What is Responsive Neurostimulation?

Epilepsy News From:

Tuesday, April 23, 2019

Introduction

Despite the availability of over 20 anti-seizure drugs1, one-third of people with epilepsy have seizures that are not fully controlled by medications2. For these drug-resistant patients — over 1 million in the United States alone3 — using surgery to remove the seizure-producing brain tissue can be a highly effective treatment4. A person is a good candidate for seizure surgery under these conditions:

  • Seizure onset (where the seizure starts) can be precisely pinpointed to a single focus (place) in the brain, like finding the epicenter of an earthquake.
  • Removal of the seizure focus is safe and unlikely to result in significant physical or cognitive deficits.
  • Chances of improved seizure control with surgery are sufficiently high to justify an irreversible procedure.

If these conditions are not met, neurostimulation can be offered as an alternative to seizure surgery. Currently, three implanted neurostimulation devices are approved for treatment of certain forms of drug-resistant epilepsy:

  1. Vagus Nerve Stimulation (VNS®; LivaNova, Inc.)
  2. Deep Brain Stimulation (DBS; Medtronic, Inc.)
  3. Responsive Neurostimulation (RNS® System; NeuroPace, Inc.).

Although all three devices work by delivering electrical impulses to the brain to reduce seizures, the RNS System is conceptually distinct and offers unique clinical capabilities5,6.

What is the RNS System? Who does it work on?

Implanted in over 2000 patients since the U.S. Food and Drug Administration (FDA) approved it in 2013, the RNS System works by delivering stimulation directly to the brain only when needed7.

  • This “on-demand” therapy uses a neurostimulator that is seated in the skull and connected to lead wires with electrodes that are implanted in the brain at one or two seizure-producing sites.
  • Using these electrodes, the neurostimulator continuously ‘listens’ to brain activity. The device responds when it detects abnormal patterns (like those that occur right before a seizure starts) by delivering short bursts of electrical pulses8, much as a pacemaker might respond to detection of an abnormal heart rhythm.
  • The RNS System stores recordings of brain waves and data about seizure activity over long periods of time.
  • People with the RNS System can transfer data stored by the device to a secure online platform accessible by their providers.
  • Candidates for the RNS System include adults with two seizure foci (two places in the brain where seizure start) and those with a single seizure focus that cannot be safely removed9.
Learn More

Learn about the placement, programming and safety of the RNS System

Clinical Outcomes: How safe and effective is the RNS System?

Safety and efficacy of the RNS System were assessed in a 9-year prospective clinical trial conducted with 256 patients across 33 epilepsy centers10. Representing 1895 patient implant-years of experience, this was the largest and longest prospective trial of a neurostimulation device.

  • By year 9, median reduction in seizure frequency was 75%.
  • Nearly 3 out of 4 people had their baseline seizure frequency reduced by at least half.
  • Quality of life improvements were sustained through 9 years.
  • On average, there were no adverse cognitive, mood, or stimulation-related side effects.
  • Risks of device-related bleeding and infection were low and comparable to rates with other similar neurosurgical procedures.
  • Finally, the risk of sudden unexpected death in epilepsy (SUDEP) for people in this study was significantly reduced relative to comparable populations of people who were not treated with the RNS System11.

Key Lessons from the RNS System Long-term Treatment Trial

  • Some people respond to treatment better than others.
    • 1 in 3 people achieved greater than 90% reduction in seizure frequency
    • 1 in 4 people experienced at least one 6-month period of seizure-freedom
    • 1 in 5 people had at least one seizure-free year
  • Location of RNS System electrodes (mesial temporal, deep within the temporal lobe vs. neocortical, on the surface of the brain) did not explain the variance in clinical outcomes, as both groups of people had similar rates of seizure frequency reduction12,13.
  • Efficacy improves steadily over time. This observation has prompted reconsideration of the likely mechanism of action of responsive neurostimulation.

Mechanism of Action: How does the RNS System work to reduce seizures?

