FormalPara Key Points

DBS of the anterior nucleus of the thalamus (ANT) has demonstrated efficacy in refractory focal epilepsies and is currently approved by the FDA for adult treatment.

In three adult patients with LGS, ANT-DBS demonstrated a dramatic reduction of seizure frequency, especially convulsive seizures and epileptic falls.

Patients experienced a major improvement in their cognitive and behavioral functioning.

The implantation technique, with its direct MRI-guided targeting, eliminates the need for electrophysiologic confirmation of electrode placement.

The benefits demonstrated in adults are promising prospects for its future use in children.

Introduction

Lennox–Gastaut Syndrome (LGS) is a severe form of epilepsy that usually begins before 8 years of age. Onset after 10 years of age is rare. In some cases, it follows a generalized or focal epilepsy or occurs under particular conditions, such as Down syndrome [7]. This developmental and epileptic encephalopathy, which corresponds to a kind of archetype of epileptic syndrome with multiple etiologies, is characterized by the following triad: (1) epileptic seizures with axial tonic seizures and atypical absences; (2) EEG abnormalities with diffuse slow spike-waves during wakefulness and bilateral fast epileptic rhythms of 10 Hz or more during sleep, and 3) progressive intellectual impairment [3, 7].

The LGS physiopathology remains unclear. Since no animal model exists for this specific electroclinical entity, LGS probably shares characteristics with the pathophysiology of generalized epilepsies. Tonic seizures and fast EEG rhythms are induced by the recruiting action of the thalamus and the slow elements by its inhibitory system [7]. In animal models of absence epilepsies, thalamocortical oscillations have been shown to induce abnormalities and absence seizures [7]. Deep brain recordings in LGS patients have been shown to demonstrate frontal cortex activity [5, 12]. LGS can be conceptualized as a “secondary network epilepsy,” in which epileptic activity is amplified through cerebral networks [7]. Deep brain structure involvement could be a pathway to adjuvant therapeutic approaches such as deep brain stimulation (DBS). Stimulation of the thalamus’ centromedian nucleus (CMN) has shown promising but incomplete results [22,23,24]. DBS targeting the anterior nucleus of the thalamus (ANT) has demonstrated efficacy in refractory focal epilepsies [11] and is currently approved by the Food and Drug Administration for adult treatment, maintaining a positive effectiveness and safety profile after 10 years' follow-up [20].

Although DBS is more expensive than vagus nerve stimulation (VNS), understanding its adult benefits can pave the way for similar success in children. LGS is a model of epileptic encephalopathies in which the epileptiform abnormalities may contribute to progressive dysfunction. Prioritizing the early management of seizures is vital for children’s intellectual development and overall well-being. Additionally, the anterior nucleus is morphologically larger than the CMN, facilitating precise targeting and potentially higher implantation success rates. Herein, we report on three adult patients with LGS who were successfully treated with ANT-DBS in addition to their antiseizure medications (ASM), with follow-up ranging from 18 months to 8 years.

Materials and methods

Three adult patients suffering from LGS with intractable epilepsy and numerous epileptic falls were included in our protocol of DBS of the anterior nucleus of the thalamus (NCT 04771065). The study protocol was reviewed and approved by the Institutional Review Board (IRB)—approval number IRB- MTP_2021_03_202100751. Consent was obtained from both principal caregivers and patients.

All three patients underwent a prolonged video EEG of 48 h as part of their presurgical assessments. EEG data were recorded using the 10–20 system. Two additional anterior/inferior temporal electrodes on each side were systematically added to explore the lower part of the temporal lobes. A polygraphic recording was also conducted, incorporating two EMG electrodes on the deltoid muscles and an electrocardiogram. Cerebral MRI was performed, regardless of whether one had been carried out previously. Diagnosis was based on the electro-clinical triad proposed by the Marseille school for LGS, which includes the mandatory criteria of slow spike-and-wave complexes, generalized fast epileptic rhythms during sleep, and axial tonic seizures [3, 7].

