaneous stimulation modality for medication-resistant epilepsy with strong evidence for safety and efficacy.

• Vagus Nerve Stimulation (VNS) has been shown to significantly reduce seizures in patients with drug-resistant epilepsy and recent advancements in VNS technology have allowed for the utilization of a closed loop stimulation approach using a heart rate-based seizure detection algorithm.

• Responsive Neurostimulation (RNS) is a closed-loop neuromodulation system that initiates stimulation in response to the detection of an epileptic event electrographically and has demonstrated a 75% median seizure reduction in patients with intractable focal onset epilepsy.

• Deep Brain Stimulation (DBS) has been shown to reduce seizures in patients with drug-resistant epilepsy and studies have highlighted the role of astrocyte activation in DBS by inducing local neuronal modulation.

• The SANTE trial demonstrated the safety and efficacy of DBS in the anterior nucleus of thalamus stimulation for epilepsy and demonstrated continued improvement of efficacy over time.

• The thalamus is a key subcortical structure implicated in the epilepsy network, making various nuclei desirable targets for neuromodulatory techniques.

• The etiology of refractory epilepsy is complex and the prevalence of epilepsy in the general population is estimated to be ∼0.5–1%, with 30% of these patients being resistant to medical therapy.

• TNS, VNS, RNS, and DBS are all viable options for refractory epilepsy with varying degrees of efficacy and safety.

• Neuromodulation techniques involve directly stimulating or impeding neuronal action potential conduction through various mechanisms, including chemical, mechanical, thermal, optogenetic, magnetic, and electrical manipulation, with electrical stimulation being the most widely used.Neuromodulatory Trends for Intractable Epilepsy: Thalamic Stimulation Targets

• Deep Brain Stimulation (DBS) was initially used as a diagnostic intervention to confirm target areas prior to lesioning.

• DBS is now a widely used therapeutic intervention for conditions such as essential tremor, Parkinson's disease, and pain.

• DBS has been approved by the FDA for patients with refractory partial-onset seizures, with and without generalization, who are 18 years of age or older.

• DBS is contraindicated in patients who are incapable of operating the neurostimulator, have significant psychiatric contraindications, or are medically frail and unable to undergo surgical implantation.

• The anti-epileptic mechanisms of DBS are largely unknown and complex, with proposed mechanisms including inhibition and activation of GABAergic neurons.

• The thalamus is a sensory relay center with widespread synaptic connectivity to many cortical regions and plays a role in the propagation of abnormal epileptiform activity.

• The anterior nucleus of the thalamus (ANT) is a key component of the Papez Circuit, whose role in seizure propagation has been extensively explored.

• Direct electrical stimulation of the thalamus allows for modulation of neural circuitry and ultimately interferes with seizure propagation.

• The centromedian nucleus (CM) is a desirable target for neuromodulation due to its connectivity with the anterior cingulate gyrus, which is part of the Papez Circuit and implicated in seizure propagation.

• The median pulvinar thalamic nucleus is a novel promising target for DBS in epilepsy patients.

• Responsive Neurostimulation (RNS) of the pulvinar was successful in treating posterior quadrant epilepsy.

• Combined open and closed loop DBS and RNS have been studied in rodent models and in a single case study in a patient, showing potential for future neuromodulatory systems.Neuromodulatory Trends for Intractable Epilepsy

• Neuromodulatory techniques have had significant success in treating epilepsy in patients who are refractory to medication or not suitable for traditional resective or ablative surgery.

• Modulation of various thalamic nuclei, through open and closed loop systems, is an effective and safe option for these patients.

• Open loop anterior thalamic nucleus (ANT) stimulation is the most established target for epilepsy.

• Concurrent stimulation of multiple thalamic nuclei on seizure frequency is not well studied.

• Closed loop stimulation carries a lower burden of stimulation, fewer stimulation related side effects, fewer cognitive and mood disruptions, and records chronic ambulatory EEG data.

• Closed loop stimulation is useful in measuring seizure burden in response to changes in antiepileptic medications, behavior modification, and in characterizing neurobehavioral spells.

