Brain stimulation therapies for epilepsy

Brain stimulation therapies for epilepsy

Overview

Illustration of deep brain stimulation (left) and responsive neurostimulation (right)
Modified from Edwards CA, Kouzani A, Lee KH, Ross EK. Neurostimulation Devices for the Treatment of Neurologic Disorders. Mayo Clin Proc 2017;92:1427-1444

Epilepsy is a chronic neurological condition characterized by recurring seizures, or abnormal bursts of electrical activity in the brain that can trigger jerky movements, strange sensations or emotions, unusual behavior, and/or loss of consciousness. Although available anti-seizure medications help the majority of people with epilepsy, a third or more receive little or no relief from medical treatment. Some people with medically refractory epilepsy experience excellent outcomes with surgery to remove or disconnect brain tissue that initiates or propagates seizures, but for others, a clear seizure focus may be difficult to identify or target safely without causing new neurological deficits. In these cases, neurostimulation devices can offer another alternative.

Research supported by NINDS and conducted by NINDS scientists figured prominently in the development of two FDA-approved devices that deliver electrical stimulation to the brain in different ways to reduce seizure frequency in people who do not achieve good seizure control with medication alone. Deep brain stimulation (DBS) for epilepsy, approved in 2018, delivers chronic stimulation to the anterior nucleus of the thalamus (ANT), a small brain structure involved in the spread of an initially localized seizure. In contrast, responsive neurostimulation (RNS®), approved in 2013, delivers stimulation directly to the source of an individual’s seizures, but only when continuously monitored brain activity suggests a seizure may be beginning.

Print Overview and Timeline (pdf, 728 kb)

Development Timeline

NIH Support
1953

During recordings of brain activity in people with epilepsy undergoing surgery, Wilder Penfield and Herbert Jasper observe that seizure-like activity could be halted with brief counter stimulation1.

Photo of Wilder Penfield (right) and Herbert Jasper (left)
1954

Low frequency stimulation in the anterior nucleus of the thalamus (ANT) is reported to synchronize brain activity, while high frequency stimulation had the opposite effect9.

1966- 1971

Surgical lesions of the ANT decreased the occurrence and duration of seizures in a small clinical study and in an animal model of epilepsy10,11.

NIH Logo NINDS Logo
1972- 1983

Studies initially suggest electrical stimulation in the cerebellum may reduce seizures, but carefully controlled trials by NINDS intramural investigators and others show no clear benefit4,5,6,7,8.

NIH Logo NINDS Logo
cerebellum
©Sebastian Kaulitzki | Dreamstime.com
1979- 1986

Small, unblinded studies show chronic ANT stimulation improves seizure control in people with medically refractory epilepsy15,16,17. While promising, these early studies used external stimulators that were inconvenient to patients.

1979

The first systems emerge for automated seizure detection based on EEG recordings of brain activity.30

Electroencephalogram or EEG. In its commonest form, it is a measurement of the electrical activity of the brain measured from an array of electrodes on the scalp.
©Dule964|Dreamstime.com
1982- 1998

Brief bursts of stimulation are shown to terminate seizures or seizure-like activity in people with epilepsy and animal models when delivered soon after onset25,26,27,28.

NIH Logo NINDS Logo
1983- 1985

Studies to understand seizure mechanisms place the ANT within a brain circuit involved in the spread of initially localized seizures12,13.

NIH Logo NINDS Logo
Neural systems Papez's Circuit
Barger N, et al; doi: 10.3389/fnhum.2014.00277, CC BY 3.0
1990

Academic and industry investigators develop more refined seizure detection algorithms that will be adapted for use in the first responsive stimulation devices31,32,33,34.

NIH Logo NINDS Logo
1996

High frequency stimulation in the ANT is shown to protect against generalized seizures in an animal model.14

1996

The FDA approves two new implantable neurostimulation devices:  Medtronic’s deep brain stimulation (DBS) system as a treatment for tremor and Cyberonics’ vagal nerve stimulator for medically refractory epilepsy18,19.

Medtronic’s deep brain stimulation (DBS) implantable neurostimulation device, as a treatment for tremor and Cyberonics’ vagal nerve stimulator for medically refractory epilepsy
European Patent Office
2000- 2004

Initial tests of responsive stimulation for safety and feasibility used prototypes with external neurostimulators in people undergoing evaluation for epilepsy surgery35,36,37.

