Electrical stimulation of the anterior nucleus of the thalamus for the treatment of intractable epilepsy

PURPOSE: Animal studies and sporadic case reports in human subjects have suggested that intermittent electrical stimulation of the anterior nucleus of the thalamus reduces seizure activity. We embarked on an open-label pilot study to determine initial safety and tolerability of bilateral stimulation of the anterior nucleus of the thalamus (ANT), to determine a range of appropriate stimulation parameters, and to begin to gather pilot efficacy data. METHODS: We report an open-label pilot study of intermittent electrical stimulation of the anterior nucleus of the thalamus in five patients (three men, two women; age range, 24-47 years), with follow-up between 6 and 36 months. All patients had intractable partial epilepsy. Four of the five patients also had secondarily generalized seizures. Stimulation was delivered by bilateral implantable, programmable devices by using an intermittent, relatively high-frequency protocol. Stimulation parameters were 100 cycles per second with charge-balanced alternating current; pulse width, 90 ms; and voltages ranging between 1.0 and 10.0 V. Seizure counts were monitored and compared with preimplantation baseline. RESULTS: Four of the five patients showed clinically and statistically significant improvement with respect to the severity of their seizures, specifically with respect to the frequency of secondarily generalized tonic-clonic seizures and complex partial seizures associated with falls. One patient showed a statistically significant reduction in total seizure frequency. No adverse events could clearly be attributed to stimulation. None of the patients could determine whether the stimulator was on or off at these parameters. CONCLUSIONS: Electrical stimulation of the ANT appears to be well tolerated. Preliminary evidence suggests clinical improvement in seizure control in this small group of intractable patients. Further controlled study of deep brain stimulation of the anterior nucleus is warranted.     

Electrical stimulation of the anterior nucleus of the thalamus for intractable epilepsy: a long-term follow-up study

PURPOSE: The anterior nucleus of the thalamus (ANT) modulates temporal lobe and hypothalamic activities, and relays information to the cingulate gyrus and entorhinal cortex. Deep brain stimulation (DBS) of the ANT has been reported to decrease seizure activity in a limited number of human subjects. However, long-term effect of chronic ANT stimulation on such patients remains unknown. We report long-term follow-up results in four patients receiving ANT stimulation for intractable epilepsy. METHODS: Four patients underwent stereotactic implantation of quadripolar stimulating electrodes in the bilateral ANT, guided by single-unit microelectrode recording. Electrode location was confirmed by postoperative magnetic resonance imaging (MRI). The stimulator was activated 2-4 weeks following electrode insertion; initial stimulation parameters were 4-5 V, 90-110 Hz, and 60-90 micros. Seizure frequency was monitored and compared with preimplantation baseline frequency. Intelligence quotient (IQ) test and auditory P300 response were performed before and after implantation of electrodes. RESULTS: Four patients (one man with generalized seizures, and three women with partial seizures and secondary generalization) aged 18-45 years old were studied with mean follow-up period of 43.8 months. The four patients demonstrated a sustained effect of 49% (range, 35-76%) seizure reduction to ANT stimulation. Simple insertion of DBS electrodes (Sham period, no stimulation) produced a mean reduction in seizures of 67% (range, 44-94%). One patient was seizure-free for 15 months with anticonvulsant medications. One patient had a small frontal hemorrhage and a second patient had extension erosion over scalp; no resultant major or permanent neurological deficit was observed. Preoperative IQ index and auditory P300 were not significantly different with those after electrodes implantation. CONCLUSIONS: Implantation of electrodes in the ANT and subsequent stimulation is associated with a significant reduction in seizure frequency. However, our study could not differentiate whether the implantation itself, the subsequent stimulation or postimplantation drug manipulation had the greatest impact. These experimental results prompt further controlled study in a large patient population.     

Chronic bilateral stimulation of the anterior thalamus of kainate-treated rats increases seizure frequency

PURPOSE: Electrical stimulation of the anterior nucleus of the thalamus (ANT) is receiving increased attention as a novel means of controlling intractable epilepsy, and has entered human clinical trial. Animal data supporting the anticonvulsant benefit of ANT stimulation, however, has been obtained from acute chemoconvulsant models of epilepsy rather than models of chronic epilepsy with spontaneous seizures. It is unknown whether ANT stimulation is effective in models of chronic epilepsy. METHODS: Bilateral ANT stimulation was evaluated in rats with chronic epilepsy following acute status epilepticus (SE) produced by systemic kainic acid (KA) administration. The evolution of epilepsy following KA SE and the effects of ANT stimulation were monitored by continuous video-EEG. RESULTS: Following KA SE, most rats have 2-8 seizures per day, and the average seizure rate increases over time, doubling over the course of 14 weeks. Behavioral seizure severity, after the initial development of epilepsy, remains stable. Seizure frequency during ANT stimulation was 2.5 times the baseline seizure frequency. In some cases stimulation triggered seizures were observed. The effects of stimulation were specific to the ANT. Stimulation applied to electrodes placed outside the ANT did not significantly worsen seizure frequency. CONCLUSIONS: ANT stimulation exacerbated seizure frequency in rats with chronic epilepsy following kainate status epilepticus.     