When it was first created, the developers thought of the RNS System as a seizure stopping device. They created it to detect, stimulate parts of the brain where seizures started, and end the seizure, similar to how an implanted cardioverter defibrillator works in the heart.

Examples recordings stored by the device show RNS System Simulation can quickly stop a seizure. There is also some experimental evidence suggesting that responsive stimulation can suppress the pathological synchrony (electrical patterns) in brain rhythms that is thought to underlie seizures14. However, some evidence suggests that efficacy of RNS may also relate to neuromodulatory effects of chronic (long-term) brain stimulation:

  • Seizures can improve slowly over time, even when RNS System settings are not changed.
  • Most people receive a high number of daily stimulations, far exceeding the number of seizures they have. Since each stimulation is brief (milliseconds), this typically amounts to only a few minutes of total stimulation each day. This stimulation is more often delivered in response to detection of brain activity patterns that happens between seizures instead of during seizures.
  • In people who respond well to RNS System therapy, the seizures they have typically show electrical features similar to seizures recorded early in the course of therapy. This suggests the effect of stimulation relates less to acute seizure termination and more to decreased excitability in brain networks and reduced propensity for seizure generation.
  • Emerging research suggests that “indirect,” or delayed, effects of stimulation on features of brain activity correlate better with clinical outcome than direct, acute effects (i.e. aborting seizures)15.

There is an open question about the importance of the “responsive” aspect of RNS System therapy. It is possible that it is the dynamic, time-varying nature of device’s stimulation, rather than its responsiveness, that minimizes a person’s brain getting used to the stimulation and promotes long-term efficacy.

Chronic Recordings: What kind of diagnostic information can the RNS System provide?

Historically, direct recordings of brain activity could only be made for short periods of time during electrode implantation procedures for seizure surgery evaluation. These short-term recordings, performed under highly constrained conditions, have several limitations:

  • Unnatural (hospital) environment
  • Post-operative pain
  • Medications to manage symptoms after surgery
  • Limited patient mobility
  • Artificial tapering of anti-seizure drugs to provoke seizures

In contrast, during normal clinical use, the RNS System stores long-term seizure recordings and data about seizure activity when people are taking their normal medications and in their normal environments. These continual and more natural recordings offer significant advantages for understanding the spatial and temporal (frequency and timing) of sporadic, seemingly random seizures16.

For example, in 1 out of 5 people whose seizures are thought to start independently from both temporal lobes, data from long-term RNS System recordings changes the originally thought lateralization (starting place)17.

  • People who were thought to have bilateral independent seizures but who are found through long-term ambulatory recordings to be “functionally unilateral” (that is, highly asymmetric distribution of seizures arising from left and right sides of the brain) may be candidates for seizure surgery18.
  • In highly select cases, data from the RNS System can also shed light on seizure localization, helping to pinpoint seizure-producing brain tissue that other diagnostic tests could not find19.

People with the RNS System can start download brain activity recordings by swiping a small magnet over the neurostimulator. This gives their health care providers the unprecedented ability to match patient-reported symptoms (such as reports in a seizure diary) with direct recordings of brain activity. With this information, the provider and patient can help determine which symptoms are due to seizure activity and which might have other causes. RNS System recordings include metrics of seizure activity that can be plotted to reveal trends and assess responses to introduction of new anti-seizure medications20, behavioral changes21, and seizure surgery22.

Recently, analysis of long-term data from the RNS System has uncovered cycles in epileptic brain activity over daily (circadian)23,24,25 and multi-day (multidien)24 timescales. Seizures occur more commonly when people are at certain phases of these cycles. So, at any given moment, the combination of where a person is on their circadian and multidien cycles helps determine their risk of having a seizure [24]. Ongoing research efforts are aimed at prospectively extrapolating cycles of brain activity revealed by RNS System data to anticipate times when seizure risk is highest, which might allow preventative treatment strategies that minimize the impact of seizures on people’s lives16,26.

