It is proposed that the bed nucleus of the stria terminalis (BNST) represents a forebrain limbic region that concurrently influences many of these physiological processes and is a promising extra-thalamic target for therapeutic neurostimulation in patients with refractory epilepsy.
Abstract
Refractory epilepsy remains a significant clinical challenge, affecting over a third of patients with epilepsy and drastically increasing their risk of sudden unexpected death in epilepsy (SUDEP). Furthermore, psychiatric comorbidities - such as depression and anxiety disorders - are highly prevalent among patients with epilepsy. As neuromodulatory therapeutic approaches evolve, it is paramount that novel targets for stimulation are explored that may concomitantly reduce seizure burden, ameliorate psychiatric comorbidities, and/or reduce SUDEP risk. Here, we review physiological factors that are thought to contribute to SUDEP and which may reduce risk of SUDEP if addressed therapeutically, then we describe how the bed nucleus of the stria terminalis (BNST) represents a forebrain limbic region that concurrently influences many of these physiological processes. We conclude by synthesizing recent findings regarding the BNST in patients and preclinical models of epilepsy and propose that this evidence positions the BNST as a promising extra-thalamic target for therapeutic neurostimulation in patients with refractory epilepsy.
Epilepsy is a chronic neurological disorder characterised by recurrent, unprovoked seizures that can significantly affect morbidity, mortality, and quality of life (QoL). Around 30% of people with epilepsy develop drug-resistant epilepsy (DRE), meaning seizures persist despite treatment with two or more adequate trials of antiseizure medications (ASM). For these individuals, alternative therapeutic approaches are often required. Vagus nerve stimulation (VNS) is a well-established adjunctive neuromodulation therapy that has been used for more than 3 decades. Clinical evidence shows that it can reduce seizure frequency and burden, extend seizure-free intervals, and may also contribute to lowering the risk of sudden unexpected death in epilepsy (SUDEP).
Evidence suggests that VNS works through the vagal afferent network to influence key brainstem nuclei and downstream brain circuits involved in seizure generation and propagation. Stimulation of the nucleus tractus solitarius (NTS) and locus coeruleus (LC) appears to increase the release of monoamines such as noradrenaline (NA) and 5-hydroxytryptamine (5-HT), better known as serotonin, which in turn modulate neurotransmission.
Here, Raman Sankar, Professor of Neurology and Paediatrics and Chief of Paediatric Neurology, David Geffen School of Medicine, University of California, Los Angeles, USA, proposes and outlines the evidence for a monoamine hypothesis of VNS function. He also argues that a clearer understanding of this mechanism of action (MOA) can help clinicians work with patients to make more informed treatment decisions.
Background Deep brain stimulation (DBS) has emerged as a palliative neurosurgical treatment option for drug-resistant epilepsy (DRE), particularly in patients who are not candidates for resective surgery or who continue to experience seizures after surgical intervention. Multiple thalamic and extrathalamic targets have been investigated; however, optimal target selection remains challenging and requires a comprehensive understanding of epileptogenic networks. Objective To provide a comprehensive overview of current evidence on DBS for DRE and refractory status epilepticus, with a focus on anatomical targets, mechanisms of action, clinical outcomes, and considerations for target selection. Methods We reviewed the existing literature on DBS in epilepsy, including randomized controlled trials, observational studies, meta-analyses, and relevant experimental data. Major targets—including the anterior nucleus of the thalamus (ANT), centromedian nucleus (CM), pulvinar, mediodorsal nucleus (DM), subthalamic nucleus (STN), and other emerging targets—were examined in terms of connectivity, proposed mechanisms, and clinical efficacy. Results Among available targets, ANT-DBS has the strongest clinical evidence, demonstrating sustained seizure reduction in randomized trials and long-term follow-up studies. CM-DBS shows particular promise in generalized epilepsy, especially Lennox–Gastaut syndrome, likely through modulation of thalamocortical and reticular networks. The pulvinar has emerged as a potential target for temporal and posterior quadrant epilepsies, reflecting its extensive cortical connectivity. Other targets, including the DM, STN, hippocampus, hypothalamus, nucleus accumbens, and cerebellum, have shown variable efficacy in smaller studies and may be relevant for specific epilepsy subtypes or network configurations. Across targets, therapeutic effects are likely mediated by modulation of distributed epileptogenic networks involving limbic, sensorimotor, and arousal systems. Conclusion DBS represents an important therapeutic option for DRE, expanding the scope of neuromodulation beyond traditional surgical approaches. Optimal outcomes depend on individualized target selection based on seizure semiology, network characteristics, and anatomical considerations. As clinical experience and technological advances continue to evolve, further studies are required to refine patient selection, improve targeting strategies, and optimize stimulation paradigms.
