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Responsive Neurostimulator Implantation Outcomes in Idiopathic Generalized Epilepsy

Grace Li, B.S.¹; Atheel Yako, D.O.²; Christopher M. Parres, M.D.²; Andrew J. Zillgitt, D.O.²; Michael D. Staudt, M.D., M.Sc.^3,4

¹Oakland University William Beaumont School of Medicine

²Department of Neurology and ³Department of Neurosurgery, Corewell Health William Beaumont University Hospital, Royal Oak

⁴Department of Neurological Surgery, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine

Idiopathic generalized epilepsy (IGE) accounts for nearly 20% of epilepsy cases, and up to 30% remain drug-resistant despite appropriate anti-seizure medications. Because seizures often arise from broad, bilateral networks, most patients are not candidates for resective surgery.
Neuromodulation therapies offer an alternative approach, but available evidence remains limited.
This study evaluates outcomes in adults with drug-resistant IGE treated with responsive neurostimulation of the centromedian thalamic nucleus (RNS-CMN).

Introduction

Aims and Objectives

Primary

Evaluate the percent reduction in generalized tonic-clonic seizures from baseline to last follow-up.�

Secondary

Determine responder rate (≥50% seizure reduction).
Compare seizure outcomes at 6 months vs. last follow-up using Engel classification.
Compare outcomes across different stimulation frequency ranges.
Evaluate charge density in relation to seizure outcomes.

Methods

Results & Discussion

References

Lesser RP, Kim SH, Beyderman L, Miglioretti DL, Webber WRS, Bare M, et al. Brief bursts of pulse stimulation terminate after-discharges caused by cortical stimulation. Neurology. 1999;53(9):2073–2081. doi:10.1212/WNL.53.9.2073
Sobayo T, Mogul DJ. Should stimulation parameters be individualized to stop seizures: evidence in support of this approach. Epilepsia. 2016;57(1):131–140. doi:10.1111/epi.13259
Nanda P, Sisterson N, Walton A, Chu CJ, Cash SS, Moura LMRV, Oster JM, Urban A, Richardson RM. Centromedian region thalamic responsive neurostimulation mitigates idiopathic generalized and multifocal epilepsy with focal to bilateral tonic–clonic seizures. Epilepsia. 2024;65(9):2626–2640. doi:10.1111/epi.18070
Speakes ME, Reznik-Schaefer K, Al-Ramadhani R, Fernandez LD, Hect JL, Abel TJ, Welch WP. Treatment of pediatric drug-resistant generalized epilepsy with responsive neurostimulation of the centromedian nucleus of the thalamus: a case series of seven patients. Epilepsy Res. 2025;210:107516. doi:10.1016/j.eplepsyres.2025.107516.
Couturier NH, Durand DM. Corpus callosum low-frequency stimulation suppresses seizures in an acute rat model of focal cortical seizures. Epilepsia. 2018;59(12):2219–2230. doi:10.1111/epi.14595
Koubeissi MZ, Kahriman E, Syed TU, Miller J, Durand DM. Low-frequency electrical stimulation of a fiber tract in temporal lobe epilepsy. Ann Neurol. 2013;74(2):223–231. doi:10.1002/ana.23915
Alcala-Zermeno JL, Starnes K, Gregg NM, Worrell G, Lundstrom BN. Responsive neurostimulation with low-frequency stimulation. Epilepsia. 2023;64(2):e16–e22. doi:10.1111/epi.17467
Kokkinos V, Urban A, Sisterson ND, Li N, Corson D, Richardson RM. Responsive neurostimulation of the thalamus improves seizure control in idiopathic generalized epilepsy: a case report. Neurosurgery. 2020;87(5):E578–E583. doi:10.1093/neuros/nyaa001

Acknowledgements

The authors thank the Neurology and Neurosurgery teams for their assistance with clinical data acquisition and patient evaluation. Institutional support from Oakland University William Beaumont School of Medicine is acknowledged. This research received no external funding.

RNS may reduce seizures through acute interruption and long-term neuromodulation¹, potentially via inhibitory neurotransmitter release or depolarization block².
The stimulation frequencies used in this cohort (≤40 Hz) differ from prior IGE RNS studies but maintained charge densities comparable to published series^3,4.
Evidence from animal and human studies supports low-frequency stimulation (LFS) as a suppressor of epileptic activity^5-7, potentially through alignment with thalamo-cortical network dynamics².
In this series, LFS (≤10 Hz) was associated with >50% GTC reduction in most recipients, suggesting its potential applicability in CMN neuromodulation for drug-resistant IGE.
RNS within the bilateral CMN produced a 79.5% average reduction in GTCs and prolonged seizure-free intervals, consistent with emerging data in drug-resistant IGE^3,8.
These findings support RNS as a safe, promising neuromodulatory option for drug-resistant IGE, with additional insight anticipated from NAUTILUS.

Conclusions

Patient	Age at RNS Implant (y/o)	Age of Epilepsy Onset to RNS implantation (years)	RNS post-operative follow up (months)	Pre-RNS GTC Frequency (Avg)	Post-RNS GTC Frequency (at last follow up)	Percent Change	Longest GTC-free interval (months)	Percent-time of GTC-freedom after RNS implantation (%)	Medication Reduction (Y/N)	VNS Therapy Changes (Y/N)
1	33	29	63	4/year	4/year	No change	18	29	Y	Y - IPG at EOS
2	27	21	55	1/year	0/year	100 decrease	55	100	Y	N/A
3	41	37	46	5/year	0/year	100 decrease	24	52	N	N/A
4	50	12	42	1/year	2/year	100 increase	21	50	N	N/A
5	25	10	40	9/year	4/year	56 decrease	9	23	Y	N/A
6	38	23	27	6/year	0/year	100 decrease	14	52	Y	N/A
7	23	13	23	1/year	0/year	100 decrease	21	91	Y	N/A
8	22	3	22	24/year	4/year	83 decresae	7	32	N	N/A
9	26	14	16	60/year	7/year	88 decrease	8	50	Y	N/A
10	48	39	14	6/year	3/year	50 decrease	6	43	Y	N/A