Research & Innovation

Learn about the Epilepsy Foundation’s Epilepsy Innovation Institute, Seizure Gauge Challenge, and My Brain Map Challenge, which are tackling issues like seizure forecasting, seizure risk, and defining an individual’s brain network to enhance diagnosis and care.

Take-Home Points

  • The RNS System delivers direct, on-demand brain stimulation and has proven safety and efficacy for adults with drug-resistant seizures arising from one or two sites in the brain.
  • The mechanisms underlying RNS System efficacy remain unclear but likely involve a combination of acute seizure termination (stopping a seizure quickly) and chronic neuromodulatory effects (long-term changes in brain electrical patterns).
  • Chronic recordings of brain activity made by the RNS System have powerful diagnostic usefulness, including revealing spatial and temporal (frequency and timing) seizure activity that is less apparent with shorter duration recordings in unnatural environments (not part of daily life).
  • Cycles of brain activity revealed by chronic RNS System recordings help determine seizure risk and may someday allow seizure forecasting. This concept remains an area of active research.

References

  1. Loscher, W., Klitgaard, H., Twyman, R.E., and Schmidt, D. (2013). New avenues for anti-epileptic drug discovery and development. Nat Rev Drug Discov 12, 757-776.
  2. Brodie, M.J., Barry, S.J., Bamagous, G.A., Norrie, J.D., and Kwan, P. (2012). Patterns of treatment response in newly diagnosed epilepsy. Neurology 78, 1548-1554.
  3. Engel, J., Jr. (2016). What can we do for people with drug-resistant epilepsy? The 2016 Wartenberg Lecture. Neurology 87, 2483-2489.
  4. Wiebe, S., Blume, W.T., Girvin, J.P., Eliasziw, M., Effectiveness, and Efficiency of Surgery for Temporal Lobe Epilepsy Study, G. (2001). A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med 345, 311-318.
  5. Geller, E.B. (2018). Responsive neurostimulation: Review of clinical trials and insights into focal epilepsy. Epilepsy Behav 88S, 11-20.
  6. Sun, F.T., and Morrell, M.J. (2014). Closed-loop neurostimulation: the clinical experience. Neurotherapeutics 11, 553-563.
  7. Morrell, M.J., and Halpern, C. (2016). Responsive Direct Brain Stimulation for Epilepsy. Neurosurg Clin N Am 27, 111-121.
  8. Sisterson, N.D., Wozny, T.A., Kokkinos, V., Constantino, A., and Richardson, R.M. (2019). Closed-Loop Brain Stimulation for Drug-Resistant Epilepsy: Towards an Evidence-Based Approach to Personalized Medicine. Neurotherapeutics 16, 119-127.
  9. Ma, B.B., and Rao, V.R. (2018). Responsive neurostimulation: Candidates and considerations. Epilepsy Behav 88, 388-395.
  10. Nair, D., RNS System Investigators, and Morrell, M.J. (2018). Nine-year prospective safety and effectiveness outcomes from the long-term treatment trial of the RNS System. American Epilepsy Society Annual Meeting 2.075.
  11. Devinsky, O., Friedman, D., Duckrow, R.B., Fountain, N.B., Gwinn, R.P., Leiphart, J.W., Murro, A.M., and Van Ness, P.C. (2018). Sudden unexpected death in epilepsy in patients treated with brain-responsive neurostimulation. Epilepsia 59, 555-561.
  12. Geller, E.B., Skarpaas, T.L., Gross, R.E., Goodman, R.R., Barkley, G.L., Bazil, C.W., Berg, M.J., Bergey, G.K., Cash, S.S., Cole, A.J., et al. (2017). Brain-responsive neurostimulation in patients with medically intractable mesial temporal lobe epilepsy. Epilepsia 58, 994-1004.