NIH Logo NINDS Logo
external neurostimulators (eRNs)
Courtesy of Eric H. W. Kossoff, MD
2001- 2003

Pilot studies report improved seizure control with chronic bilateral ANT stimulation using Medtronic’s implantable deep brain stimulation (DBS) system20,21.

NIH Logo NINDS Logo
2009- 2014

The SANTE (Stimulation of the Anterior Nucleus of the Thalamus in Epilepsy) trial and a seven-year follow up period show lasting reductions in seizure frequency in those who were treated and meaningful improvements in quality of life22,23.

Deep brain stimulation (DBS)
NINDS
2010

The pivotal clinical trial of the NeuroPace responsive neurostimulation system (RNS®) shows that seizure frequency decreased in individuals receiving stimulation39.

NeuroPace responsive neurostimulation system (RNS)
NeuroPace, Inc.
2012

The NeuroPace RNS® receives approval from the FDA for use in adults with medically refractory focal epilepsy.40

Food and Drug Administration logo
FDA.gov
2017

Medtronic’s DBS System for Epilepsy receives approval from the FDA for use in adults with medically refractory focal epilepsy24.

Food and Drug Administration logo
FDA.gov

History of Development

Research supported by NINDS and conducted by NINDS scientists proved critical to the development of the first brain stimulation therapies for epilepsy, including studies to rigorously test early approaches, find new stimulation targets by understanding seizure mechanisms, and develop algorithms for automated seizure detection.

Pioneering neurosurgeons set the stage

Neurostimulation therapies for epilepsy follow a longer history of attempts to quiet seizures through surgical interventions. In the 1930s, Canadian neurosurgeon Wilder Penfield pioneered modern methods for surgery to treat epilepsy. He used electroencephalography (EEG) to identify where seizures originated in the brain of individuals with epilepsy and then more finely mapped targets for surgical resection with direct electrical stimulation through electrodes inserted into the brain. This basic approach to surgical evaluation in epilepsy remains in practice today, with ongoing improvements as brain imaging and recording technologies have advanced.

Beyond improving the success of surgery for people with epilepsy, intraoperative recording also provided new insights about how seizures originate and propagate in the brain and laid the foundation for therapeutic stimulation. Indeed, Penfield and colleague Herbert Jasper were among the first to observe that electrical stimulation to the cortex could silence seizure discharges1. By the 1960s, with the advent of the cardiac pacemaker and the exploration of deep brain stimulation (DBS) therapies to treat pain and motor disorders, researchers began to pursue similar treatments for epilepsy. The choice of targets for stimulation were based in part on research using electrical stimulation to understand seizure mechanisms in animal models. For example, in the 1970s, neurosurgeon Irving Cooper hypothesized that stimulation in the cerebellum could reduce seizures in people with epilepsy, a suggestion supported by NIH-funded studies in cats2,3. Although Cooper’s initial trials were promising4,5, placebo-controlled trials and animal studies conducted by NINDS intramural scientists and others failed to confirm the benefit of treatment6,7,8. Nevertheless, these early efforts were important for demonstrating the feasibility and safety of brain stimulation for epilepsy, and for establishing the need to control for a strong placebo effect and for changes related to surgery alone.

Identifying the anterior nucleus of the thalamus as a target for seizure control

In the search for other targets, several lines of evidence pointed to a small brain region called the anterior nucleus of the thalamus (ANT). Low frequency stimulation in this region was reported to synchronize brain activity, while high frequency stimulation had the opposite effect, suggesting it may also disrupt seizures9. NIH-supported investigators found that surgical lesions of the ANT decreased the occurrence and duration of seizures in a small clinical study10 and in an animal model11. A series of NINDS-funded studies on the mechanisms of experimentally induced seizures placed the ANT within a brain circuit that mediates seizure generalization, in which seizure activity initiated in a small focused area (focal seizure) spreads to larger areas of the brain12,13. A subsequent study prompted by these findings showed that high-frequency stimulation in the ANT could protect against generalized seizures14. Altogether, the ANT’s anatomically defined position and its role in seizure spread from other locations made it an appealing therapeutic target, potentially for a wide range of individuals with seizures initially originating in different areas.

