Responsive neurostimulation of thalamic nuclei for regional and multifocal drug-resistant epilepsy in children and young adults.

OBJECTIVE: Responsive neurostimulation (RNS) is a US FDA-approved form of neuromodulation to treat patients with focal-onset drug-resistant epilepsy (DRE) who are ineligible for or whose condition is refractory to resection. However, the FDA approval only extends to use in patients with one or two epileptogenic foci. Recent literature has shown possible efficacy of thalamic RNS in patients with Lennox-Gastaut syndrome and multifocal epilepsy. The authors hypothesized that RNS of thalamic nuclei may be effective in seizure reduction for patients with multifocal or regionalized-onset DRE. METHODS: The authors performed a retrospective chart review of all patients who had an RNS device managed at Texas Children's Hospital between July 2016 and September 2023, with at least one active electrode in the thalamic nuclei and ≥ 12 months of postimplantation follow-up. Information conveyed by the patient or their caregiver provided data on the change in the clinical seizure frequency, quality of life (QOL), and seizure severity between the preimplantation baseline visit and the last office visit (LOV). RESULTS: Thirteen patients (ages 8-24 years) were identified with active RNS leads in thalamic nuclei (11 centromedian and 2 anterior nucleus). At LOV, 46% of patients reported 50%-100% clinical seizure reduction (classified as responders), 15% reported 25%-49% reduction, and 38% reported < 25% reduction or no change. Additionally, 42% of patients reported subjective improvement in QOL and 58% reported improved seizure severity. Patients with focal cortical dysplasia (FCD) responded strongly: 3 of 5 (60%) reported ≥ 80% reduction in seizure burden and improvement in seizure severity and QOL. Patients with multifocal epilepsy and bilateral thalamocortical leads also did well, with all 3 reporting ≥ 50% reduction in seizures. CONCLUSIONS: RNS of thalamic nuclei shows promising results in reducing seizure burden for patients with multifocal or regional-onset DRE, particularly in a bilateral thalamocortical configuration or when addressing an underlying FCD.

Responsive Neurostimulation for the Treatment of Children With Drug-Resistant Epilepsy in Tuberous Sclerosis Complex.

BACKGROUND: To review seizure outcomes in children with tuberous sclerosis complex (TSC) and drug-resistant epilepsy (DRE) treated with the responsive neurostimulation (RNS) System. METHODS: We retrospectively reviewed children (<21 years old) with TSC implanted with the RNS System at Texas Children's Hospital between July 2016 and May 2022. RESULTS: Five patients meeting the search criteria were identified (all female). The median age of the RNS implantation was 13 years (range: 5 to 20 years). The median epilepsy duration before the RNS implantation was 13 years (range: 5 to 20 years). Surgeries before RNS implantation included vagus nerve stimulator placement (n = 2), left parietal resection (n = 1), and corpus callosotomy (n = 1). The median number of antiseizure medications tried before RNS was 8 (range: 5 to 12). The rationale for the RNS System implantation included seizure onset in eloquent cortex (n = 3) and multifocal seizures (n = 2). The maximum current density for each patient ranged between 1.8 and 3.5 µC/cm2, with an average daily stimulation of 2240 (range: 400 to 4200). There was an 86% median seizure reduction (range 0% to 99%) at a median follow-up duration of 25 months (range: 17 to 25 months). No patient experienced implantation or stimulation-related complications. CONCLUSIONS: We observed a favorable improvement in seizure frequency in pediatric patients with DRE secondary to TSC treated with the RNS System. The RNS System may be a safe and effective treatment for DRE in children with TSC.

Behavioral Improvements following Lesion Resection for Pediatric Epilepsy: Pediatric Psychosurgery?