Under general anesthesia, two electrodes (3389-lead model, Medtronic Inc., MN, USA) were implanted using direct targeting with intra-operative MRI and a micro-endoscope to reduce hemorrhagic complications during the transventricular approach. This technique has been published in detail elsewhere [18]. For cases 1 and 3, an implantable pulse generator (IPG) (Medtronic) was positioned in the abdominal area in accordance with our local protocol. For case 2, the VNS generator was removed and the IPG was positioned within the same anatomical lodge (left pectoral region). An immediate post-operative MRI was performed under general anesthesia to determine the exact placement of electrodes and verify the absence of any complications (Fig. 1).

Fig. 1
figure 1

Post-operative Magnetic Resonance Imaging (MRI) of patients 1, 2, and 3. Axial T2-weighted MRI images showing the leads in the anterior nucleus of the thalamus

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Primary caregivers were required to complete a daily self-reported diary card for 3 months prior to brain surgery and throughout the follow-up period to assess seizure frequency, adverse effects, compliance with ASMs, and any behavioral changes (positive or negative).

Activation and programming of the implanted pulse generator was started 1 week after the implantation procedure. Neurosurgeons adjusted parameter settings (G.P, E. CS, Ph. C) during follow-up (1 month after surgery, every 3 months for 2 years, then every 6 months). Electrical settings were adapted to the clinical evolution and individually determined for each patient.

Seizure frequency and severity were evaluated by neurologists specializing in epilepsy and trained to administer questionnaires on quality of life (A. C, Ph. G) [10, 16, 17]. The cognitive-behavioral assessment was specifically evaluated during structured interviews with the patients' primary caregivers, who were asked to specify any positive or negative changes since the previous visit.

Results

Three adult patients (one male and two females), all experiencing daily seizures that included episodes of falling, underwent ANT-DBS, one at the age of 22 years and two at 28 years. One patient achieved seizure freedom 3 years post-surgery, confirmed by a current follow-up of 8 years after DBS, which represents a total seizure-free period of five years (Case 1). Two patients who were followed for 18 and 24 months, respectively, achieved a seizure reduction of over 75% (Case 2 and 3). Patient 3 is currently seizure-free but has been so only for 3 months. All patients demonstrated considerable improvements in adaptive behavior. No side effects were observed with the applied therapeutic stimulation parameters. One patient was able to have her ASMs slightly reduced (Case 2), while the other two prefer to keep their medications unchanged for fear of relapsing. The clinical history and DBS results of these three patients are detailed below.

Case 1

This man, with slight mental retardation and infantile psychosis, began experiencing focal seizures at age 17. Initially, his EEG showed interictal sharp waves and spikes in the left frontal region. A brain MRI demonstrated a white-matter signal anomaly without cortex abnormality of the left frontal lobe. The genetic tests were negative. Despite the use of multiple ASMs, this epilepsy was refractory and progressively evolved to LGS, with the appearance on his EEGs of diffuse slow spike-and-waves, evolving to atypical absences during wakefulness, bilateral fast epileptic rhythms (Fig. 2), and tonic seizures during nocturnal sleep associated with a significant cognitive aggravation. At evaluation, the patient’s epilepsy was characterized by daily seizures, primarily tonic, with up to 15 episodes per day, resulting in numerous falls, despite polytherapy, which included perampanel, levetiracetam, valproate, rufinamide, and clonazepam. Because of the progression of his clinical and EEG condition, demonstrating a bihemispheric epileptogenic activity and typical EEG patterns of LGS (Fig. 2), following a multidisciplinary case conference, DBS of the ANT was proposed at the age of 28 years. The decision-making process for selecting ANT-DBS over VNS was influenced by our center’s extensive experience in DBS [6], the promising results of electrical stimulation of the ANT published in 2010 [11], the extreme severity of the disease in this patient, and above all, our extensive experience with VNS over the past 15 years in LGS.