• Open loop stimulation lacks the capability to personalize therapy.

• Closed loop stimulation has the ability to provide a more personalized approach to care by configuring stimulation in response to the patient’s specific needs and epileptic activity.

• Treatment decision making should be guided by patient specific factors.

• Closed loop stimulation is limited by our current insufficient understanding of optimal stimulation parameters and electrode selection, which prevents maximal efficacy.

• Future larger scale studies are needed to draw substantial conclusions on the effects of stimulation of more than one thalamic nucleus on seizure control.

• Neuromodulatory techniques have the potential to significantly improve the quality of life for patients with medically resistant epilepsy.Neuromodulatory Trends for Intractable Epilepsy

• Stimulation and neuromodulation are effective treatment options for epilepsy.

• Vagus nerve stimulation (VNS) is a commonly used method for epilepsy treatment.

• Long-term treatment with VNS has been shown to reduce seizure frequency.

• Closed-loop VNS is a newer technology that may improve efficacy and reduce side effects.

• Trigeminal nerve stimulation (TNS) is a promising alternative to VNS.

• TNS has been shown to reduce seizure frequency in some patients with refractory epilepsy.

• Deep brain stimulation (DBS) of the thalamus is another option for epilepsy treatment.

• DBS of the anterior nucleus of the thalamus (ANT) has been shown to reduce seizure frequency in some patients.

• DBS of the centromedian nucleus (CM) and medial pulvinar (MP) are newer targets for epilepsy treatment.

• Responsive neurostimulation (RNS) is a newer technology that detects and responds to seizure activity in real-time.

• RNS has been shown to reduce seizure frequency in some patients with refractory epilepsy.

• Further research is needed to fully understand the mechanisms and efficacy of these neuromodulatory treatments for epilepsy.

Emerging Trends in Neuromodulation for Treatment of Drug-Resistant Epilepsy

• Epilepsy affects over 70 million people globally and a significant proportion is resistant to anti-epileptic drugs.

• Neuromodulation has emerged as a pivotal alternative in the management of drug-resistant epilepsy for patients who are not candidates for resection or ablation.

• Candidates for neuromodulation include those who have seizure foci involving the eloquent cortex, decline traditional surgical resection, have multifocal or generalized epilepsy, or have continued seizures despite resection/ablation.

• Trigeminal Nerve Stimulation (TNS) is a non-invasive, transcutaneous stimulation modality for medication-resistant epilepsy with strong evidence for safety and efficacy.

• Vagus Nerve Stimulation (VNS) has been shown to significantly reduce seizures in patients with drug-resistant epilepsy and recent advancements in VNS technology have allowed for the utilization of a closed loop stimulation approach using a heart rate-based seizure detection algorithm.

• Responsive Neurostimulation (RNS) is a closed-loop neuromodulation system that initiates stimulation in response to the detection of an epileptic event electrographically and has demonstrated a 75% median seizure reduction in patients with intractable focal onset epilepsy.

• Deep Brain Stimulation (DBS) has been shown to reduce seizures in patients with drug-resistant epilepsy and studies have highlighted the role of astrocyte activation in DBS by inducing local neuronal modulation.

• The SANTE trial demonstrated the safety and efficacy of DBS in the anterior nucleus of thalamus stimulation for epilepsy and demonstrated continued improvement of efficacy over time.

• The thalamus is a key subcortical structure implicated in the epilepsy network, making various nuclei desirable targets for neuromodulatory techniques.

• The etiology of refractory epilepsy is complex and the prevalence of epilepsy in the general population is estimated to be ∼0.5–1%, with 30% of these patients being resistant to medical therapy.

• TNS, VNS, RNS, and DBS are all viable options for refractory epilepsy with varying degrees of efficacy and safety.

• Neuromodulation techniques involve directly stimulating or impeding neuronal action potential conduction through various mechanisms, including chemical, mechanical, thermal, optogenetic, magnetic, and electrical manipulation, with electrical stimulation being the most widely used.Neuromodulatory Trends for Intractable Epilepsy: Thalamic Stimulation Targets

• Deep Brain Stimulation (DBS) was initially used as a diagnostic intervention to confirm target areas prior to lesioning.

