Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy.

OBJECTIVE: To prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years. METHODS: Adults treated with brain-responsive neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL with the Quality of Life in Epilepsy (QOLIE-89) inventory. RESULTS: Of 256 patients treated in the initial trials, 230 participated in the LTT. At 9 years, the median percent reduction in seizure frequency was 75% (p < 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency. We found that 18.4% (47 of 256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-up and an average seizure-free period of 3.2 years (range 1.04-9.6 years). Overall QOL and epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved (p < 0.05). There were no serious AEs related to stimulation, and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators (p < 0.05, 1-tailed χ2). CONCLUSIONS: Adjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS with improved QOL. Stimulation was well tolerated; implantation-related AEs were typical of other neurostimulation devices; and SUDEP rates were low. CLINICALTRIALSGOV IDENTIFIER: NCT00572195. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.

Brain-responsive neurostimulation in patients with medically intractable mesial temporal lobe epilepsy.

OBJECTIVE: Evaluate the seizure-reduction response and safety of mesial temporal lobe (MTL) brain-responsive stimulation in adults with medically intractable partial-onset seizures of mesial temporal lobe origin. METHODS: Subjects with mesial temporal lobe epilepsy (MTLE) were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. RESULTS: There were 111 subjects with MTLE; 72% of subjects had bilateral MTL onsets and 28% had unilateral onsets. Subjects had one to four leads placed; only two leads could be connected to the device. Seventy-six subjects had depth leads only, 29 had both depth and strip leads, and 6 had only strip leads. The mean follow-up was 6.1 ± (standard deviation) 2.2 years. The median percent seizure reduction was 70% (last observation carried forward). Twenty-nine percent of subjects experienced at least one seizure-free period of 6 months or longer, and 15% experienced at least one seizure-free period of 1 year or longer. There was no difference in seizure reduction in subjects with and without mesial temporal sclerosis (MTS), bilateral MTL onsets, prior resection, prior intracranial monitoring, and prior vagus nerve stimulation. In addition, seizure reduction was not dependent on the location of depth leads relative to the hippocampus. The most frequent serious device-related adverse event was soft tissue implant-site infection (overall rate, including events categorized as device-related, uncertain, or not device-related: 0.03 per implant year, which is not greater than with other neurostimulation devices). SIGNIFICANCE: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including patients with unilateral or bilateral MTLE who are not candidates for temporal lobectomy or who have failed a prior MTL resection.

Brain-responsive neurostimulation in patients with medically intractable seizures arising from eloquent and other neocortical areas.

OBJECTIVE: Evaluate the seizure-reduction response and safety of brain-responsive stimulation in adults with medically intractable partial-onset seizures of neocortical origin. METHODS: Patients with partial seizures of neocortical origin were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. Additional analyses considered safety and seizure reduction according to lobe and functional area (e.g., eloquent cortex) of seizure onset. RESULTS: There were 126 patients with seizures of neocortical onset. The average follow-up was 6.1 implant years. The median percent seizure reduction was 70% in patients with frontal and parietal seizure onsets, 58% in those with temporal neocortical onsets, and 51% in those with multilobar onsets (last observation carried forward [LOCF] analysis). Twenty-six percent of patients experienced at least one seizure-free period of 6 months or longer and 14% experienced at least one seizure-free period of 1 year or longer. Patients with lesions on magnetic resonance imaging (MRI; 77% reduction, LOCF) and those with normal MRI findings (45% reduction, LOCF) benefitted, although the treatment response was more robust in patients with an MRI lesion (p = 0.02, generalized estimating equation [GEE]). There were no differences in the seizure reduction in patients with and without prior epilepsy surgery or vagus nerve stimulation. Stimulation parameters used for treatment did not cause acute or chronic neurologic deficits, even in eloquent cortical areas. The rates of infection (0.017 per patient implant year) and perioperative hemorrhage (0.8%) were not greater than with other neurostimulation devices. SIGNIFICANCE: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including adults with seizures of neocortical onset, and those with onsets from eloquent cortex.

Long-term repetitive transcranial magnetic stimulation therapy: new research questions arising from one tinnitus case?

