
==== Front
Clin Neurophysiol Pract
Clin Neurophysiol Pract
Clinical Neurophysiology Practice
2467-981X
Elsevier

S2467-981X(24)00022-2
10.1016/j.cnp.2024.08.001
Case Report
Directional deep brain stimulation of the centromedian thalamic nucleus reduces DBS-induced ataxia and dysarthria in Lennox-Gastaut Syndrome: A single case study
Neidhart Stephan Stephan.Neidhart@kliniklengg.ch
a⁎
Kohnen Oona Oona.Kohnen@kliniklengg.ch
a
Stieglitz Lennart Lennart.Stieglitz@usz.ch
b
Imbach Lukas Lukas.Imbach@kliniklengg.ch
ac
a Swiss Epilepsy Center, Klinik Lengg, Zurich, Switzerland
b University Hospital Zurich, Department of Neurosurgery, Zurich, Switzerland
c Zurich Neuroscience Center, ETH Zurich and University of Zurich, Switzerland
⁎ Corresponding author at: Swiss Epilepsy Center, Bleulerstrasse 60, 8008 Zurich, Switzerland. Stephan.Neidhart@kliniklengg.ch
12 8 2024
2024
12 8 2024
9 233235
17 5 2024
19 7 2024
6 8 2024
© 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V.
2024
International Federation of Clinical Neurophysiology
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Highlights

• Deep brain stimulation (DBS) of the centromedian thalamic nucleus (CMT) can lead to ataxia and dysarthria.

• Advances in directional DBS based on neuroanatomical considerations may lead to better results in alleviating unwanted side effects of stimulation.

• Stimulation induced dysarthria in CMT-DBS may be improved by targeted reduction of lateral and/or superior thalamic stimulation.

Background

We present a case of a 46-year-old man with Lennox-Gastaut syndrome and drug-resistant epilepsy. An adjunctive neurostimulation therapy strategy was implemented involving bilateral deep brain stimulation (DBS) of the centromedian thalamic nucleus (CMT).

Methods

Robotically assisted implantation of bilateral DBS directional lead system with 8 contacts in the CMT was performed. The clinical course was assessed in repeated in-patient follow-ups.

Results

Initial DBS stimulation resulted in progressive ataxia and dysarthria significantly beyond the level seen before surgery. Deactivation of DBS coincided with improvement of dysarthria. A DBS stimulation paradigm with reduction of lateral and superior stimulation resulted in improvement and eventually complete resolution of the stimulation side effect.

Discussion

This case suggests that stimulation-induced dysarthria in DBS can be improved by targeted reduction of lateral and/or superior thalamic stimulation. When dysarthria and ataxia occur during DBS, directed stimulation to medial thalamic structures and more inferior electrode contacts offers a promising strategy to reduce side effects while maintaining positive effects.

Keywords

Deep brain stimulation
Centromedian thalamic nucleus
Lennox-Gastaut syndrome
Ataxia
Dysarthria
==== Body
pmc1 Introduction

Lennox-Gastaut syndrome (LGS) is a childhood-onset epilepsy characterized by multiple, mostly drug-resistant seizure types, severe cognitive impairment and specific EEG patterns. Recent data derived from the prospective ESTEL trial demonstrates reduction in electrographic seizure frequency in up to 50% of LGS patients by deep brain stimulation (DBS) of the centromedian thalamic nucleus (CMT) (Dalic et al., 2022). In this clinical case, we illustrate how stimulation induced dysarthria in CMT-DBS may be improved by targeted reduction of lateral and/or superior thalamic stimulation.