INTRODUCTION: Resection of brain lesions associated with refractory epilepsy to achieve seizure control is well accepted. However, concurrent behavioral effects of these lesions such as changes in mood, personality, and cognition and the effects of surgery on behavior have not been well characterized. We describe 5 such children with epileptogenic lesions and significant behavioral abnormalities which improved after surgery. CASE DESCRIPTIONS: Five children (ages 3-14 years) with major behavioral abnormalities and lesional epilepsy were identified and treated at our center. Behavioral problems included academic impairment, impulsivity, self-injurious behavior, and decreased social interaction with diagnoses of ADHD, oppositional defiant disorder, and autism. Pre-operative neuropsychiatric testing was performed in 4/5 patients and revealed low-average cognitive and intellectual abilities for their age, attentional difficulties, and poor memory. Lesions were located in the temporal (2 gangliogliomas, 1 JPA, 1 cavernoma) and parietal (1 DNET) lobes. Gross total resection was achieved in all cases. At mean 1-year follow-up, seizure freedom (Engel 1a in 3 patients, Engel 1c in 2 patients) and significant behavioral improvements (academic performance, attention, socialization, and aggression) were achieved in all. Two patients manifested violence pre-operatively; one had extreme behavior with violence toward teachers and peers despite low seizure burden. Since surgery, his behavior has normalized. CONCLUSION: We identified 5 patients with severe behavioral disorders in the setting of lesional epilepsy, all of whom demonstrated improvement after surgery. The degree of behavioral abnormality was disproportionate to epilepsy severity, suggesting a more complicated mechanism by which lesional epilepsy impacts behavior. We propose a novel paradigm in which lesionectomy may offer behavioral benefit even when seizures are not refractory. Thus, behavioral improvement may be an important novel goal for neurosurgical resection in children with epileptic brain lesions.

Celiac Disease in Children: An Association With Drug-Resistant Epilepsy.

BACKGROUND: Neurological manifestations are commonly reported in patients with celiac disease (CD). We aimed to characterize epilepsy features in a pediatric population with CD and the effect of a gluten-free diet (GFD) on seizure burden. METHODS: A retrospective chart review was performed on pediatric patients treated at the University of Utah and Primary Children's Hospital in Salt Lake City, Utah, with both epilepsy and CD and compared with a control group with epilepsy only. RESULTS: We identified 56 patients with epilepsy and biopsy-confirmed CD (n = 36, 64%) or elevated tissue transglutaminase antibodies (tTG-Ab) without biopsy-confirmed CD (n = 20, 36%). Age- and gender-matched controls were selected from patients with epilepsy only (n = 168). Patients with biopsy-proven CD or positive tTG-Ab had high percentage of drug-resistant epilepsy (DRE) compared with the control group (P < 0.05). Age at seizure onset preceded the diagnosis of CD on average by 5.9 years for patients with DRE (P < 0.01) compared with 2.2 years for those with drug-responsive epilepsy. Adhering to a GFD reduced seizure frequency or resulted in weaning dosage or weaning off of one or more antiseizure medications in a majority of patients with DRE. CONCLUSIONS: DRE was more prevalent in pediatric patients with biopsy-confirmed CD and positive tTG-Ab compared with the control group (which included childhood epilepsy syndromes), but comparable with the prevalence of DRE in the general population. Adherence to a GFD in combination with antiseizure medications appears to reduce seizure burden for those with CD and DRE.

Influence of experimental subarachnoid hemorrhage on nicotine-induced contraction of the rat basilar artery in relation to nicotinic acetylcholine receptors, calcium, and potassium channels.

BACKGROUND: Cigarette smoking is associated with symptomatic vasospasm after subarachnoid hemorrhage (SAH). METHODS: Rat basilar arteries of a normal group and SAH groups (1 hour, 2 days, and 1 week) were removed from the brain and cut into spiral preparations. RESULTS: A central nervous system (CNS) nicotinic acetylcholine receptor (nAChR) and autonomic ganglionic nAChR antagonist (mecamylamine) and skeletal muscle nAChR antagonist (gallamine) concentration-dependently attenuated the nicotine-induced contraction. An autonomic ganglionic nAChR antagonist (hexamethonium) did not affect nicotine-induced contractions in normal rats or rats with SAH. The various nAChR antagonists showed no significant differences in their effects between normal and SAH (1 hour, 2 days, and 1 week) rats. An L-type Ca(2+) channel antagonist (nifedipine) attenuated the nicotine-induced contraction in a concentration dependent manner. Inhibition by nifedipine was significantly enhanced in the 1-hour and 2-day SAH groups compared with normal and 1-week SAH groups. Levcromakalim showed a greater attenuation of nicotine-induced contraction in SAH (1 hour, 2 days, and 1 week) than in normal rats. CONCLUSIONS: Nicotine-induced contraction of the rat basilar artery involved the CNS nAChR subfamily, skeletal muscle nAChR subfamily, and L-type Ca(2+) channel pathways. SAH did not affect any of the subfamilies of nAChR, but the Ca(2+) channel was reduced and the adenosine triphosphate-sensitive K(+) channel was enhanced by SAH.

