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 »  Abstract
 » RNS Overview
 » Outcomes
 »  Safety and Compl...
 »  Future Direction...
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Table of Contents    
SYMPOSIUM
Year : 2020  |  Volume : 68  |  Issue : 8  |  Page : 278-281

The Impact of Responsive Neurostimulation on the Treatment of Epilepsy


1 Drexel University College of Medicine Student, Philadelphia, PA, USA
2 Post-Doctoral Fellow, Department of Neurological Surgery, Thomas Jefferson University Hospitals, Philadelphia, PA, USA; Neurosurgeon, Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
3 Assistant Professor, Department of Neurological Surgery, Thomas Jefferson University Hospitals, Philadelphia, PA, USA
4 Professor, Department of Neurological Surgery, Thomas Jefferson University Hospitals, Philadelphia, PA, USA

Date of Web Publication5-Dec-2020

Correspondence Address:
Dr. Ashwini Sharan
909 Walnut Street, Philadelphia, PA 19107
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.302468

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 » Abstract 


There is a considerable number of patients with epilepsy that have drug resistant epilepsy (DRE). An additional option for these patients is resective surgery of ictal onset zones. However, a significant portion of DRE patients have unidentified or unresectable ictal zones. For these patients, RNS is a potential treatment option. The RNS system is a closed loop system that delivers stimulation in response to ECoG changes at seizure foci. It is programmed with an algorithm capable of detecting specific patterns of epileptogenic activity and triggers focal stimulation to interrupt seizures. The long term monitoring potential of the RNS system allows for a better understanding of the circadian rhythms behind epilepsy.


Keywords: Responsive stimulation, closed-loop neurostimulation, neuromodulation, circadian rhythm
Key Message: The RNS System is a programmable device composed of depth or subdural strip leads, a pulse generator, and an external programmer.
The RNS system can detect specific patterns of ECoG activity and trigger stimulation to stop the seizure.
The RNS system is approved for patients at least 18 years old that have no more than 2 epileptogenic foci with at least 3 disabling seizures per month.
The RNS system is an effective and safe treatment option for DRE patients.
The long term ECoG recording provided by RNS allows for circadian patterns of epilepsy to be further explored.


How to cite this article:
Mandloi S, Matias CM, Chengyuan W, Sharan A. The Impact of Responsive Neurostimulation on the Treatment of Epilepsy. Neurol India 2020;68, Suppl S2:278-81

How to cite this URL:
Mandloi S, Matias CM, Chengyuan W, Sharan A. The Impact of Responsive Neurostimulation on the Treatment of Epilepsy. Neurol India [serial online] 2020 [cited 2021 Feb 28];68, Suppl S2:278-81. Available from: https://www.neurologyindia.com/text.asp?2020/68/8/278/302468




The gold standard for seizure patients is antiepileptic drug therapy. However, approximately 30% of patients have minimal relief of seizures and thus have drug-resistant epilepsy (DRE).[1] An underutilized option for these patients is resective surgery of ictal onset zones. While this has been associated with seizure freedom, a significant portion of DRE patients have unidentified or unresectable ictal zones.[1] Thus, neuromodulation can be used as a treatment option for this subset of patients. The Responsive Neurostimulation (RNS) system (Neuropace, Inc, Mountainview, CA) is a closed-loop system that delivers stimulation only in response to changes in neural activity at seizure foci.[1] The RNS system is approved by the US Food and Administration (FDA) as a treatment option for adults with medically refractory focal onset seizures arising from one or two foci.[1] This review will summarize both the benefits and complications of the RNS system.


 » RNS Overview Top


The RNS System provides a closed-loop brain responsive neurostimulation in response to abnormal electrocorticography (ECoG). Abnormal ECoG is typically observed at the onset of seizure activity.[1] As described in detail by Matias and colleagues, the patient's seizure foci are identified through video-EEG monitoring, noninvasive EEG, MRI imaging, PET, SPECT, fMRI and MEG. Once seizure foci are identified, depth and cortical leads can be placed. The depth and/or cortical leads are attached to a cranially implanted neurostimulator.[1] The neurostimulator continuously monitors ECoG activity and is programmed to detect specific ECoG patterns that are set by the managing physician. There are three seizure detection tools that are available: line-length, area, and bandpass. The line-length tool measures the total length of a signal in a window of time and compares it to recent measurements.[1] A detection is made if there is a frequency or amplitude increase. The area tool functions by measuring the area between the EcoG signal and baseline. A detection is made if the area is different from past measurements. In the band pass tool, the physician sets the upper frequency, lower frequency, and amplitude. If the frequency and amplitude surpass a threshold, a detection is made. Once a detection is made, stimulation occurs in biphasic square waves.[1] For additional details regarding lead placement refer to Matias and colleagues.[1] The RNS software allows ECoG data to be uploaded and stored in an online data system, allowing physicians to monitor interictal, ictal, and longitudinal activity among the population.