  13. Jobst, B.C., Kapur, R., Barkley, G.L., Bazil, C.W., Berg, M.J., Bergey, G.K., Boggs, J.G., Cash, S.S., Cole, A.J., Duchowny, M.S., et al. (2017). Brain-responsive neurostimulation in patients with medically intractable seizures arising from eloquent and other neocortical areas. Epilepsia 58, 1005-1014.
  14. Sohal, V.S., and Sun, F.T. (2011). Responsive neurostimulation suppresses synchronized cortical rhythms in patients with epilepsy. Neurosurg Clin N Am 22, 481-488, vi.
  15. Kokkinos, V., Sisterson, N.D., Wozny, T.A., and Richardson, R.M. (2019). Modulation of electrographic seizure features predicts response to closed-loop brain stimulation. in press.
  16. Baud, M.O., and Rao, V.R. (2018). Gauging seizure risk. Neurology 91, 967-973.
  17. King-Stephens, D., Mirro, E., Weber, P.B., Laxer, K.D., Van Ness, P.C., Salanova, V., Spencer, D.C., Heck, C.N., Goldman, A., Jobst, B., et al. (2015). Lateralization of mesial temporal lobe epilepsy with chronic ambulatory electrocorticography. Epilepsia 56, 959-967.
  18. Hirsch, L.J., Mirro, E., Salanova, V., Witt, T.C., Drees, C., Brown, M.-G., Lee, R.W., Sadler, T.L., Felton, E.A., Rutecki, P.A., et al. (2018). Outcomes After Mesial Temporal Lobe Resection Following Long-Term Ambulatory Recording by the RNS® System. American Epilepsy Society Annual Meeting 1.336.
  19. Chan, A.Y., Knowlton, R.C., Chang, E.F., and Rao, V.R. (2018). Seizure localization by chronic ambulatory electrocorticography. Clin Neurophysiol Pract 3, 174-176.
  20. Skarpaas, T.L., Tcheng, T.K., and Morrell, M.J. (2018). Clinical and electrocorticographic response to antiepileptic drugs in patients treated with responsive stimulation. Epilepsy Behav 83, 192-200.
  21. Mackow, M.J., Krishnan, B., Bingaman, W.E., Najm, I.M., Alexopoulos, A.V., and Nair, D.R. (2016). Increased caffeine intake leads to worsening of electrocorticographic epileptiform discharges as recorded with a responsive neurostimulation device. Clin Neurophysiol 127, 2341-2342.
  22. Geller, A.S., Friedman, D., Fang, M., Doyle, W.K., Devinsky, O., and Dugan, P. (2018). Running-down phenomenon captured with chronic electrocorticography. Epilepsia Open 3, 528-534.
  23. Spencer, D.C., Sun, F.T., Brown, S.N., Jobst, B.C., Fountain, N.B., Wong, V.S., Mirro, E.A., and Quigg, M. (2016). Circadian and ultradian patterns of epileptiform discharges differ by seizure-onset location during long-term ambulatory intracranial monitoring. Epilepsia 57, 1495-1502.
  24. Baud, M.O., Kleen, J.K., Mirro, E.A., Andrechak, J.C., King-Stephens, D., Chang, E.F., and Rao, V.R. (2018). Multi-day rhythms modulate seizure risk in epilepsy. Nat Commun 9, 88.
  25. Duckrow, R.B., and Tcheng, T.K. (2007). Daily variation in an intracranial EEG feature in humans detected by a responsive neurostimulator system. Epilepsia 48, 1614-1620.
  26. Dumanis, S.B., French, J.A., Bernard, C., Worrell, G.A., and Fureman, B.E. (2017). Seizure Forecasting from Idea to Reality. Outcomes of the My Seizure Gauge Epilepsy Innovation Institute Workshop. eNeuro 4.

Contributed by Vikram R. Rao MD, PhD of the University of California, San Francisco

Authored by: Vikram R. Rao MD, PhD on 4/2019
Reviewed by: Mohamad Koubeissi MD on 4/2019

Our Mission

The mission of the Epilepsy Foundation is to lead the fight to overcome the challenges of living with epilepsy and to accelerate therapies to stop seizures, find cures, and save lives.

 
24/7 helpline