Influence of experimental subarachnoid hemorrhage on nicotine-induced contraction of the rat basilar artery in relation to arachidonic acid metabolites signaling pathway.

BACKGROUND: Smoking is one of the most important risk factors for cerebral circulatory disorders. The purpose of this study was to investigate the influence of experimental subarachnoid hemorrhage (SAH) on nicotine-induced contraction (arachidonic acid metabolites) in the basilar arteries of rats. METHODS: Rats were killed at 1 hour and 1 week after blood injection, and the basilar artery was isolated and cut into a spiral strip. RESULTS: Testing of cyclooxygenase-1 (COX-1) and 5-lipoxygenase (5-LOX) inhibitors revealed no significant differences in their effects on normal and SAH (1 hour and 1 week). Phospholipase C (PLC) inhibitor (1-(6-((17beta-3-methoxyestra-1,3,5(10)-trien-17yl)amino)hexyl)-1H-pyrrole-2,5,-dione [U-73122]) slightly inhibited contraction of SAH (1 hour and 1 week) when compared to controls. Phospholipase A2 (PLA2) inhibitor (manoalide) and cytosolic PLA2 (cPLA2) inhibitor (arachidonyltrifluoromenthylketone [AACOCF3]) more strongly attenuated contraction in SAH (1 hour and 1 week) than in controls. Secreted PLA2 (sPLA2) inhibitor (indoxam), PLC inhibitor (2-nitro-4-carboxyphenyl N, N-diphenylcarbamate [NCDC]), and COX-2 inhibitors (nimesulide, (5-methanesulfonamido-6-(2,4-difluorothiophenyl)-1-indanone) [L-745337], and celecoxib) only slightly inhibited contraction of SAH (1 week) when compared to normal and SAH (1 hour). The calcium-independent PLA2 (iPLA2) inhibitor bromoenol lactone (BEL) showed greater inhibition of contraction in SAH (1 hour) when compared to normal and SAH (1 week). CONCLUSIONS: One week after exposure to SAH, PLC, sPLA2, and COX-2 activity were enhanced and cPLA2 activity was inhibited. One hour after exposure to SAH, PLC activity was enhanced and cPLA2 and iPLA2 activity was inhibited. Such changes of inflammatory arachidonic acid metabolites by smoking after SAH may play important roles in fatal cerebral circulatory disorders, suggesting important implications for the etiology and pathogenesis of SAH.

Effects of the experimental subarachnoid hemorrhage on the eicosanoid receptors in nicotine-induced contraction of the rat basilar artery.

BACKGROUND: Smoking is one of the most important risk factors for subarachnoid hemorrhage (SAH). The purpose of this study was to investigate the influence of experimental SAH and arachidonic acid metabolites on nicotine-induced contraction in the rat basilar artery. METHODS: Rats were killed at 1 hour and 1 week after SAH, and the basilar artery was isolated and cut into a spiral strip. The effects of various eicosanoid receptor antagonists on nicotine-induced contraction in the rat basilar artery were investigated. RESULTS: Antagonists of thromboxane A2 (TXA2) and cysteinyl leukotriene (CysLT) receptors did not affect nicotine-induced contraction. In contrast, the antagonists of leukotriene B4 (LTB4) receptors (BLT1 and BLT2) attenuated the nicotine-induced contraction in the rat basilar artery. We also observed that SAH did not influence the effect of TXA2, LTB4, and CysLTs receptor antagonists on the nicotine-induced contraction. These results suggest that TXA2 and CysLTs are not involved in nicotine-induced contraction, while LTB4 potentates this contraction in rat basilar artery. CONCLUSIONS: BLT2 receptor seemed to be more involved in the nicotine-induced contraction than the BLT1 receptor. SAH did not affect the involvement of eicosanoids in the nicotine-induced contraction of the rat basilar artery. The present study shows the involvement of some of the arachidonic acid metabolites into signaling pathways of nicotine-induced contraction. It will serve to improve therapeutic interventions of SAH and suggests a promising approach to protect the cerebral vasculature of cigarette smokers.