Fig. 2
figure 2

Case 1. EEG recorded at 25 years of age. International 10–20 electrode placement system and supplementary anterior/inferior temporal electrodes (TA1/TA2: Temporal-Anterior; T1/T2: zygomatic electrode), electrocardiogram, right deltoid, and left deltoid. Recording at 30 mm/s and 70 μV/cm. A The patient is awake. Short atypical absence seizure with bilateral slow spike-waves. B Stage N2 sleep. At the beginning of the plate, there is a sleep spindle. Fast bilateral rhythm at 12 Hz followed by slow spike-waves

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No postoperative complications were reported and the immediate post-operative MRI confirmed correct electrode positioning in the ANT (Fig. 1A). The frequency of seizures decreased significantly during the post-operative follow-up, and the patient achieved seizure freedom from the third year following surgery, classified as Engel 1A. This clinical improvement was accompanied by a clear cognitive enhancement, allowing the patient to engage in discussions, participate in leisure activities, and travel on vacation with his parents. This seizure-free condition persisted 8 years after surgery, the date of the last follow-up. The patient remains under ASMs, and he and his mother are very happy with the outcome. At present, they do not wish to make any changes in his treatment.

DBS settings at the last follow-up were for the left ANT: 1-, 2-, 3-, 0.9 V, 450 µs, 130 Hz; for the right ANT: 1-, 2-, 3-, 1.2 V, 450 µs, 130 Hz. Five years after surgery, the IPG was changed for a rechargeable generator (Medtronic Activa RC).

Case 2

This woman, with moderate intellectual disability, began experiencing epileptic spasms at 6 months of age, with hypsarrhythmia indicated on her EEG. This led to a diagnosis of West syndrome. Throughout her childhood, she experienced various types of seizures, including daily epileptic spasms upon waking, tonic and GTCS, and atypical absence seizures. Epileptic spasms continued into adulthood. At 18 years of age, the patient underwent VNS, which initially provided some benefit, but daily seizures persisted. This patient received multiple ASMs, including valproate and felbamate. EEGs were characteristic of LGS. Genetic testing performed during adolescence was negative. She had no family history of epilepsy or neurological/psychiatric disorders. Due to daily seizures, including several falls per day, a psychomotor slowdown, and some home confinement due to the severity of her epilepsy, ANT-DBS was proposed at age 28. A pre-operative MRI showed no abnormalities. Her medical treatment included rufinamide, lamotrigine, perampanel, topiramate, cannabidiol, and clobazam.

The first 4 months following the ANT-DBS surgery were characterized by a significant reduction in seizure frequency along with noticeable behavioral improvement. After this period, seizures became more frequent. Ten months after surgery, she was experiencing only one or two seizures each day, sometimes accompanied by falls, compared to four or five seizures daily prior to the stimulation. The patient now had one or two clonic seizures per week rather than one per day. Epileptic spasms were also less frequent, and her mother reported only rare atypical absence seizures. She described her daughter as more lively, singing and engaging a bit in family conversations, and walking 1 km per day with her mother. People who had not seen her in a year were amazed by her transformation, including her neurologist. Previously, she had never spoken during her medical consultations, but now she was able to do so.

DBS settings at 1-year follow-up were left and right ANT: C + 0–1–2- 1.8 V, 450 µs, 130 Hz. The effectiveness against seizures remained stable, except for a 15-day period of worsening that coincided with the end of the generator’s life. At 24-month follow-up, her mother reported one convulsive seizure (tonic or clonic) per day, which was described as shorter, with faster recovery. This reflected a 75% to 80% reduction in convulsive seizure frequency. Qualitatively, her mother reported a significant change in life quality, with the patient sleeping less and being more easily rested, leading to increased engagement in daily activities. At her most recent visit, this patient was able to have her ASM slightly reduced (progressive decrease in the daily dose of lamotrigine). DBS settings at the 28-month follow-up were left and right ANT: C + 0–1–2- 1.8 V, 450 µseconds, 130 Hz. Two years after surgery, the IPG was changed for a rechargeable generator (Medtronic Activa RC).

