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]. In this case report, repetitive Transcranial Magnetic Stimulation coupled with EEG (rTMS-EEG) was used to demonstrate that focal cortical stimulation can reduce EPC symptoms and that rTMS-EEG can suggest whether a patient could potentially benefit from long-term intracranial cortical stimulation.
2. Methods
We present a 58 year-old man with EPC consisting on debilitating right arm jerks. He had his first generalised tonic-clonic seizure aged 19, carbamazepine was prescribed, and he was seizure-free until age 42. Subsequently, he developed seizures consisiting on right shoulder jerks that could be induced by arm touch or movement, occasionally involving the right arm and leg, leading to falls. The frequency of seizures progressively worsened, becoming almost continuous during day-time, raising the diagnosis of EPC (video of seizures and EEG in supplementary material). At age 50, an episode of status epilepticus was associated with hypoxic brain injury and aspiration pneumonia, requiring ITU admission. A 3T brain MRI showed left nodular sub-ependymal grey matter heterotopia adjacent to the trigone of the left lateral ventricle (Supplementary Material Fig. 1). Although treatment with carbamazepine (600 mg BD), topiramate (400 mg BD) and phenobarbital (60 mg OD) decreased the number of jerks, they remained frequent enough to reduce right arm function. Inpatient video-telemetry and brain positron emission tomography (PET) were performed for presurgical evaluation. PET showed hypometabolism in the left parietal region.
3. Results
On video-telemetry, isolated jerks of the right arm were associated with left central and parietal epileptiform discharges (Fig. 1A). rTMS (Magstim Rapid) with a figure-of-eight coil was tried as a diagnostic procedure. Two trials of 750 pulses with intensity 1.2 times motor threshold (TMS Motor Threshold Assessment Tool - MTAT 2.0) [
], were delivered at 0.5Hz to the left central fronto-parietal region and were associated with a discontinuation of EPC (supplementary video). An improvement with less severe focal motor seizures was noted for two weeks after the rTMS-EEG session. Intracranial telemetry (iEEG) was planned to assess potential resection or chronic cortical stimulation. A 20-contact subdural grid, two subdural 8-contact strips and one 8-contact depth electrode were implanted over the left posterior frontal and parietal regions. The back-averaging of more than 1500 jerks showed that the leading epileptiform activity was over the central region (Fig. 1B–C, Supplementary Material Fig. 2). A 120-h period of subacute cortical stimulation (0.5–1 mA, 130 Hz, 450 microseconds pulse duration) [
] at different contacts over parietal cortex caused a clear reduction in the frequency of the epileptiform activity and decreased the number of seizures. As the epileptogenic area was located over primary sensory cortex, resective surgery was declined and chronic cortical stimulation (CCS) was chosen for treatment. In the same surgical procedure, iEEG electrodes were removed and a Medtronic Activa™ RC was implanted with two permanent four-electrode stimulating strips over the anterior parietal cortex (Fig. 1D). CCS was activated two days after implantation (1.5 mA, 450 microseconds, 130Hz), and an immediate improvement was noted as the patient was able to move his right arm and hand without inducing clonic jerks. Within five years of follow-up the patient reported occasional recurrence of right arm jerks which mitigated by adjusting stimulation intensity up to 3.5mA. Only a minor reduction on topiramate (300 mg BD) has been tried since implantation.
Fig. 1A) Pre-surgical video telemetry sample showing jerks during sleep associated with very low voltage left centro-parietal spikes (C3; P3). B) Subacute cortical stimulation over the parietal cortex caused a clear reduction in the frequency of the epileptiform activity on EEG. C) Intracranial telemetry subdural electrode grids over the left posterior frontal and parietal region. Red dots indicate contacts located in precentral gyrus (1, 2, 6, 7, 11, 12 and 16) and at postcentral gyrus. D) Post-surgical MRI 3D reconstruction showing electrodes positioned over the left parieto-frontal cortices.
The efficacy of CCS was anecdotally reassured when CCS battery failed, causing an increase in right sided jerking for two weeks, which reduced after battery replacement.
4. Discussion
rTMS is a non-invasive technique shown to be safe for depression and other psychiatric disorders [
]. rTMS-EEG during video-telemetry helped in deciding this patient's treatment by inducing significant electroclinical improvement, suggesting that CCS could be considered as long-term treatment.
A PubMed literature search revealed seven papers reporting 16 patients with EPC who had rTMS-EEG without significant side effects (Supplementary Material: Table 1) [
]. Thirteen patients showed a reduction in their clinical seizures while three had no change. Given the small number of reported cases, this may not be representative of the number of negative results due to positive reporting bias.
A PubMed literature search for CCS in EPC found three papers (Supplementary Material: Table 2). Rizzi et al. described one patient with EPC with stimulation at the left caudal zona incerta, which significantly decreased seizure frequency but after two years resective surgery of the left motor cortex was required [
]. No significant side effects were reported from CCS. The ability to modify parameters, and the area of stimulation, suggests that the efficacy of CCS can be improved, and adverse events minimised, in long-term follow-up by appropriate handling.
The pathophysiology of EPC is still unclear, although it has been hypothesised that EPC can originate from an impairment of inhibitory intra-cortical networks activated by thalamo-cortical projections [
]. It is described that the cortex above areas of subependymal heterotopias might also be epileptogenic and this might be related to excellent outcome [
]. In our case, CCS over anterior parietal cortex was chosen as treatment based on intracranial recordings and initial rTMS results.
5. Conclusion
rTMS can modulate ongoing seizures by interrupting neural activity or changing cortical excitability. In our case, the patient's responsiveness to rTMS-EEG suggested a diagnostic predictive role of this technique to estimate CCS efficacy in EPC. Although rTMS-EEG could potentially be useful as stand-alone therapy, the results reported in the literature are inconsistent and further studies are needed.
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Declaration of competing interest
None of the authors has any conflict of interest to disclose.
Acknowledgments
We would like to acknowledge the patient and his family for their support, including consent for the video as supplementary material without facial anonymization.
The analysis of clinical and EEG effects of subacute cortical stimulation were supported in part by a grant from Epilepsy Research UK and by a jointly grant from both Action Medical Research and Great Ormond Street Hospital Children's charity. The EEG was partially reviewed in pilot use of a platform in development by the Multidisciplinary Expert System for the Assessment & Management of Complex Brain Disorders (MES-CoBraD), a project funded with a European Union's Horizon 2020 grant with grant agreement ID: 965422.
Appendix A. Supplementary data
The following are the Supplementary data to this article.
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