Key Points:

• Gregory Worrell, MD, PhD (Mayo Clinic, Rochester, MN) recalls that the first grant that he received was from CURE Epilepsy and credits it with having a tremendous impact on both his career path and his groundbreaking contributions to epilepsy research.
• According to Dr. Worrell, the initial one-year grant, awarded almost 20 years ago, was a catalyst for his research to improve devices for monitoring brain activity and forecasting seizures. 
• The CURE Epilepsy grant, along with an NIH career developmental award, and subsequently additional ongoing NIH and foundation grants, has firmly established Dr. Worrell as an important investigator in the fields of brain neurophysiology, seizure detection, seizure forecasting, and neural modulation. 

Deep Dive:

Dr. Gregory Worrell’s path towards ultimately engaging in epilepsy research did not follow a direct road. He first trained and worked as a PhD-level physicist before entering medical school and then completed a neurology residency followed by an epilepsy fellowship. It took several additional years to reach his current role as a physician-scientist caring for epilepsy patients while simultaneously maintaining a productive research laboratory. Nevertheless, Dr. Worrell’s unique training in engineering and physics, along with the computational analyses, gave him the expertise required to understand and develop devices to monitor and modulate electrical activity of the brain.

Dr. Worrell credits his mentors, including Dr. Gregory Cascino, also at the Mayo Clinic, and Drs. Marc Dichter (a former advisor to CURE Epilepsy) and Brian Litt (a former CURE Epilepsy grantee), both at the University of Pennsylvania, with influencing his career direction. They provided the model, encouragement, and opportunity for a career as a clinician-scientist. Dr. Worrell’s first research grant was from CURE Epilepsy, and he attributes this critical funding for getting him started in epilepsy research. Even though he was also awarded an NIH training award, he feels that, in many ways, the CURE Epilepsy grant was more important because it introduced him to the community of epilepsy researchers

Dr. Worrell’s grant from CURE Epilepsy focused on high-frequency oscillations (HFO), brain waves with a frequency of greater than approximately 80 Hz that are often associated with seizure activity in specific regions of the brain [1]. This electrical activity can be detected on an electroencephalogram (EEG), but at the time (approximately 20 years ago), HFOs were rarely observed simply because the range of a typical EEG was limited to no greater than 70 Hz, biased by then-accepted practice [2]. Basic research with animal models, however, had suggested that an epileptic brain exhibits a much wider dynamic range of activity, sometimes out to frequencies greater than 1,000 Hz, and so Dr. Worrell focused his early efforts on broadening the spatial and temporal sampling of brain waves [2-4]. These so-called “wide-bandwidth” recordings have now become standard in the field. 

The early learnings achieved through the CURE Epilepsy funded research have carried over into the development of “next-generation” implantable therapeutic devices [5], done as part of an NIH Brain Initiative public-private partnership with Medtronic, a company with a long history of creating medical devices. The “public” component is funded through two NIH grants awarded to Dr. Worrell. The aims are to develop new device technology that will permit the tracking of a patient’s brain state, identify periods of increased seizure probability, and adaptively intervene to modulate the brain, moving it to a state of low seizure probability to prevent seizures from ever occurring. Importantly, it has the potential of providing something akin to a “daily weather report”, giving the patient a sense of when a seizure might occur. This is particularly crucial given that one of the most disabling aspects of epilepsy is not necessarily the seizures themselves but their unpredictability. With this type of technology, there is an opportunity to administer therapies, e.g., anti-seizure medications and/or brain stimulation, both of which have considerable side effects, in a time-limited way instead of a continual process. Creating the next generation of electrical stimulation and sensing devices for epilepsy has remained a focus of Dr. Worrell’s research. 