脑深部电刺激治疗难治性癫癎

目的探讨脑深部电刺激（deep brain stimulation,DBS）在治疗难治性癫中的应用。方法回顾性分析接受DBS治疗的4例难治性癫病人的临床资料,1例选择丘脑前核电刺激,3例选择杏仁核-海马复合体电刺激。分析DBS治疗难治性癫的术前评估、手术方法及治疗效果。结果随访11-33个月,3例病人发作均减少50%以上,1例无效。结论对于不适合接受开颅切除性手术治疗的药物难治性癫病人,DBS治疗为安全而有效地治疗方式之一。靶点的选择主要依据癫癎样放电的部位及特点。     

Mesial temporal inhibition in a patient with deep brain stimulation of the anterior thalamus for epilepsy

We investigated the electrophysiological effects of high-frequency anterior thalamic deep brain stimulation using intracerebral mesial and lateral temporal depth electrodes in a patient with intractable focal epilepsy. Monopolar and bipolar stimulation delivered to the thalamic anterior nucleus using the programmable ITREL II stimulation device led to a significant decrease of cross power spectral density and a nonsignificant decrease of coherence in ipsilateral hippocampal structures. No such effect was found in lateral temporal or contralateral sites. The hippocampal inhibition was clearly related to the voltage (> or =7 V) and frequency (> or =70 Hz) of the thalamic stimulus and occurred with a delay of approximately 60 s after stimulus onset.     

Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy

Purpose: We report a multicenter, double‐blind, randomized trial of bilateral stimulation of the anterior nuclei of the thalamus for localization‐related epilepsy. Methods: Participants were adults with medically refractory partial seizures, including secondarily generalized seizures. Half received stimulation and half no stimulation during a 3‐month blinded phase; then all received unblinded stimulation. Results: One hundred ten participants were randomized. Baseline monthly median seizure frequency was 19.5. In the last month of the blinded phase the stimulated group had a 29% greater reduction in seizures compared with the control group, as estimated by a generalized estimating equations (GEE) model (p = 0.002). Unadjusted median declines at the end of the blinded phase were 14.5% in the control group and 40.4% in the stimulated group. Complex partial and “most severe” seizures were significantly reduced by stimulation. By 2 years, there was a 56% median percent reduction in seizure frequency; 54% of patients had a seizure reduction of at least 50%, and 14 patients were seizure‐free for at least 6 months. Five deaths occurred and none were from implantation or stimulation. No participant had symptomatic hemorrhage or brain infection. Two participants had acute, transient stimulation‐associated seizures. Cognition and mood showed no group differences, but participants in the stimulated group were more likely to report depression or memory problems as adverse events. Discussion: Bilateral stimulation of the anterior nuclei of the thalamus reduces seizures. Benefit persisted for 2 years of study. Complication rates were modest. Deep brain stimulation of the anterior thalamus is useful for some people with medically refractory partial and secondarily generalized seizures.     

难治性颞叶癫痫术后生活质量的评估

目的调查药物难治性颞叶癫痫术后患者生活质量的改善情况,评估手术对该类患者生活质量的影响。方法将自理能力、学习能力、工作能力、经济收入四个指标作为生活质量的评定标准,对比168例药物难治性颞叶癫痫患者手术前后生活质量的变化,并进行统计学分析。结果 168例药物难治性颞叶癫痫患者经过严格的术前评估均行前颞叶切除,随访1-3年,术后生活质量较术前明显改善,有统计学意义。结论药物难治性颞叶癫痫患者术后生活质量明显改善,手术显示出良好的性价比,有手术指证的患者应积极手术治疗。     

Chronic high-frequency deep-brain stimulation in progressive myoclonic epilepsy in adulthood--report of five cases

