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Background
Focal epileptiform discharges are frequently encountered in hospitalized patients with acute brain injuries or structural brain abnormalities. They constitute an increased risk for future seizures1-3, show a frequency-dependent association with brain tissue hypoxia4, 5, and are independently associated with poor outcome in patients with and without brain injury6-10. Whether the discharges themselves are causally related to outcome is unknown. Testing this would require a tool capable of reducing epileptiform discharge burden rapidly.
A 1-2 week course of daily Repetitive Transcranial magnetic stimulation (rTMS) is a non-invasive means of focally inhibiting an underlying brain region. One fundamental barrier to testing this intervention is that it takes 1-2 weeks, not a feasible time frame for an acutely needed therapy. rTMS protocols for psychiatric conditions have recently been shown to have equivalent treatment efficacy after consolidation from months-long daily treatments to 10 hourly treatments over several days15, 16. This pilot study aims to assess a similarly accelerated course of rTMS for patients with symptomatic epileptiform discharges.
Methods
We conducted an open-label Phase I prospective clinical study of TMS in patients with symptomatic focal epileptiform discharges and seizures. We enrolled adult patients receiving continuous EEG monitoring with focal status epilepticus or focal periodic discharges and (a) symptoms attributable to these discharges including time-locked focal motor activity, encephalopathy or focal deficits, or concomitant clinical or electrographic seizures emanating from the same brain region or (b) electrographic characteristics associated with brain tissue hypoxia. Patients were only enrolled if there was no intention of the treating clinical team at time of enrollment to add an antiseizure medication. Enrolled patients completed two consecutive days of three 30 min sessions of 1 Hz rTMS spaced 1 hour apart at 100% of resting motor threshold, targeting the site of maximal discharge amplitude or focal seizure onset on a full montage scalp EEG montage. We measured epileptic discharge and/or seizure burden for 24 hours preceding and 24 hours following the treatment. Our primary outcome was the proportion of patients able to complete the full protocol and our primary safety outcome was treatment-emergent serious adverse events, as adjudicated by an independent panel. Here, we report an interim analysis of the first 4 patients.
Results
Between November 2022 and March 2024, four patients have been enrolled. The mean +/- SD age was 73 (5.7). 3 of 4 patients (75%) completed the study protocol. One patient had treatment aborted after a single TMS session due to an adverse event (focal electrographic seizure). Independent review concluded this seizure was not clearly caused by the treatment (the patient had been having frequent seizures). Comparing the normalized burden of epileptiform activity 24 hours after compared to before treatment, subject 1 experienced at 42.5% decline in seizures, subject 2 had a 5.9% increase in epileptiform discharges and subject 3 had a 9.1% decline in discharges.
Conclusion
The interim analysis shows that accelerated rTMS treatment may be safe and feasible in patients with refractory focal epileptiform activity.
References
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