Candidate selection

The RNS system has been approved for the adult population that has disabling partial onset of seizures. As only two leads can be connected to the stimulator, no more than two foci can be identified and selected for implantation. The patients must have medically intractable epilepsy and be unresponsive to at least two antiepileptic drugs.[1]


 » Outcomes Top


Overall seizure control

The RNS System's safety and efficacy is supported by Class I evidence from a double blind, randomized, pivot trial. The initial results of this was published in 2011 by Morell and Colleagues.[2] The patients in this trial had intractable epilepsy for several years with an average age 34 years old. The median number of disabling seizures prior to RNS treatment was more than 10 a month.[2] 49% of patients had a neocortical onset and 44% had a mesial temporal onset.[2] Approximately 1/3 of the patients had prior epilepsy surgery and another 1/3 was treated with vagus nerve stimulation.[2] Three months after implantation (a 12 week blinded period including one month with no activation), the seizure frequency was reduced for the stimulation and the sham groups, 37.9% and 17.3% respectively.[2] In the same study, there is a significant reuction in seizure frequency during the open-label phase as well.[2] More importantly, over time the difference between the groups increased with a statistically significant difference providing evidence for the efficacy of the RNS system.[2] Using a last observation carried forward analysis (LOCF), the median seizure reduction at year 8 is 66% with 30% achieving more than 90% reduction in the most recent 3 months of observation.[3] Additionally, seizure reductions are not significantly different for patients whose foci was the mesial temporal lobe compared to people whose seizures started in the neocortex.[3] The data obtained from companion 2017 publications indicates that the median percent reduction in seizures was ˜70% for mesial temporal, frontal, and parietal lobes.[4],[5] Additionally, a small number of patients with seizures in the lateral temporal and occipital lobes received benefit.[4],[5] The average follow-up time on these patients was greater than 6 years.[4],[5]

Seizure control with hippocampal stimulation

Currently, mesial temporal lobe resection can eliminate seizures in patients with unilateral mesial temporal lobe (MTL) seizures.[4],[5],[6] Resection is not optimal in patients with bilateral MTL due to an increased risk of anticipated memory deficits. However, unilateral resection of a patient with bilateral MTL could palliate the seizures substantially.[4],[6],[7] It is not always possible to establish MTL lateralization within the 1-2 weeks of inpatient video-EEG. Therefore, in select patients, RNS might have utility to localize seizure foci so resection can be performed.[4],[6],[7] Hirsch and colleagues detailed the use of RNS in the determination of seizure foci as well as the outcomes of resection. 24 patients underwent bilateral MTL lead placement for the RNS system treatment.[6] Prior to MTL resection, following a three month implant of the RNS system, the median percent reduction of frequency disabling seizures was 37%.[6] The data collected from the RNS system was used to determine the seizure foci. 9 patients had exclusive unilateral MTL seizures recorded, while the remaining 15 had bilateral seizures recorded.[6] 13 out of the 15 patients with bilateral seizures had more than 90% of the seizures on one side.[6] Thus, localization of the primary point of seizure activity could be located in patients with bilateral MTL seizures using RNS. With an average of a 35 month follow-up, the median reduction of in-patient reported seizures following unilateral MTL resection was 100%.[6] 71% of patients were free of disabling seizures for at least three months.[6] [Table 1] summarizes the results obtained by Hirsch and colleagues.[6] MTL resection can cause adverse events that include worsening in baseline depression (12.5%) and worsening of preexisting memory complaints (8.3%).[6] Lateralization of MTL seizure foci could be a multimodal approach that can include the RNS system to monitor seizure foci over an extended period of time.
Table 1: Reduction in seizure frequency with hippocampal stimulation following unilateral MTL resection

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Seizure control with thalamic stimulation

Most commonly, thalamic stimulation involves open looped stimulation of the anterior nucleus of the thalamus.[8],[9],[10],[11] Currently, there has been research detailing the impact of RNS (closed loop stimulation) on the thalamus.[8],[9],[10],[11] The centromedian thalamus has been targeted in research due to the diffuse cortical projections involving the neocortex. The centromedian thalamus (CMT) plays a critical role in cortical excitability and wakefulness. Thus, there is evidence that the CMT plays a role in seizures.[9],[11] Burdette and colleagues analyzed the clinical utility of brain-responsive corticothalamic stimulation of the CMT and neocortex in seven patients.[8] The median seizure frequency was 52 per month and all patients were receiving multiple antiepileptic drugs. Five out of the seven patients have been treated with cortical resection.[8] All seven patients had one lead in a neocortical region within the seizure onset zone and the second lead in the ipsilateral CMT.[8] One patient had a bilateral regional foci; therefore, two neurostimulators were placed with 2 depth leads each respectively ipsilateral in each CMT. The charge density delivered to the CMT was between 0.3 μC/cm2 to 4.7 μC/cm2 with durations of 2,000-5,000 ms2. Burdette and colleagues found that the median % reduction in disabling seizures was 88% while the median % reduction in all seizures was 73%.[8] [Table 2] summarizes the results obtained by Burdette and colleagues.[8] Their results showed that for some patients with regional neocortical focal seizures, RNS targeting the CMT and neocortex can achieve meaningful seizure reductions.[8] Additionally, it was found that stimulation related contralateral paresthesias of the face and arm occurred in all patients during the in office testing.
Table 2: Reduction in seizure frequency with thalamic stimulation