Inclusion criteria	Exclusion criteria
1. ≥ 18 years of age 2. Diagnosed with medically intractable idiopathic generalized epilepsy 3. Has undergone implantation of a responsive neurostimulator device at Beaumont Hospital, RO (from 01/01/2020 to 11/30/2023)	1. < 18 years of age 2. Not diagnosed with medically intractable idiopathic generalized epilepsy 3. Has not undergone implantation of a responsive neurostimulator device at Beaumont Hospital, RO 4. Pregnant women

Retrospective EMR Review

Patient Information

Demographics
Epilepsy history
MRI/EEG findings

Surgical parameters
Device programming settings
Clinic follow-up duration

Outcomes

Percent reduction in generalized tonic-clonic seizures
Responder rate (≥50% reduction)
Last clinic follow-up

Engel classification at 6 months

I-II = good
III-IV = poor

Patient	Sex	Age (y/o)	Age at Epilepsy Onset (y/o)	Age at RNS implant	Epilepsy Duration Before Implantation	Epilepsy Risk Factors	Seizure Types	EEG Findings	Brain MRI	Electroclinical Syndrome	ASMs (total #)	Previous ASMs (total #)	VNS (Y/N)
1	F	39	4	33	29	FS	M, GTC	3 Hz Generalized S/PSW, GPFA	No epileptic lesions	JME	CNB, BRV, LTG, VPA (4)	CBZ, TPM, ETS, ZNS, LCM, CBD, GBP, CLB (8)	Y
2	F	32	6	28	22	None	A, M, GTC	3-4 Hz Generalized S/PSW	No epileptic lesions	JME	LTZ, ZNS (2)	ETS, LEV (2)	N
3	F	44	4	41	37	FHx	A, M, GTC	3-4 Hz Generalized S/PSW, GPFA	No epileptic lesions	JME	BRV, LTG, ZNS, CZP (4)	VPA, CBD, LEV, TPM, PER, ETS (6)	N
4	M	54	38	50	12	FHx	A, GTC	4-5 Hz Generalized S/PSW, GPFA	No epileptic lesions	JAE	BRV, CBD, LTG (3)	VPA, TPM, ZNS, LCM (4)	N
5	F	28	15	25	10	None	A, GTC	3.5 Hz Generalized S/PSW	No epileptic lesions	JAE	TPM, ETS (2)	CBZ, VPA, LEV, LTG, CZP, BRV, CBD, CNB, LCM, PER (10)	N
6	F	40	15	38	23	FHx	A, GTC	Generalized S/PSW in sleep architecture	No epileptic lesions	JAE	LCM (1)	ZNS, TPM, VPA, LEV, PB, PHT, CBZ, LTG, BRV, ETS (10)	N
7	M	25	10	23	13	FHx	M, GTC	3-5 Hz Generalized S/PSW, GPFA	No epileptic lesions	JME	LCM, CLB, ETS (3)	BRV, LEV, VPA, LTG, TPM (5)	N
8	F	24	19	22	3	None	M, GTC	3-4 Hz Generalized S/PSW	No epileptic lesions	JME	LTG, CLB (2)	TPM, LEV, PER, BRV, ZNS, CNB (6)	N
9	F	27	12	26	14	None	A, M, GTC	3-4 Hz Generalized S/PSW	Cerebellar volume loss, nonspecific white matter changes	JME	LTG (1)	ETS, LEV, VPA, BRV, ZNS, PER, LCM, CBD, CLB, CNB (10)	N
10	M	49	9	47	38	FHx	A, GTC	3 Hz Generalized S/PSW, GPFA	No epileptic lesions	JAE	OXC, ZNS (2)	PHT, VPA, LTG, LCM, LEV (5)	N

RNS Implantation

Table 1: General Patient Information

Table 2: Patient Outcomes

Figure 1. Pre- and post-RNS implantation GTC frequency. RNS therapy in patients with drug-resistant IGE resulted in a substantial reduction in generalized tonic–clonic (GTC) seizure burden. Across all ten patients, the average annual GTC frequency decreased from 11.7 to 2.4 seizures/year, reflecting a 79.5% reduction after implantation. Notably, 80% of the cohort achieved ≥50% seizure reduction, and 40% were GTC-free at last follow-up, demonstrating robust and durable seizure control following bilateral CMN neuromodulation.

Figures 2–3. Electrocorticography (ECoG) and representative clinical outcomes following RNS implantation. Patient 1, who averaged 1 GTC per year pre-implantation (Table 2), demonstrated no net change in annual frequency but achieved an 18-month GTC-free interval and a reduction in antiseizure medication burden (Fig. 2A–D). Patient 2, whose baseline frequency was 2 GTCs per year, became GTC-free throughout follow-up (Fig. 3A–D). These cases illustrate the variability of clinical benefit observed with bilateral CMN RNS in drug-resistant IGE.

Figures 4–5. Electrocorticography (ECoG) and clinical outcomes in patients with partial GTC reduction. Patient 5 demonstrated a 56% decrease in annual GTC frequency, improving from 9 to 4 GTCs per year (Table 2), with sustained reductions throughout follow-up (Fig. 4A–D). Patient 10 achieved a 50% decrease in GTCs, from 6 to 3 per year, reflecting a stable partial response to RNS therapy (Fig. 5A–D). These cases represent intermediate outcomes within the cohort, illustrating meaningful seizure reduction even when complete remission is not achieved.