In the 1980s, Cooper reported that chronic ANT stimulation improved seizure control in small numbers of people with medically refractory epilepsy15,16,17. While promising, these studies were unblinded and uncontrolled, and the use of an external stimulator was impractical. A decade later, the FDA had approved two implantable neurostimulation devices, Medtronic’s deep brain stimulation (DBS) system as a treatment for tremor18 and Cyberonics’ vagal nerve stimulator for medically refractory epilepsy19.  These approvals helped renew interest in further development of DBS for epilepsy, and in the early 2000s, preliminary studies assessed the use of Medtronic’s DBS system for bilateral ANT stimulation20,21, including one study conducted by investigators with NINDS and NIMH support19.  Medtronic subsequently sponsored a randomized, controlled clinical trial 110 patients. The SANTE (Stimulation of the Anterior Nucleus of the Thalamus in Epilepsy) trial and a seven-year follow up period23 showed lasting benefits of treatment in terms of reduced seizure frequency and meaningful improvements in quality of life. These results led the FDA to approve Medtronic’s DBS System for Epilepsy in 2018, for use along with medical treatment in adults with focal epilepsy who have not achieved seizure control after trying three or more epilepsy medications24.

Responsive neurostimulation to halt seizures at their source

The DBS system for epilepsy delivers ongoing, or open loop, stimulation intended to alter brain activity just enough to prevent or limit the initiation or spread of a seizure. In contrast, closed loop or responsive stimulation, delivers stimulation only when brain activity patterns suggest a seizure is beginning or very likely to occur. Beyond Jasper and Penfield’s original observations1 in 1954, later studies–in people undergoing surgery for epilepsy and in animal models with experimentally induced seizures–provided a rationale for this approach. This research supported by NINDS and others showed that brief bursts of stimulation could terminate seizures or seizure-like activity when delivered soon after onset, either to brain structures remote from seizure activity25,26, or directly to the onset site27,28,29. For example, brain stimulation used to map an individual’s seizure focus for surgery sometimes elicits rhythmic activity called afterdischarges that resemble spontaneous seizure activity. In 1999, NINDS-supported investigators reported that brief counter stimulation at the same site could terminate such afterdischarges28.

In parallel, an expanding area of research sought to develop algorithms for automated seizure detection. By analyzing brain activity data from people with epilepsy, investigators worked to identify features that reliably indicated a seizure was beginning or very likely to occur. Early seizure detection systems emerged30 around the 1980s, and by the late 1990s, academic and industry investigators supported by NINDS, NIMH, and private sources were developing more refined algorithms that would ultimately be adapted for use in the first responsive stimulation devices31,32,33,34. Initial tests for safety and feasibility used prototypes with non-implantable external neurostimulators in individuals with epilepsy undergoing evaluation for surgery35,36,37. After promising preliminary results38, the device company NeuroPace was the first to launch a large, randomized, multi-center trial for their implantable responsive neurostimulation system39. The pivotal trial showed that seizure frequency decreased in study participants receiving stimulation compared to those in a control group who received a sham procedure. Based on these findings, the NeuroPace RNS® was approved by the FDA in 2013, for use along with medical treatment in adults with medically refractory focal epilepsy40. A key feature of the RNS® system is the ability for physicians to fine-tune detection and stimulation parameters for each person, possibly improving outcomes over time.

Future directions in neurostimulation and responsive therapies for epilepsy

Research continues to improve neurostimulation therapies for epilepsy. Efforts are underway to incorporate seizure forecasting and responsive stimulation into DBS for epilepsy, including a project supported through the NIH BRAIN Initiative Public-Private Partnership Program to facilitate clinical research using industry-supplied cutting-edge devices41. In addition, there is hope that future algorithms for triggering responsive epilepsy therapies will more accurately detect or even predict seizures, allowing advanced warning for patients and potentially better seizure control. In 2014, NINDS, the American Epilepsy Society, and the Epilepsy Foundation launched a crowd-sourced seizure detection and prediction challenge in which amateur computer programmers, scientists, and others from around the world competed to develop algorithms tested on long-term intracranial EEG data42. The best algorithms significantly increased seizure prediction accuracy over prior methods, a success that bolstered interest in further innovation:  a second international contest was held43 in 2016, and an online portal provides access to datasets for ongoing algorithm development.