Purpose: To assess the efficacy and tolerability of chronic high‐frequency deep brain stimulation (DBS) in adult patients with progressive myoclonic epilepsy (PME) syndromes. Methods: Five adult patients (four male, 28–39 years) with PME underwent chronic high‐frequency DBS according to a study protocol that had been approved by the local ethics committee. Electrodes were implanted in the substantia nigra pars reticulata (SNr)/subthalamic nucleus (STN) region in the first patient and additionally in the ventral intermediate nucleus (VIM) bilaterally in the following four cases. Follow‐up took place in intervals of 3 months and DBS effects were compared with baseline frequency of passive and activation‐induced myoclonic jerks and daily life performance 8 weeks prior to implantation. Key Findings: Follow‐up periods ranged from 12–42 months (median 24 months). The best clinical effects were seen with SNr/STN DBS in all patients. VIM stimulation failed to achieve acute therapeutic effects and revealed low side‐effect thresholds and even triggering of myoclonia. In all patients the reduction of myoclonic seizures was observed and ranged between 30% and 100% as quantified by a standardized video protocol. All patients reported clinically relevant improvements of various capabilities such as free standing and walking or improved fine motor skills. In one patient with an excellent initial response generalized tonic–clonic seizures increased after 3 months of stimulation following extensive trauma‐related surgery. The best effect was seen in the least impaired patient. Significance: DBS of the SNr/STN may be an effective treatment option for patients with PME. Less impaired patients may benefit more markedly.     

迷走神经刺激治疗药物难治性癫痫的随访研究（附62例分析）

目的研究迷走神经刺激治疗药物难治性癫痫的疗效。方法回顾性分析62例接受迷走神经刺激（vNs）治疗的药物难治性癫痫患者的临床资料。通过患者来院或电话对患者的发作频率、持续时间和生活质量等进行随访。结果62例患者,失访5例,1例患者刺激时间小于2个月未纳入统计范围,对接受迷走神经刺激治疗3～40个月的56例患者进行统计分析,McHughⅠ级22例（39．3％）,Ⅱ级16例（28．6％）,Ⅲ级13例（23．2％）,Ⅳ级＋Ⅴ级5例（8．9％）。其中3例（5．4％）术后无发作,38例（67．9％）发作减少50％以上。结论迷走神经刺激是治疗药物难治性癫痫安全、有效的方法。VNS刺激时间和刺激参数可能是影响其对药物难治性癫痫疗效的重要因素,随刺激时间延长疗效增加。     

Microendoscopic transventricular deep brain stimulation of the anterior nucleus of the thalamus as a safe treatment in intractable epilepsy: A feasibility study

IntroductionDeep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is proposed in patients with severe intractable epilepsy. When used, the transventricular approach increases the risk of bleeding due the anatomy around the entry point in the thalamus. To avoid such a complication, we used a transventricular microendoscopic technique.MethodsWe performed a retrospective study of nine adult patients who were surgically treated for refractory epilepsy between 2010 and 2019 by DBS of the anterior thalamic nucleus.ResultsEndoscopy provides a direct visual control of the entry point of the lead in the thalamus through the ventricle by avoiding ependymal vessels. No hemorrhage was recorded and accuracy was systematically checked by intraoperative stereotactic MRI. We reported a responder rate improvement in 88.9% of patients at 1 year and in 87.5% at 2 years. We showed a significant decrease in global seizure count per month one year after DBS (68.1%; P = 0.013) leading to an overall improvement in quality of life. No major adverse effect was recorded during the follow-up. ANT DBS showed a prominent significant effect with a decrease of the number of generalized seizures.ConclusionWe aimed at a better ANT/lead collimation using a vertical transventricular approach under microendoscopic monitoring. This technique permitted to demonstrate the safety and the accuracy of the procedure.     

Deep brain stimulation of the anterior nucleus of the thalamus in a patient with super-refractory convulsive status epilepticus

We report the first patient to die from refractory convulsive status epilepticus (SE) after the removal of a stimulator. The removal occurred after a two-year period of successful control of super-refractory convulsive SE with deep brain stimulation of the bilateral anterior nucleus of the thalamus (ANT-DBS). The female patient, born in 1990, suffered from high fever and seizures, and was diagnosed with viral encephalitis in 2005. After four weeks of medical treatment, she recovered with no neurological disabilities, but suffered from monthly seizures. Ten years later, the patient presented with convulsive SE, while four months pregnant in February of 2015. Her SE remained super-refractory to drugs despite the termination of pregnancy. Therefore, ANT-DBS was performed in March of 2015. The patient became SE-free following activation of an ANT-DBS stimulator. However, the stimulation treatment was terminated according to the family's request when a tremor developed two years after the treatment had begun. Subsequently, four SE episodes occurred and the tremor did not improve. The stimulator and electrodes were removed in August of 2017. The patient died of an uncontrolled SE two months later. This case demonstrates the effectiveness of ANT-DBS for emergency super-refractory convulsive SE with both positive and negative outcomes.     