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Furthermore, Gummadavelli and colleagues reported the first use of the RNS system in the CMT nucleus of a human and ambulatory recordings.[9] In this patient, the depth electrode array was placed in the CM nucleus and the two strip electrodes were placed on the onset region of the posterior parietal lobe.[9] The patient had 3-6 seizures per day and was resistant to six antiepileptic drugs prior to treatment. It was found from the initial report of ambulatory icEEG (intracranial EEG) recordings that many seizures on the parietal strip were also present on the CM electrode.[9] The thalamic electrode can then be used not only as a stimulation target but also as a detection source. It was reported that the CM thalamic electrode has episodes of electrographic seizures that correlate to clinical seizures more often. Gummadavelli and colleagues postulated that the CM nucleus may play a role in the clinical manifestation of seizures; however, more research must be done on this. RNS was also conducted on two pediatric patients, one with Lennox-Gastaut Syndrome and one the Autism Spectrum disorder.[10],[16] There was no safety or efficacy difference found in these two patients, thus broadening the scope of RNS utilization.[10],[16]

Utilization of RNS data allows for circadian monitoring

At present, there is still controversy related to seizure activity and interictal epileptiform discharges.[12] The rate of pathological discharges can fluctuate overtime and increase or decrease before seizures. As the RNS system records electrocorticographic activity at the seizure foci, it is suited for analysis of interictal epileptiform activity rhythms on a chronic longitudinal scale. Baud and colleagues used the data from the RNS system of 37 patients to analyze the periodicity associated with interictal epileptiform activity over a long time scale.[12] The patients had placement of the RNS system in the mesial temporal and neocortical regions.[12] It was found that the multidien wavelength coefficient with daily interictal epileptiform activity (IEA) time had a Pearson correlation of r = 0.93 with P = 0.[12] Spectral decomposition revealed ultradian and circadian rhythms as well as longer periodicities of 5.5-33 days.[12] It was revealed that in addition to circadian rhythms, IEA fluctuates over multidien rhythms that can vary across subjects.[12] The multidien rhythm is however stable within subjects for many years. It was also found that seizures occur during narrow phases of the circadian and multidien rhythms indicating that seizures may be organized by underlying biological clocks that operate across a variety of timescales. Past quantitative methods, not focused on the RNS system, have shown both circadian and ultradian rhythms associated with IEA. The use of the RNS system has allowed a longer periodicity trend to be discovered within patients.[12] The results obtained by Baud and colleagues indicate the existence of unidentified factors that regulate slow epileptic fluctuations. The results additionally point to circadian and multidien oscillators may be comodulated. Spencer and colleagues detailed the strong 24-hour circadian pattern of epileptic discharge using the RNS system.[13] It was found that short duration epileptiform activity had a nonrandom circadian pattern with peaks during sleep hours. Long-duration epileptiform bursts showed differences in rhythmicity deepening on seizure focus.[13] Non Limbic episodes occurred in a monophasic nocturnal prevalent circadian pattern. Mesial temporal/limbic episodes occurred in a more complicated 24 hour pattern.[13] Mesial temporal epilepsy showed a diurnal pattern of seizures in both children and adults. Frontal and neocortical onset was also modeled by a circadian rhythm corresponding to the nocturnal portion.[13] As the RNS system records brain activity for an extended period of time, it can be used to identify different underlying patterns of seizure onset.


 » Safety and Complications Top


The FDA has approved and clinical trials have shown that the RNS system is a safe procedure. Complications that have been reported include hemorrhage, infections, nonconvulsive epilepticus, convulsive status epilepticus, lead damage, lead revision, scalp dehiscence, hematomas, third nerve palsy, photopsia, depression, and memory impairments. Death has also been reported due to a variety of factors listed in [Table 3]. [Table 3] additionally summarizes the frequency of reported complications.
Table 3: Safety and Complications

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 » Future Directions and Summary Top