References

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  2. Cooke PM, Snider RS. Some cerebellar influences on electrically-induced cerebral seizures. Epilepsia. 1955 Nov;4:19-28. PMID: 13305547 (Office of Naval Research and the U.S. Public Health Service/NIH)

  3. Dow RS, Fernandez-Guardiola A, Manni E. The influence of the cerebellum on experimental epilepsy. Electroencephalogr Clin Neurophysiol. 1962 Jun;14:383-98.PMID: 13887605 (NIH/NINDS, grant B-2289)

  4. Cooper IS, Amin I, Gilman S. The effect of chronic cerebellar stimulation upon epilepsy in man. Trans Am Neurol Assoc. 1973;98:192-6. PMID: 4206369 (funding source not stated)

  5. Cooper IS, Amin I, Riklan M, Waltz JM, Poon TP. Chronic cerebellar stimulation in epilepsy. Clinical and anatomical studies. Arch Neurol. 1976 Aug;33(8):559-70. PMID: 821458 (Private support)

  1. Van Buren JM, Wood JH, Oakley J, Hambrecht F. Preliminary evaluation of cerebellar stimulation by double-blind stimulation and biological criteria in the treatment of epilepsy. J Neurosurg. 1978 Mar;48(3):407-16. PMID: 344840 (NIH/NINDS, intramural)

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  4. Jasper H, Naquet R, KingEV. Thalamocortical recruiting responses in sensory receiving areas in the cat. Electroencephalogr Clin Neurophysiol. 1955 Feb;7(1):99-114. PMID: 14353024 (Rockefeller Foundation)

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  12. Upton AR, Amin I, Garnett S, Springman M, Nahmias C, Cooper IS. Evoked metabolic responses in the limbic-striate system produced by stimulation of anterior thalamic nucleus in man. Pacing Clin Electrophysiol. 1987 Jan;10(1 Pt 2):217-25. PMID: 2436182. (source not provided, Canada)

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  20. Psatta DM. Control of chronic experimental focal epilepsy by feedback caudatum stimulations. Epilepsia. 1983 Aug;24(4):444-54. PMID: 6603358 (Romania, funding source not stated)

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  27. Osorio I, Frei MG, Giftakis J, Peters T, Ingram J, Turnbull M, Herzog M, Rise MT, Schaffner S, Wennberg RA, Walczak TS, Risinger MW, Ajmone-Marsan C. Performance reassessment of a real-time seizure-detection algorithm on long ECoG series. Epilepsia. 2002 Dec;43(12):1522-35. PMID: 12460255 (NIH/NINDS, grant NS34530-03; Medtronic)

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  29. Echauz J, Esteller R, Tcheng T, Pless B, Gibb B, Litt B. Long‐term validation of detection algorithms suitable for an implantable device. Epilepsia 2001;42(suppl 7):35–6. (conference abstract)

  30. Peters TE, Bhavaraju NC, Frei MG, Osorio I. Network system for automated seizure detection and contingent delivery of therapy. J Clin Neurophysiol. 2001 Nov;18(6):545-9. PMID: 11779967 (NIH/NINDS, grant NS34630)

  31. Kossoff EH, Ritzl EK, Politsky JM, Murro AM, Smith JR, Duckrow RB, Spencer DD, Bergey GK. Effect of an external responsive neurostimulator on seizures and electrographic discharges during subdural electrode monitoring. Epilepsia. 2004 Dec;45(12):1560-7. PMID: 15571514 (NeuroPace)

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  33. Barkley GL, Smith B, Bergey G, Worrell G, Chabolla D, Drazkowski J, Labar D, Duckrow R, Murro A, Smith M, Gwinn R, Fisch B, Hirsch L, and Morrell M. Safety and Preliminary Efficacy of the RNS Responsive Neurostimulator for the Treatment of Intractable Epilepsy in Adults. Epilepsia 2006; 47(S4):5. (conference abstract; ClinicalTrials.gov NCT00079781)

  34. Morrell MJ; RNS System in Epilepsy Study Group. Responsive cortical stimulation for the treatment of medically intractable partial epilepsy. Neurology. 2011 Sep 27;77(13):1295-304. PMID: 21917777 (NeuroPace; ClinicalTrials.gov NCT00264810)

  35. FDA. Premarket Approval (PMA) Database. NeuroPace RNS System. Retrieved from https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P100026.

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  37. NINDS. News Articles. Winners announced in NIH-supported crowdsourcing contest of seizure prediction. Retrieved from http://wayback.archiveit.org/1170/20150104175408/http://www.ninds.nih.gov/news_and_events/news_articles/pressrelease_epilepsy_challenge_12162014.htm

  38. Kaggle. Melbourne University AES/MathWorks/NIH Seizure Prediction. Retrieved from https://www.kaggle.com/c/melbourne-university-seizure-prediction#evaluation.

Hand touching medical scans on board