Ryota Sasaki, Masako Kinoshita, Abbas F. Sadikot et al.· Frontiers in Neurology· 0 citations
Epilepsy and cerebral palsy (CP) are among the most frequently co-occurring neurological disorders and are characterized by high comorbidity. This article provides a brief overview of the issue and presents clinical cases of patients with CP combined with focal epilepsy of childhood with structural brain changes and benign epileptiform discharges of childhood on electroencephalogram (FECSBC-BEDC) and infantile epileptic spasms syndrome. Vigabatrin is a first-line drug for the treatment of infantile epileptic spasms syndrome and can also be successfully used for focal epilepsy in patients with CP. Due to its GABA-mediated mechanism of action, vigabatrin has demonstrated the ability to reduce symptoms of spasticity in dystonia. Although the FECSBC-BEDC syndrome has been described in patients with CP, it has not yet been assigned a taxonomic position in the International Classification of Epilepsies and Epileptic Syndromes. Sulthiame has demonstrated efficacy and good tolerability in patients with FECSBC-BEDC.
T. R. Tomenko, Zhuzhuna M. Tsotsonava, M. Y. Shchennikova et al.· Russian Journal of Child Neu...· 0 citations
Epilepsy is increasingly recognized not merely as a functional electrical disorder but as a condition associated with progressive and, in many cases, region-specific structural reorganization of the brain. Neuroimaging and histopathological studies over the past two decades have demonstrated that recurrent seizures are accompanied by hippocampal sclerosis, mossy fiber sprouting, granule cell dispersion, cortical thinning, white matter tract disruption, and, in some models, alterations extending to extra-limbic and even extra-cranial structures. These structural alterations are not static end-points but evolve dynamically with disease duration, seizure frequency, and etiology, and they carry important implications for diagnosis, prognosis, and surgical planning. This review synthesizes current evidence on structural brain changes in epilepsy, drawing on human neuroimaging and histopathology literature as well as preclinical rodent studies, including several recent Nigerian experimental studies using lithium chloride-pilocarpine and kainic acid models that have examined hippocampal, prefrontal cortical, and limbic architecture following induced seizures and after treatment with plant-derived neuroprotective agents. We discuss the cellular and molecular underpinnings of hippocampal sclerosis, cortical and subcortical atrophy, white matter and network level changes, and the emerging use of structural biomarkers, while highlighting therapeutic strategies, including antiepileptic drugs, ketogenic diet, and Phyto therapeutic agents, that may attenuate or reverse these structural sequelae.
O. Kolawole, O. Fabiyi, O. Olayinka et al.· World Journal of Biology Pha...· 0 citations
The evidence indicates that epilepsy management should extend beyond seizure control to incorporate routine cognitive surveillance, and practical screening tools such as the Montreal Cognitive Assessment demonstrate higher sensitivity than the Mini-Mental State Examination for detecting mild impairment.
Y. Imran, Ainaya Az Zahra· Journal of Society Medicine· 0 citations
Epilepsy is not merely a chronic neurological disorder characterized by recurrent, spontaneous seizures at the clinical level; rather, it represents a complex pathophysiological condition involving profound structural, functional, and molecular reorganization within neuronal networks. The marked heterogeneity of epilepsy arises from the multilayered interplay of genetic susceptibility, acquired brain insults such as trauma, ischemia, or infection, developmental abnormalities, and environmental factors. This multifactorial etiology poses substantial challenges for clinical management and limits the effectiveness of current therapeutic approaches, which are largely restricted to symptomatic seizure suppression. Experimental epilepsy models constitute indispensable tools for addressing these unmet clinical and scientific needs. Chemical, electrical, genetic, and acquired models enable systematic investigation of epilepsy across multiple biological scales, ranging from alterations in neuronal excitability and synaptic plasticity to neuroinflammatory processes and network-level synchronization disturbances. Beyond providing mechanistic insight, these models serve as essential platforms for preclinical evaluation of novel pharmacological agents and neuromodulation-based therapeutic strategies. The review encompasses a broad experimental spectrum, including chemoconvulsant models such as pentylenetetrazol, pilocarpine, and kainic acid; electrical stimulation paradigms; genetic and developmental models; and acquired epilepsy models. In addition, in vitro and ex vivo systems, outcome measures, and model optimization strategies for drug screening and therapeutic development are discussed. By highlighting the limitations of single-model approaches and emphasizing complementary experimental strategies, this review aims to advance a comprehensive understanding of epilepsy pathophysiology and support the development of more effective, mechanism-based therapies.
Ali Osman Arslan, Sevdenur Akcay, G. Akcay· Discover Neuroscience· 0 citations
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