Tinnitus may become refractory to treatment and disabling. Brain transcranial magnetic stimulation (TMS) has shown promise as a therapy, but has been employed primarily short-term. We treated a patient with 5 weeks of weekly repetitive TMS (rTMS), followed by 6 months of monthly rTMS. He was a 75-year-old dentist with chronic tinnitus from occupational noise exposure. Physical examination and MRIs of the auditory canals and brain had revealed no lesions. The patient showed a general gradual, progressive improvement on per cent of severe tinnitus diary days (from baseline 100% to 33%), tinnitus handicap inventory (from baseline score 70 to 18), and mini-tinnitus questionnaire (from baseline score 17 to 6). No changes occurred in serial audiograms. Transient adverse events were a headache during stimulation, and dizziness 30 min after treatment. Implications and questions for future non-invasive neuromodulation clinical research raised by our case are discussed.

Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy.

PURPOSE: We report a multicenter, double-blind, randomized trial of bilateral stimulation of the anterior nuclei of the thalamus for localization-related epilepsy. METHODS: Participants were adults with medically refractory partial seizures, including secondarily generalized seizures. Half received stimulation and half no stimulation during a 3-month blinded phase; then all received unblinded stimulation. RESULTS: One hundred ten participants were randomized. Baseline monthly median seizure frequency was 19.5. In the last month of the blinded phase the stimulated group had a 29% greater reduction in seizures compared with the control group, as estimated by a generalized estimating equations (GEE) model (p = 0.002). Unadjusted median declines at the end of the blinded phase were 14.5% in the control group and 40.4% in the stimulated group. Complex partial and "most severe" seizures were significantly reduced by stimulation. By 2 years, there was a 56% median percent reduction in seizure frequency; 54% of patients had a seizure reduction of at least 50%, and 14 patients were seizure-free for at least 6 months. Five deaths occurred and none were from implantation or stimulation. No participant had symptomatic hemorrhage or brain infection. Two participants had acute, transient stimulation-associated seizures. Cognition and mood showed no group differences, but participants in the stimulated group were more likely to report depression or memory problems as adverse events. DISCUSSION: Bilateral stimulation of the anterior nuclei of the thalamus reduces seizures. Benefit persisted for 2 years of study. Complication rates were modest. Deep brain stimulation of the anterior thalamus is useful for some people with medically refractory partial and secondarily generalized seizures.

Vagus nerve stimulation for 1 year in 269 patients on unchanged antiepileptic drugs.

PURPOSE: To study, in patients on unchanged antiepileptic drugs (AEDs): (1) seizure rates after 3 and 12 months of vagus nerve stimulation (VNS); (2) effects of VNS parameters; (3) patient characteristics versus VNS responsiveness. METHODS: We located in the VNS registry 269 patients treated for 1 year with no changes in AEDs. Seizure rates were calculated at 3 and 12 months. We analyzed: (1) 3 months versus 12 months seizure rates; (2) effects of changing duty cycles between 3 and 12 months; (3) effects of output current; (4) seizure rate changes associated with patient characteristics. RESULTS: Seizure rates improved between 3 months (median = -45%) and 12 months (median = -58%) (P < 0.0001). There were no differences between patients who stayed on standard or rapid cycling, or changed from standard to rapid. Stimulation parameters did not affect seizure rates. VNS responsiveness was associated with older age (P = 0.016), longer duration epilepsy (P = 0.033), and syndromes other than Lennox-Gastaut (P = 0.003). CONCLUSIONS: This was an analysis of treatment outcomes, not a prospective clinical trial. Nonetheless, our results suggest: (1) seizure rates decline with increasing VNS duration; (2) this decline occurs without AED changes; (3) this decline is not due to changes in stimulation parameters; (4) patient characteristics predictive of VNS responsiveness remain elusive.

Observations on the use of vagus nerve stimulation earlier in the course of pharmacoresistant epilepsy: patients with seizures for six years or less.