Case 3

This woman, with slight mental retardation, began experiencing focal seizures of the left hemisphere at 3 months of age, followed at 5–6 months by epileptic spams. At this point, her EEG showed a hypsarrhythmia pattern. Convulsive seizures occurred during infancy and atypical absence seizures were observed a short time later. Throughout childhood and adolescence, despite using various ASMs, including lamotrigine, topiramate, levetiracetam, zonisamide, oxcarbazepine and carbamazepine, convulsive seizures and atypical absences persisted. Initially, the brain MRI appeared normal, but a follow-up MRI at age 12 revealed a left parietal porencephalic cavity with hemosiderin deposits linked to a head injury. The genetic tests were negative. EEGs revealed bilateral bursts of slow spike-and-wave activity, predominantly in the left hemisphere, along with brief subclinical atypical absence seizures. During nocturnal sleep, there were fast epileptic rhythms and short tonic seizures with apnea. At evaluation for DBS, she had tonic seizures every night, sometimes accompanied by falls during the day, and two or three GTCS per week. She could receive treatment for clusters of seizures using intrabuccal midazolam. She was treated with valproate, lamotrigine, clobazam, brivaracetam and cenobamate. Perampanel and lacosamide were previously used but discontinued due to lack of demonstrated efficacy. Based on the severity of the epilepsy and the very positive results in case one, DBS was proposed at age 22. Two months after DBS, seizure frequency and behavior improvements were observed. Four months after DBS, her parents and educators reported only one convulsive seizure per month. Twelve months after DBS, it was reported that the patient experienced two convulsive seizures during the day and two convulsive seizures during nocturnal sleep each month. At the time of her last visit, which took place 18 months after DBS, she had been seizure-free for 3 months.

Accompanying the improvement in epilepsy, her parents and the educators at her care home noted a significant change in her behavior. She became more autonomous and capable of preparing breakfast, participated in household chores, and engaged in discussions. Recently, she was a star member of the cast acting and singing for a show at her life care home. She also currently joins in outings with other residents at her life care home and has a boyfriend. The patient remains under ASMs. DBS settings at the 18-month follow-up were left and right ANT: C + 0–1–2- 1.8 V, 450 µs, 130 Hz.

Discussion

Despite the emergence of new ASMs and neuromodulation therapies, such as VNS, LGS remains a therapeutic challenge [2]. The factors of unfavorable long-term outcomes include age of onset before 3 years, high seizure frequency, long exacerbation periods, frequent episodes of status epilepticus and numerous iatrogenic complications [13, 19]. Complete seizure remission in LGS is exceptional. The prerequisites for seizure-free recovery are an absence of structural brain abnormalities on MRI and vigorous treatment from the onset [13]. Fifty years ago, the mortality rate in LGS was estimated to be anywhere from 5 to 17% [7]. Specifically, over a 26-year follow-up period, the mortality ratio was 13.92 for LGS patients compared to 3.11 for all children with epilepsy [1]. Taking in all of these considerations, early effective seizure management in LGS is crucial to supporting intellectual growth and overall health.

LGS is often not considered for surgical approaches. However, given the drug resistance and progressive cognitive decline, exploring surgical options seems a legitimate option [9]. Resective surgeries are only applicable in cases with identifiable cerebral lesions. The observations of healing the LGS by surgery are very rare and evoke the possibility of frontal lobe epilepsy with generalized electro-clinical expression [7, 9]. In addition, children with drug-resistant focal epilepsy may have a more-or-less long transitional phase of generalization with slow spike-waves, fast epileptic rhythms on their EEG, and the possibility of cognitive regression [7]. If they have removable focal lesions, these patients may benefit from surgery. Callosotomy has been addressed in numerous publications, including those focused on LGS, and is considered a palliative treatment when drug therapies fail. This procedure is particularly effective in reducing falls during atonic and tonic seizures and is more effective when performed at an early stage [7]. A more complete surgical resection increases the risk of complications, especially neuropsychological ones. Callosotomy has been demonstrated to be more effective than VNS for atonic seizures [14], although it is associated with a higher morbidity rate. An evidence-based guideline published by the American Academy of Neurology (AAN) included a pooled analysis of four studies with a total of 113 LGS patients treated with VNS, demonstrating a responder rate of 55%. The AAN recommended that VNS may be considered as a treatment option with an evidence level of C [15]. Similarly, a recent meta-analysis of 480 patients showed a responder rate of 54% [8]. As approximately 50% of patients do not have sufficient seizure control, other forms of therapy (such as DBS) offer new and highly promising treatment options.