Pharmacological nature of nicotine-induced contraction in the rat basilar artery: involvement of arachidonic acid metabolites.

The pharmacological nature of nicotine-induced contraction in the rat basilar artery is poorly understood. The purpose of this study was to investigate the endothelium dependency and involvement of arachidonic acid metabolites in nicotine-induced contraction in the rat basilar artery. The rat basilar artery was removed from the brain and cut into a spiral preparation. Nicotine (3x10(-5) to 10(-2) M) induced the concentration-dependent contraction in the rat basilar artery, and the maximal contraction was obtained at 3x10(-3) M. The contraction induced by nicotine (3x10(-3) M) was significantly attenuated by the presence of saponin (0.05 mg/ml, 15 min). Phospholipase C (PLC) inhibitors (NCDC and U-73122), calcium-independent phospholipase A(2) (iPLA(2)) inhibitor (BEL), cyclooxygenase-2 (COX-2) inhibitors (nimesulide, L-745,337 and celecoxib), and a 5-lipoxygenase (5-LOX) inhibitor (ZM-230487) concentration-dependently attenuated the nicotine-induced contraction. A cytosolic phospholipase A(2) (cPLA(2)) inhibitor (AACOCF3), secretory phospholipase A(2) (sPLA(2)) inhibitor (indoxam), and cyclooxygenase-1 (COX-1) inhibitors (flurbiprofen and ketoprofen) did not affect the nicotine-induced contraction. From these results, it was suggested that nicotine-induced contraction in the rat basilar artery is endothelium-dependent and is due to arachidonic acid metabolites.

Cysteinyl leukotrienes and leukotriene B mediate vasoconstriction to arginine vasopressin in rat basilar artery.

Arginine vasopressin (AVP) has been reported to be involved in the development of cerebral vasospasm after haemorrhage and cerebral oedema following ischaemia. Endogenously produced 5-lipoxygenase metabolites are able to contract isolated endothelium-preserved arterial strips and modulate vascular permeability. The present study addresses the role of 5-lipoxygenase and its products, namely cysteinyl leukotrienes (CysLTs) and leukotriene (LT) B4, in the contraction induced by AVP in rat basilar artery. Contractile responses to LTD4, LTC4, LTB4 or AVP were assessed in spiral preparations of rat endothelium-intact basilar artery. Contractions to AVP were determined in the absence or presence of 5-lipoxygenase inhibitors or CysLT1 or BLT receptor antagonists. Contractile responses to leukotrienes and AVP are expressed as a percentage of the contraction induced by 80 mmol/L KCl. Leukotriene D4, LTC4 and LTB4 acted as vasoconstrictor agents in rat basilar artery, causing contractions (all at concentrations of 1 micromol/L) of 42 +/- 13, 54 +/- 15 and 25 +/- 6% of the response to 80 mmol/L KCl, respectively. A concentration-response curve was constructed for AVP over the range 1 pmol/L to 10 nmol/L and an EC50 value of 0.19 +/- 0.02 nmol/L (n = 30) was determined. The presence of the 5-lipoxygenase inhibitors ZM 230487 (10 nmol/L and 0.1 and 1 micromol/L) and AA 861 (1, 3, 10, and 30 micromol/L), the CysLT1 receptor antagonist MK 571 (3, 10 and 30 micromol/L) or the BLT receptor antagonists CP 105696 and LY 255283 (3, 10 and 30 micromol/L for both) in the organ bath significantly attenuated the contractions induced by AVP in rat basilar artery (P < 0.05). The experimental results of the present study provide the first evidence for the involvement of CysLTs and LTB4 in the in vitro constriction induced by AVP in rat basilar artery. In the context of previously reported involvement of AVP in the development of cerebral vasospasm and oedema, the present study draws attention to the potential role played by the 5-lipoxygenase pathway in these pathological processes.