Refractory epilepsy and deep brain stimulation

Up to one-third of all patients with epilepsy have epilepsy refractory to medical therapy. Surgical options include temporal lobectomy, focal neocortical resection, stereotactic lesioning and neurostimulation. Neurostimulatory options comprise vagal nerve stimulation, trigeminal nerve stimulation and deep brain stimulation (DBS). DBS enables structures in the brain to be stimulated electrically by an implanted pacemaker after a minimally invasive neurosurgical procedure and has become the therapy of choice for Parkinson’s disease refractory to or complicated by drug therapy. Here we review DBS for epilepsy, a powerful emerging treatment in the surgical armamentarium for drug refractory epilepsy, with a focus on extratemporal epilepsy.     

Electrophysiological effects and clinical results of direct brain stimulation for intractable epilepsy

Objective: Epilepsy can be considered as a result of the imbalance of the excitatory and inhibitory processes. Therefore, the artificial enhancement of the activity of brain inhibitory mechanisms might lead to a beneficial therapeutic effect for intractable epilepsy patients. Material and methods: Studies of the inhibitory effects of electrical stimulation of the head of the caudate nucleus (HCN), cerebellar dentate nucleus (CDN), thalamic centromedian nucleus (CM), and neocortical and temporal lobe mesiobasal epileptic foci were performed on 150 patients with implanted intracerebral electrodes. Chronic brain stimulation with implanted neurostimulators was performed on 54 patients. Sixteen were followed up to 1.5 years (mean 1.2 years). Results: The study demonstrated that 4–8 Hz HCN and 50–100 Hz CDN stimulation suppressed the subclinical epileptic discharges and reduced the frequency of generalized, complex partial, and secondary generalized seizures. CM stimulation (20–130 Hz) desynchronized the EEG and suppressed partial motor seizures. Direct subthreshold 1–3 Hz stimulation of the epileptic focus may suppress rhythmic afterdischarges (ADs). Seizures were eliminated for 26 of 54 patients (48%), worthwhile improvement was achieved for 23 of 54 patients (43%), and no improvement was observed in 5 of 54 patients (9%). Conclusion: The artificial increase of the activity of brain inhibitory system may suppress the activity of epileptic foci, and, in long run, stabilize this epileptic foci activity at a lower, perhaps normal, level. Therapeutic direct brain stimulation, therefore, might serve as a useful tool in the treatment of intractable and multifocal epilepsy, and might be combined with ablative surgical methods.     

迷走神经刺激术治疗五例顽固性癫痫及其随访研究

寻求顽固性癫痫的有效治疗方法。方法用迷走神经刺激术治疗５例顽固性癫痫患者，并进行１年的随访。结果４例患者的癫痫发作频率较术前减少５０％以上；另１例为失张力伴强直－阵挛发作，失张力发作无明显改变，但１年中未见强直－阵挛发作。所有患者的发作强度均有所减轻，持续时间缩短。迷走神经刺激术后血浆抗癫痫药物浓度未见明显改变。５例中４例患者的脑电图所见较术前有明显改进，表现为原有的棘波、尖波消失，阵发性异常消失或时间缩短；另１例脑电图改变不明显。５例患者除在植于体内脉冲发生器刺激时感到喉部有轻微震动感和声音略有低哑外，未见有其他副作用。心电图均正常。结论迷走神经刺激术治疗顽固性癫痫安全并可有一定效果，但其确切疗效仍有待于进一步研究。     

脑运动区皮质慢性电刺激治疗顽固性中枢性疼痛

目的 探讨运动区皮质电刺激(motor cortex stimulation，MCS)治疗顽固性中枢性疼痛的手术细节及关键。方法 用条形电极对1例右侧丘脑出血后左侧肢体顽固性疼痛患者行运动区皮质慢性硬膜下刺激并分期植入电子脉冲发生器。结果 患者取得满意疗效，无癫痫、偏瘫等并发症。结论 运动区皮质慢性电刺激是目前治疗顽固性中枢性疼痛的有效方法，中央沟的精确定位和选择合适的刺激参数是手术成功的关键。     

Memory rescue and enhanced neurogenesis following electrical stimulation of the anterior thalamus in rats treated with corticosterone

Deep brain stimulation has been investigated as a treatment for memory disturbance but its mechanisms remain elusive. We show that anterior thalamic nucleus (ATN) stimulation administered to corticosterone-treated rats one month prior to testing improved performance on a delayed non-matching to sample task and increased hippocampal neurogenesis. In contrast, no behavioral changes were observed in animals that were tested a few days after surgery. Results of this study suggests that the behavioral effects of ATN stimulation in corticosterone-treated animals was likely dependent on long-term plastic changes, including the development of newly borne dentate gyrus cells of sufficient functional maturity.     