The RNS system is an effective treatment option for patients that have medically refractory focal onset seizures. This review article highlights some of the outcomes, current applications, and complications of the RNS System. Utilization of RNS allows for a longer monitoring period of brain activity. This allows for physicians to determine which seizure focus in patients with bilateral MTL foci is contributing to the majority of seizures. Additionally, RNS stimulation to the CMT has shown promising results of seizure reduction. Two articles highlighted in this paper focused on using the RNS data to monitor overall seizure patterns. We highlighted these articles as the application of understanding seizure onset as a biological clock mechanism provides exciting opportunities for management of epilepsy in the future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Matias CM, Sharan A, Wu C. Responsive neurostimulation for the treatment of epilepsy. Neurosurg Clin N Am 2018;30:231-42.  Back to cited text no. 1
    
2.
Morrell MJ. Responsive cortical stimulation for the treatment of medically intractable partial epilepsy. Neurology 2011;77:1295-304.  Back to cited text no. 2
    
3.
Weber PB, Kapur R, Gwinn RP, Zimmerman RS, Courtney TA, Morrell MJ. Infection and erosion rates in trials of a cranially implanted neurostimulator do not increase with subsequent neurostimulator placements. Stereotact Funct Neurosurg 2017;95:325-9.  Back to cited text no. 3
    
4.
Geller EB, Skarpaas TL, Gross RE, Goodman RR, Barkley GL, Bazil CW, et al. Brain-responsive neurostimulation in patients with medically intractable mesial temporal lobe epilepsy. Epilepsia 2017;58:994-1004.  Back to cited text no. 4
    
5.
Jobst BC, Kapur R, Barkley GL, Bazil CW, Berg MJ, Bergey GK, et al. Brain-responsive neurostimulation in patients with medically intractable seizures arising from eloquent and other neocortical areas. Epilepsia 2017;58:1005-14.  Back to cited text no. 5
    
6.
Hirsch LJ, Mirro EA, Salanova V, Witt TC, Drees CN, Brown MG, et al. Mesial temporal resection following long-term ambulatory intracranial EEG monitoring with a direct brain-responsive neurostimulation system. Epilepsia 2020;61:408-20.  Back to cited text no. 6
    
7.
King-Stephens D, Mirro E, Weber PB, Laxer KD, Van Ness PC, Salanova V, et al. Lateralization of mesial temporal lobe epilepsy with chronic ambulatory electrocorticography. Epilepsia 2015;56:959-67.  Back to cited text no. 7
    
8.
Burdette DE, Haykal MA, Jarosiewicz B, Fabris RR, Heredia G, Elisevich K, et al. Brain-responsive corticothalamic stimulation in the centromedian nucleus for treatment of regional neocortical epilepsy. Epilepsy Behav 2020;112:107354. doi: 10.1016/j.yebeh. 2020.107354.  Back to cited text no. 8
    
9.
Gummadavelli A, Zaveri HP, Spencer DD, Gerrard JL. Expanding brain–computer interfaces for controlling epilepsy networks: Novel thalamic responsive neurostimulation in refractory epilepsy. Front Neurosci 2018;12:474.  Back to cited text no. 9
    
10.
Ma BB, Fields MC, Knowlton RC, Chang EF, Szaflarski JP, Marcuse LV, et al. Responsive neurostimulation for regional neocortical epilepsy. Epilepsia 2019;61:96-106.  Back to cited text no. 10
    
11.
Warren AEL, Dalic LJ, Thevathasan W, Roten A, Bulluss KJ, Archer, J. Targeting the centromedian thalamic nucleus for deep brain stimulation. J Neurol Neurosurg Psychiatry 2020;91:339-49.  Back to cited text no. 11
    
12.
Baud MO, Kleen JK, Mirro EA, Andrechak JC, King-Stephens D, Chang EF, et al. Multi-day rhythms modulate seizure risk in epilepsy. Nat Commun 2018;9:88.  Back to cited text no. 12
    
13.
Spencer DC, Sun FT, Brown SN, Jobst BC, Fountain NB, Wong VS, et al. Circadian ultradian patterns of epileptiform discharges differ by seizure-onset location during long-term ambulatory intracranial monitoring. Epilepsia 2016;57:1495-502.  Back to cited text no. 13
    
14.
Nair DR, Laxer KD, Weber PB, Murro AM, Park YD, Barkley GL, et al. Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy. Neurology 2020;95:1244-56.  Back to cited text no. 14
    
15.
Razavi B, Rao VR, Lin C, Bujarski KA, Patra SE, Burdette DE, et al. Real-world experience with direct brain-responsive neurostimulation for focal onset seizures. Epilepsia 2020;61:1749-57.  Back to cited text no. 15
    
16.
Kwon CS, Schupper AJ, Fields MC, Marcuse LV, Vega-Talbott ML, Panov F, et al. Centromedian thalamic responsive neurostimulation for Lennox Gastaut epilepsy and autism. Ann Clin Transl Neurol 2020;7:2035-40.  Back to cited text no. 16
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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