• DBS is now a widely used therapeutic intervention for conditions such as essential tremor, Parkinson's disease, and pain.

• DBS has been approved by the FDA for patients with refractory partial-onset seizures, with and without generalization, who are 18 years of age or older.

• DBS is contraindicated in patients who are incapable of operating the neurostimulator, have significant psychiatric contraindications, or are medically frail and unable to undergo surgical implantation.

• The anti-epileptic mechanisms of DBS are largely unknown and complex, with proposed mechanisms including inhibition and activation of GABAergic neurons.

• The thalamus is a sensory relay center with widespread synaptic connectivity to many cortical regions and plays a role in the propagation of abnormal epileptiform activity.

• The anterior nucleus of the thalamus (ANT) is a key component of the Papez Circuit, whose role in seizure propagation has been extensively explored.

• Direct electrical stimulation of the thalamus allows for modulation of neural circuitry and ultimately interferes with seizure propagation.

• The centromedian nucleus (CM) is a desirable target for neuromodulation due to its connectivity with the anterior cingulate gyrus, which is part of the Papez Circuit and implicated in seizure propagation.

• The median pulvinar thalamic nucleus is a novel promising target for DBS in epilepsy patients.

• Responsive Neurostimulation (RNS) of the pulvinar was successful in treating posterior quadrant epilepsy.

• Combined open and closed loop DBS and RNS have been studied in rodent models and in a single case study in a patient, showing potential for future neuromodulatory systems.Neuromodulatory Trends for Intractable Epilepsy

• Neuromodulatory techniques have had significant success in treating epilepsy in patients who are refractory to medication or not suitable for traditional resective or ablative surgery.

• Modulation of various thalamic nuclei, through open and closed loop systems, is an effective and safe option for these patients.

• Open loop anterior thalamic nucleus (ANT) stimulation is the most established target for epilepsy.

• Concurrent stimulation of multiple thalamic nuclei on seizure frequency is not well studied.

• Closed loop stimulation carries a lower burden of stimulation, fewer stimulation related side effects, fewer cognitive and mood disruptions, and records chronic ambulatory EEG data.

• Closed loop stimulation is useful in measuring seizure burden in response to changes in antiepileptic medications, behavior modification, and in characterizing neurobehavioral spells.

• Open loop stimulation lacks the capability to personalize therapy.

• Closed loop stimulation has the ability to provide a more personalized approach to care by configuring stimulation in response to the patient’s specific needs and epileptic activity.

• Treatment decision making should be guided by patient specific factors.

• Closed loop stimulation is limited by our current insufficient understanding of optimal stimulation parameters and electrode selection, which prevents maximal efficacy.

• Future larger scale studies are needed to draw substantial conclusions on the effects of stimulation of more than one thalamic nucleus on seizure control.

• Neuromodulatory techniques have the potential to significantly improve the quality of life for patients with medically resistant epilepsy.Neuromodulatory Trends for Intractable Epilepsy

• Stimulation and neuromodulation are effective treatment options for epilepsy.

• Vagus nerve stimulation (VNS) is a commonly used method for epilepsy treatment.

• Long-term treatment with VNS has been shown to reduce seizure frequency.

• Closed-loop VNS is a newer technology that may improve efficacy and reduce side effects.

• Trigeminal nerve stimulation (TNS) is a promising alternative to VNS.

• TNS has been shown to reduce seizure frequency in some patients with refractory epilepsy.

• Deep brain stimulation (DBS) of the thalamus is another option for epilepsy treatment.

• DBS of the anterior nucleus of the thalamus (ANT) has been shown to reduce seizure frequency in some patients.

• DBS of the centromedian nucleus (CM) and medial pulvinar (MP) are newer targets for epilepsy treatment.

• Responsive neurostimulation (RNS) is a newer technology that detects and responds to seizure activity in real-time.

• RNS has been shown to reduce seizure frequency in some patients with refractory epilepsy.

• Further research is needed to fully understand the mechanisms and efficacy of these neuromodulatory treatments for epilepsy.