BACKGROUND: This study retrospectively compared the effectiveness of vagus nerve stimulation (VNS) therapy among a constant cohort of patients in the patient outcome registry, which systematically monitors outcomes of patients receiving VNS therapy. Patients in the study had pharmacoresistant seizures for 6 years or less (early treatment group) or more than 6 years (late treatment group) before initiation of VNS therapy, and results are provided after both 3 and 12 months. REVIEW SUMMARY: Of 405 patients, 51 were in the early and 354 in the late treatment groups. Median age at onset of seizures was 7 years in the early and 4.5 years in the late treatment group. Seizure reduction of 100% was reported in 7.8% (early) and 3.7% (late) patients at 3 months and 11.8% (early) and 4.5% (late) at 12 months (P = 0.033). Reductions in seizure frequency greater than or equal to 90% for early and late treatment groups were similar: 11.8% (early) and 11.0% (late) at 3 months and 23.5% (early) and 17.0% (late) at 12 months. CONCLUSIONS: Patients treated earlier with VNS therapy were twice as likely to report no seizures as patients who had seizures for more than 6 years before they received VNS therapy. The effectiveness of VNS therapy should be assessed among other patients with pharmacoresistant seizures and lesser cumulative seizure loads.

Cerebral activation during vagus nerve stimulation: a functional MR study.

PURPOSE: To study the short-term effects of vagus nerve stimulation (VNS) on brain activation and cerebral blood flow by using functional magnetic resonance imaging (fMRI). METHODS: Five patients (three women, two men; mean age, 35.4 years) who were treated for medically refractory epilepsy with VNS, underwent fMRI. All patients had a nonfocal brain MRI. The VNS was set at 30 Hz, 0.5-2.0 mA for intervals of activation of 30 s on and 30 s off, during which the fMRI was performed. Statistical parametric mapping (SPM) was used to determine significant areas of activation or inhibition during vagal nerve stimulation (p < 0.05). RESULTS: VNS-induced activation was detected in the thalami bilaterally (left more than right), insular cortices bilaterally, ipsilateral basal ganglia and postcentral gyri, right posterior superior temporal gyrus, and inferomedial occipital gyri (left more than right). The most robust activation was seen in the thalami (left more than right) and insular cortices. CONCLUSIONS: VNS-induced thalamic and insular cortical activation during fMRI suggests that these areas may play a role in modulating cerebral cortical activity, and the observed decrease in seizure frequency in patients who are given VNS may be a consequence of this increased activation.

Antiepileptic drug use during the first 12 months of vagus nerve stimulation therapy: a registry study.

Understanding interrelationships between antiepileptic drugs (AEDs) and vagus nerve stimulation (VNS) therapy can guide research into epilepsy treatment. A constant cohort of patients with data available at baseline and 12 months were drawn from the VNS patient outcome registry and analyzed for changes in AEDs and seizure rates. Of the 1,407 patients, group 1 (n = 896) took fewer (n = 228) or the same (n = 668) AEDs at 12 months compared to baseline. Group 2 (n = 511) took additional (n = 251) or different (n = 260) AEDs. Median seizure rate reductions after 12 months of VNS therapy were 58% in group 1 and 55% in group 2. The number of and specific AEDs remained unchanged for 668 patients and dosages remained the same for 269 (40%) of these patients. The most commonly discontinued drugs were topiramate (n = 115), tiagabine (n = 78), carbamazepine (n = 62), lamotrigine (n = 56), and gabapentin (n = 52). Changes in seizure rates were not significantly different among patients who added levetiracetam (n = 151), zonisamide (n = 71), or oxcarbazepine (n = 46) to VNS. Changes in seizure rates were not significantly different among patients whose baseline AEDs were carbamazepine (n = 273), lamotrigine (n = 238), valproate (n = 201), topiramate (n = 190), or phenytoin (n = 151). Our results suggest the following: (a) patients commonly stay on the same AEDs during 12 months of treatment with VNS; (b) the registry cohort who had reduced AEDs by month 12 did not appear to experience any seizure exacerbation; and (c) no specific AED shows promise of unique additive antiepileptic effects in combination with VNS.

Neurostimulation therapy for epilepsy.

Neurostimulation therapy for epilepsy is growing in popularity. By appropriate targeting of applied electrical activation at selected nervous system sites, antiseizure effects may be achieved without the common sedative side effects of antiepileptic medications. Risks of neurostimulation therapy are those associated with the device implantation surgical procedures. Vagus nerve stimulation (VNS) reduces seizures by 45% and has been employed in over 13,000 patients worldwide. New reports suggest VNS is particularly beneficial for patients with Lennox-Gastuat syndome. VNS also reduces sudden unexpected death in epilepsy. New publications describing small, uncontrolled case series also suggest deep brain stimulation and transcranial magnetic stimulation may develop into effective antiepileptic therapies in the future.