2 Case

We report a case of a 46-year-old male with Lennox-Gastaut syndrome of unknown etiology and drug-resistant epilepsy with axial tonic seizures, epileptic spasms and atypical absences. Pregnancy of the mother, birth and early childhood development was unremarkable (sitting at 7 months, walking at 1 year, speaking in sentences at 1½ years), no febrile seizures, no vaccination complications, negative family history and no history of meningitis or encephalitis. Repeated MRI scans showed no evidence of a potentially epileptogenic lesion. No systematic genetic testing was performed. Epilepsy was first diagnosed at the age of 6 years. At the age of 40 years, the diagnosis of Lennox Gastaut syndrome was confirmed based on the clinical presentation and in the context of a long-term EEG examination with evidence of nocturnal tonic seizures as well as typical slow spike-and-waves and paroxysms of fast activity in the EEG. Furthermore, the patient over the years presented with slowly progressive ataxic-dysarthric speech with fluctuation in pitch and reduced articulation acuity as well as bilateral symmetric gait ataxia. The patient has been treated with antiseizure medication for 40 years, whereby satisfactory seizure control could not be achieved by pharmacological polytherapy and vagal nerve stimulation. Previous therapies included valproate, mesuximide, ethosuximide, phenobarbital, phenytoin, barbexaclone, acetazolamide, lamotrigine, levetiracetam, topiramate, sultiame, felbamate, oxcarbazepine carbamazepine, clobazam, mesuximide, zonisamide, lacosamide, rufinamide, brivaracetam, perampanel, pregabalin, clonazepam, cannabidiol. Under the most recent antiseizure therapy (valproate, lamotrigine, pregabaline, clonazepam) adequate seizure control still appeared unattainable; serial epileptic seizures persisted, especially at night with tonic seizures and ictal urine loss. Recently, the shared decision was made to pursue an adjunctive neurostimulation therapy strategy involving DBS of the CMT based on a recent clinical study (ESTEL trial (Dalic et al., 2022)). Before surgery, the patient presented with pre-existing dysarthria and ataxia without signs of other focal neurological deficits. Robotically assisted implantation of bilateral DBS directional lead system with 8 contacts (Medtronic Sensight B3300533) in the CMT was performed and connected to a Medtronic Percept pulse generator (Fig. 1A).Fig. 1 (A) Robotically assisted implantation of bilateral DBS in the CMT, surgical planning at University Hospital Zurich, Department of Neurosurgery. The upper left, upper right and the lower left panel illustrate the DBS electrodes and thalamic structures in an MRI projection in a coronal, sagittal and transversal plane respectively. The right DBS electrode is shown in red, entering the ipsilateral CMT, which is highlighted as a structure within a circular red marking. The lower right panel depicts a 3D representation of the two DBS electrodes entering thalamic structures (right DBS electrode in red). The light green area in both the planar views and the 3D representation correspond to the VIM. The stimulation target zone (CMT) is represented as a red circular depiction in the planar views, is not visible in the 3D representation and is only highlighted on the right side. (B) Deep brain stimulation paradigms, DBS parameters and severity of dysarthria under stimulation.

Intraoperative electrocorticography with mapping of the CMT demonstrated complication-free lead implantation in the CMT with detection of single cell- and local field potentials along the implantation trajectory. Contacts 1 and 9 were identified as optimal stimulation points based on post-operative lead reconstruction in CT/MRI-fusion-imaging and comparison to implantation in previous studies (Geevarghese et al., 2016). Since implantation, the patient demonstrated pronounced ataxic dysarthria and bilateral cerebellar ataxia. A CT scan on postoperative day six revealed a 8 × 6 mm intracerebral hemorrhage adjacent to the left DBS electrode, 1.8 cm after intracerebral entry. After gradual increasing of the stimulation amplitude, on postoperative day 70, the patient exhibited progressive ataxia and dysarthria significantly beyond the level seen before surgery. During this time, bilateral monopolar stimulation (contact 1 and 9) with 145 Hz, 90 μsec and 2.15 mA was delivered (Fig. 1B, A). Resolution of the hemorrhage and edema was expected (and confirmed in a further CT). We therefore considered a stimulation-induced adverse effect.

Seventy-five days post-implantation, OFF-testing with deactivation of DBS-stimulation was performed, which resulted in improved ataxia and dysarthria. Subsequent ON-testing with stimulation of more superior electrode contacts (2 and 10) resulted in exacerbation of ataxia and dysarthria, further substantiating the hypothesis of a simulation-induced effect. We then pursued a medial-directional stimulation approach with contacts 2b, 2c, 10a, 10b and initial simulation amplitude 1.00 mA, 125 Hz, 90 μsec. The patient subsequently again demonstrated pronounced improvements in dysarthria and ataxia. Stimulation amplitude was incrementally increased to 2.1 mA (Fig. 1B, B).