Various thalamic nuclei, such as CMN, have been investigated for DBS efficacy in LGS, showing improvements in seizure control, neuropsychological outcomes, and quality of life. Velasco et al. first reported a favorable outcome of CMN-DBS in LGS [22,23,24]. In their latest publication, the authors reported that patients with the most severe seizures and psychomotor deterioration responded best to stimulation. The decrease in seizures began as early as the first month of stimulation, but peaked only at 7 months. A prospective, double-blind, randomized study was conducted to evaluate CMN-DBS in patients with LGS. At the end of the study, there was a median 50% reduction in all seizure types across all patients. Shlobin et al. (2023) conducted a systematic review assessing DBS targeting the CMN, and reported a mean seizure reduction of 62.9% ± 31.2% [21]. Three patients (6.4%) experienced seizure freedom. However, individual outcomes varied significantly, and the need for alternative targets remains evident. In addition, quality of life improved in 30 out of 34 (88.2%) patients and was unchanged in four (12%) [21]. Bonda et al. (2024) shared their experience with six pediatric patients aged 6 to 19 years. Among these patients, one showed no change in seizure frequency, one had a 10% reduction, and the remaining four experienced a decrease of more than 60% in their seizure frequency [4].

Recent advancements in DBS have sparked interest in alternative treatment targets. The ANT has been chosen as a target for DBS in many studies in refractory epilepsies [11, 20], but never in LGS. Our cases demonstrate that ANT-DBS can result in complete seizure freedom, and this outcome remained consistent at the patient’s most recent follow-up visit. As previously mentioned, LGS can be conceptualized as a form of secondary network epilepsy, where epileptic activity is enhanced through cerebral networks [7]; as such, it is crucial that the placement of DBS electrodes within the anatomical and physiological target be precise [22]. The ANT is morphologically larger than the CMN, which facilitates precision targeting and potentially increases implantation success rates. The implantation technique, with its direct MRI-guided targeting, eliminates the need for electrophysiologic confirmation of electrode placement, thus reducing procedure duration and decreasing surgery-associated morbidity. Furthermore, the use of a micro-endoscope to secure the thalamus entry point within the ventricle—without affecting the vascular structures—plays a pivotal role in further minimizing surgical risks [18].

Conclusion

Despite these encouraging results, there are still several gaps in our knowledge. The mechanisms underlying ANT stimulation in LGS are not yet fully elucidated, thereby warranting further research to comprehensively understand its mode of action and validate these preliminary findings. The impressive effectiveness is promising, as indicated by a seizure-free period of five years after surgery for case 1, the dramatic improvement in cases 2 and 3 with greater than a 75% reduction in convulsive seizure frequency and falls, and the remarkable enhancement in the patients’ quality of life which allows them to engage in social activities. This suggests that electrical stimulation of the ANT could be more broadly considered for controlling disabling seizures in LGS, especially in patients who experience falls. In this series, no side effects of ANT-DBS were observed, particularly no psychiatric disorders. On the contrary, all patients exhibited improvements in cognitive and behavioral functioning. Thalamic stimulation may serve as a complementary therapy or provide an alternative in cases where standard treatment has failed. The current use of pediatric thalamic stimulation is limited, but the benefits demonstrated in adults are promising prospects for its future use. The better epilepsy is controlled in childhood, the better the child’s cognitive development will be.