顽固性癫痫的组合手术治疗

目的对部分顽固性癫痫病人，在严格充分的术前评价之后．依据结果将几种手术方式适当的组合使用，并对其临床效果进行评价。方法对同济大学东方医院神经外科收治的116例顽固性癫痫中的25例病人施行联合手术的治疗方法。发作形式为全身强直一阵挛性发作、复杂部分性发作及失神发作等，其中有14例存在两种发作形式。术前均服过多种抗癫痫药．病程后期同时服用2～3种抗癫痫药。25例病人术前均行24h脑电监测及头颅MRI检查．有19例术前行硬膜下皮层电极和深部电极检测，其中1例行头颅PET检查。手术在皮层脑电及深部电极监测下进行。13例行额颢开颅，颞前叶及海马、杏仁核切除＋额部部分区域的软膜下横切术（MST），其中7例附加胼胝体前部切开术；11例行额部开颅，额部软化灶切除＋运动区MST，其中2例附加胼胝体前部切开术；1例行双侧枕顶部开颅，左枕叶萎缩皮层切除＋胼胝体后部切开＋右侧顶枕的MST。结果术后无死亡及严重并发症。术后抗癫痫药物使用减少，术后23例服用一种抗癫痫药，2例服用两种抗癫痫药。术后随访6～12个月，17例手术效果为Engel 1级，4例为Engel2级，4例为Engel3级。40岁以下的患者手术后癫痫控制的可能性显著大于40岁以上者（P〈0．05）；病程在10年以下的患者术后癫痫无发作的可能性显著大于10年以上者（P〈0．05）。头颅MRI上有无明显的结构异常对病人的预后没有影响（P〉0．05）。结论在严格术前评价的前提下，尤其是在有精通神经电生理知识的神经外科医生综合分析下，采用多种手术方式组合治疗顽固性癫痫效果显著。     

慢性难治性丛集性头痛的深部脑刺激治疗

丛集性头痛（cluster headache，CH）是一种剧烈的爆炸样原发性疼痛，位于一侧眼眶、球后和额颞部，并伴有同侧眼球结膜充血、流泪、鼻塞及Homer综合征等。此病人群发病率为（2～6）／10000，年龄20～50岁，平均约30岁，其中男性发病率高于女性。约10％的CH病人可发展为慢性CH（chronic cluster headache，CCH）并且持续1年以上不消退。对于急性发作的CH药物或者吸氧等治疗作用尚可，而对于一些难治性的CCH药物效果欠佳，外科使用三叉神经毁损术效果也不理想，且并发症较多。自用深部脑刺激术（deep brain stimulation，DBS）治疗运动障碍性疾病取得良好临床效果以来，一些学者尝试用DBS来治疗CCH，也取得了良好的效果。现就CCH的诊断、病理生理、DBS的治疗进展作一综述。     

Deep brain stimulation in patients with refractory temporal lobe epilepsy

PURPOSE: This pilot study prospectively evaluated the efficacy of long-term deep brain stimulation (DBS) in medial temporal lobe (MTL) structures in patients with MTL epilepsy. METHODS: Twelve consecutive patients with refractory MTL epilepsy were included in this study. The protocol included invasive video-EEG monitoring for ictal-onset localization and evaluation for subsequent stimulation of the ictal-onset zone. Side effects and changes in seizure frequency were carefully monitored. RESULTS: Ten of 12 patients underwent long-term MTL DBS. Two of 12 patients underwent selective amygdalohippocampectomy. After mean follow-up of 31 months (range, 12-52 months), one of 10 stimulated patients are seizure free (>1 year), one of 10 patients had a >90% reduction in seizure frequency; five of 10 patients had a seizure-frequency reduction of > or =50%; two of 10 patients had a seizure-frequency reduction of 30-49%; and one of 10 patients was a nonresponder. None of the patients reported side effects. In one patient, MRI showed asymptomatic intracranial hemorrhages along the trajectory of the DBS electrodes. None of the patients showed changes in clinical neurological testing. Patients who underwent selective amygdalohippocampectomy are seizure-free (>1 year), AEDs are unchanged, and no side effects have occurred. CONCLUSIONS: This open pilot study demonstrates the potential efficacy of long-term DBS in MTL structures that should now be further confirmed by multicenter randomized controlled trials.