Before brain MRI 245 days post operation, DBS was again deactivated, which again coincided with improvement of dysarthria. Imaging revealed a proper on-target placement of the DBS electrodes without evidence of hemorrhage. Directional DBS-stimulation with deactivation of laterally directed contacts was continued; however, deeper contacts were now selected (1 & 9; instead of 2 & 10). Contact 9b was deactivated due to high impedances (0.9 mA, 90 μsec, 145 Hz) (Fig. 1B, C). With subjective aggravation of dysarthria under 1.0 mA, we employed a probatory paradigm using the deepest contacts (0 & 8) with stimulation amplitude 0.9 mA (Fig. 1B, D). We assumed no residual stimulation side effects with this stimulation setting. Seven months later, electrode contacts 1b, 1c and 9a (as in Fig. 1B, C) were again stimulated with bilateral amplitudes now up to 1.8 mA without aggravation of dysarthria/ataxia, but clear reemerging dysarthria/ataxia at 2.1 mA amplitude. The therapeutic effect on seizure frequency remains to be further evaluated. Subjective effects on seizure frequency are reported under the now established stimulation paradigm with contact 1b, 1c and 9a at 1.8 mA. Electrographically, the patient habitually demonstrated two ictal patterns in long-term EEG recordings. Type 1 with anteriorly starting, then diffusely spreading rapid activity, usually with increasing amplitude, partly with embedded spike and spike-wave complexes with overlaying muscle artifacts for a duration of 2–14 seconds; and Type 2 with rather low-amplitude rapid activity in the same region, partly with embedded spike and spike-wave complexes for a duration of 2–6 seconds. With DBS activated as in Fig. 1B, B (2b, 2c, 10a, 10b) with 2.00 mA, 90 µs, 145 Hz, in total 54 ictal EEG patterns were observerd (37 type 1 and 17 type 2) in 24 hours. In a 24 hour period with inactivated DBS, we registered 91 ictal patterns (28 type 1 and 63 type 2). We therefore deduce the presence of a partial therapeutic effect on electrographic seizures as observed previously by Dalic et al. (2022). A clinical correlation for these EEG patterns with distinct seizure types was not possible in all cases. Both patterns did occur during short lasting tonic seizures, but were also observed as subclinical EEG patterns. In the analyzed long term EEG, the majority of these patterns corresponded to previously documented nocturnal tonic seizures.

3 Discussion

Dysarthria as a DBS stimulation-induced side effect has been described by several authors, primarily in patients with Parkinsońs disease and stimulation of subthalamic or ventral intermediate thalamic nuclei (VIM) (Tripoliti et al., 2014). It has been hypothesized that this adverse effect is evoked by functional alteration of corticobulbar and/or cerebellothalamic pathways (Pinto et al., 2005). Therefore, we speculated that this adverse effect may be due to functional alteration of corticobulbar or cerebellothalamic pathways by inadvertent VIM co-stimulation. The VIM is located lateral and superior to the CMT and DBS leads are implanted along a superolateral to inferiomedial trajectory. Stimulation configurations with the aim of minimizing stimulation of superior and/or lateral regions showed improvement stimulation-induced dysarthria in CMT-DBS.

4 Conclusion

This case highlights how advancements in directional DBS guided by neuroanatomical considerations can lead to improved outcomes in mitigating adverse stimulation side effects. Conceptually, this case also suggests that stimulation induced dysarthria in CMT-DBS may be improved by targeted reduction of lateral and/or superior thalamic stimulation. As an important clinical implication, we argue that upon occurrence of dysarthria and ataxia under CMT-DBS, directional stimulation towards medial thalamic structures and more inferior electrode contacts offers a promising strategy to reduce DBS-induces side effects while preserving beneficial effects.

CRediT authorship contribution statement

S. Neidhart: Writing – original Draft, Writing – review & editing, Data curation, Visualization, Investigation, Formal analysis, Methodology; O. Kohnen: Writing – review & editing, Investigation; L. Stieglitz: Writing – review & editing, Visualization, Investigation; L. Imbach: Conceptualization, Data curation, Writing – review & editing, Formal analysis, Methodology, Supervision, Resources, Project administration.

Declarations of interest

None.
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References

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