Combined Neuromodulation (Vagus Nerve Stimulation and Deep Brain Stimulation) in Patients With Refractory Generalized Epilepsy: An Observational Study

Published:September 12, 2022DOI:



      This article describes our findings while treating patients with refractory generalized epilepsy with combined vagus nerve stimulation (VNS) and centro-median deep brain stimulation (CMDBS).

      Materials and Methods

      A total of 11 consecutive patients with refractory generalized epilepsy (ten with Lennox-Gastaut syndrome) previously submitted to VNS and who subsequently underwent CMDBS were retrospectively studied. The VNS final parameters were 2 to 2.5 mA, 30 Hz, and 500 μs, cycling mode, 30 seconds “on” and 5 minutes “off” for all patients. The CMDBS final parameters were 4 to 5 V, 130 Hz, and 300 μs, bipolar, continuous stimulation in all patients.


      There were eight male participants, ranging in age from eight to 49 years (mean 19 years). Follow-up time after VNS ranged from 18 to 132 months (mean 52 months) and from an additional 18 to 164 months (mean 42 months) during combined VNS-CMDBS. All patients had daily seizures. Atypical absences were noted in eight patients, tonic seizures in seven, bilateral tonic-clonic seizures in four, atonic seizures in three, and myoclonic seizures in two patients. Four patients were initially considered responders to VNS. All these patients also had an additional >50% seizure frequency reduction during combined VNS-CMDBS. Seven patients were not responders to VNS, and of those, four had an additional >50% seizure frequency reduction during combined VNS-CMDBS. Eight patients had an additional >50% reduction in seizure frequency when moved from VNS alone to VNS-CMDBS therapy. There were two nonresponders during combined VNS-CMDBS therapy, and both were nonresponders to VNS alone. Nine patients were considered responders during VNS-CMDBS combined therapy compared with baseline.


      This study showed that combined VNS-CMDBS therapy was able to double the number of responders compared with VNS alone in a cohort of patients with refractory generalized epilepsy. We believe these data represent the first evidence that combined neuromodulation may be useful in this quite homogeneous patient population.


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        • Toffa D.H.
        • Touma L.
        • El Meskine T.
        • Bouthillier A.
        • Nguyen D.K.
        Learnings from 30 years of reported efficacy and safety of vagus nerve stimulation (VNS) for epilepsy treatment: a critical review.
        Seizure. 2020; 83: 104-123
        • Cukiert A.
        • Cukiert C.M.
        • Burattini J.A.
        • et al.
        A prospective long-term study on the outcome after vagus nerve stimulation at maximally tolerated current intensity in a cohort of children with refractory secondary generalized epilepsy.
        Neuromodulation. 2013; 16 ([discussion: 556]): 551-556
        • Geller E.B.
        • Skarpaas T.L.
        • Gross R.E.
        • et al.
        Brain-responsive neurostimulation in patients with medically intractable mesial temporal lobe epilepsy.
        Epilepsia. 2017; 58: 994-1004
        • Salanova V.
        • Witt T.
        • Worth R.
        • et al.
        Long-term efficacy and safety of thalamic stimulation for drug-resistant partial epilepsy.
        Neurology. 2015; 84: 1017-1025
        • Velasco F.
        • Velasco M.
        • Velasco A.L.
        • Jimenez F.
        • Marquez I.
        • Rise M.
        Electrical stimulation of the centromedian thalamic nucleus in control of seizures: long-term studies.
        Epilepsia. 1995; 36: 63-71
        • Cukiert A.
        • Cukiert C.M.
        • Burattini J.A.
        • Mariani P.P.
        Seizure outcome during bilateral, continuous, thalamic centromedian nuclei deep brain stimulation in patients with generalized epilepsy: a prospective, open-label study.
        Seizure. 2020; 81: 304-309
        • Vonck K.
        • Boon P.
        • Claeys P.
        • Dedeurwaerdere S.
        • Achten R.
        • Van Roost D.
        Long-term deep brain stimulation for refractory temporal lobe epilepsy.
        Epilepsia. 2005; 46: 98-99
        • Cukiert A.
        • Cukiert C.M.
        • Burattini J.A.
        • Mariani P.P.
        Long-term seizure outcome during continuous bipolar hippocampal deep brain stimulation in patients with temporal lobe epilepsy with or without mesial temporal sclerosis: an observational, open-label study.
        Epilepsia. 2021; 62: 190-197
        • Velasco A.L.
        • Velasco F.
        • Velasco M.
        • Jiménez F.
        • Carrillo-Ruiz J.D.
        • Castro G.
        The role of neuromodulation of the hippocampus in the treatment of intractable complex partial seizures of the temporal lobe.
        Acta Neurochir Suppl. 2007; 97: 329-332
        • Fisher R.
        • Salanova V.
        • Witt T.
        • et al.
        Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy.
        Epilepsia. 2010; 51: 899-908
        • Morrell M.J.
        • RNS System in Epilepsy Study Group
        Responsive cortical stimulation for the treatment of medically intractable partial epilepsy.
        Neurology. 2011; 77: 1295-1304
        • Cukiert A.
        • Cukiert C.M.
        • Burattini J.A.
        • Mariani P.P.
        • Bezerra D.F.
        Seizure outcome after hippocampal deep brain stimulation in patients with refractory temporal lobe epilepsy: a prospective, controlled, randomized, double-blind study.
        Epilepsia. 2017; 58: 1728-1733
        • Cukiert A.
        • Lehtimäki K.
        Deep brain stimulation targeting in refractory epilepsy.
        Epilepsia. 2017; 58: 80-84
        • Parisi V.
        • Lundstrom B.N.
        • Kerezoudis P.
        • Alcala Zermeno J.L.
        • Worrell G.A.
        • Van Gompel J.J.
        Anterior nucleus of the thalamus deep brain stimulation with concomitant vagus nerve stimulation for drug-resistant epilepsy.
        Neurosurgery. 2021; 89: 686-694
        • Park H.R.
        • Choi S.J.
        • Joo E.Y.
        • et al.
        The role of anterior thalamic deep brain stimulation as an alternative therapy in patients with previously failed vagus nerve stimulation for refractory epilepsy.
        Stereotact Funct Neurosurg. 2019; 97: 176-182
        • Zhu J.
        • Wang X.
        • Xu C.
        • et al.
        Comparison of efficiency between VNS and ANT-DBS therapy in drug-resistant epilepsy: a one year follow up study.
        J Clin Neurosci. 2021; 90: 112-117
        • Kulju T.
        • Haapasalo J.
        • Lehtimäki K.
        • Rainesalo S.
        • Peltola J.
        Similarities between the responses to ANT-DBS and prior VNS in refractory epilepsy.
        Brain Behav. 2018; 8e00983
        • Martin R.A.
        • Cukiert A.
        • Blumenfeld H.
        Short-term changes in cortical physiological arousal measured by electroencephalography during thalamic centromedian deep brain stimulation.
        Epilepsia. 2021; 62: 2604-2614