While Dr. Worrell is proud of his individual achievements, he notes that consequential advances in medicine are usually the outcome of team efforts, with dozens perhaps even hundreds of clinicians and scientists collaborating [5,6] To this end, he has participated in numerous clinical trials to test novel devices, including the FDA approved responsive neurostimulator (RNS®) manufactured by Neuropace Inc, to control seizures, and he derives considerable satisfaction from these collective undertakings. Dr. Worrell enthusiastically admits that he receives additional joy in life from taking care of his patients, following their progress over time, and being able to improve their quality of life through the neurophysiology/neuroengineering research performed in his own lab and through collaborations with other clinicians and scientists. In his mind, there is no greater reward than having the ability to help patients in this way

CURE Epilepsy is proud to have played a role in the illustrious career of Dr. Gregory Worrell in advancing research so that we, as a society, will one day be truly able to say that we live in a world of “no seizures and no side effects.” 

Literature Cited

1. Chen, Z., Maturana, M.I., Burkitt, A.N., Cook, M.J., and Grayden, D.B. High-frequency oscillations in epilepsy: what have we learned and what needs to be addressed. Neurology 2021; 96(9): 439-448. 
2. Worrell, G.A., Parish, L., Cranstoun, S.D., Jonas, R., Baltuch, G., and Litt, B. High-frequency oscillations and seizure generation in neocortical epilepsy. Brain 2004; 127: 1496-1506. 
3. Worrell, G.A., Gardner, A.B., Stead, S.M., Hu, S., Goerss, S., Cascino, G.J. et al. High-frequency oscillations in human temporal lobe: simultaneous microwire and clinical macroelectrode recordings. Brain 2008; 131: 928-937.
4. Stead, M., Bower, M., Brinkmann, B.H., Lee, K., Marsh, W.R., Meyer, F.B., Litt, B., Van Gompel, J.V., and Worrell, G.A. Microseizures and the spatiotemporal scales of human partial epilepsy. Brain 2010; 133(9): 2789-2797.  
5. Kremen, V., Brinkman, B.H., Kin, I., Guragain, H., Nasseri, M., Magee, A.L. et al. Integrating brain implants with local and distributed computing devices: a next generation epilepsy management system. IEEE J. Transl. Eng. Health Med. 2018; 6: 2500112. 
6. Brinkmann, B. H., Wagenaar, J., Abbot, D., Adkins, P., Bosshard, S.C., Chen, M., Tieng, Q.M. et al. Crowdsourcing reproducible seizure forecasting in human and canine epilepsy. Brain 2016; 139(6): 1713-1722. 

Key Points:

• CURE Epilepsy awardee, Dr. Aristea Galanopoulou and colleagues at Albert Einstein College of Medicine in New York sought a way to prevent the devastating consequences of already-established infantile spasms (IS). 
• They used a novel, more clinically relevant IS rat model [1] to test the effect of a specific substance known as rapamycin on motor seizures, spasms, and sleep wave patterns, both immediately and over time.  
• Data show that rapamycin appears to be an effective treatment for IS and that short-term administration early in life and during the peak of spasms can prevent future seizures in adulthood and even improve cognitive outcomes.  

Deep Dive:

Infantile spasms (IS) is a rare (~0.03% of all live births) and catastrophic type of epilepsy that usually first manifests between 3 to 7 months of age [2,3], and infants with poor response to first-line treatment are at an increased risk for a more serious form of epilepsy known as Lennox-Gastaut syndrome (LGS) [4]. Because one of the symptoms includes stereotypical jerks resembling colic, IS is difficult for parents and sometimes even pediatricians to recognize. Conclusive diagnosis is made by the spasms themselves, developmental delay, and often an abnormal, disorganized electroencephalographic (EEG) pattern known as hypsarrhythmia. This chaotic EEG pattern is observed between seizures and characterized by irregular, nonrhythmic waves and spikes of electrical activity [2,3].

IS is commonly treated with a combination of one or two specific steroids (adrenocorticotropic hormone [ACTH] and/or prednisone) and/or the antiseizure medication (ASM) vigabatrin [3,5,6]. These treatments are only effective in approximately 50% of patients [7] and, for those who do respond, diagnosis must be made early enough to minimize significant cognitive deterioration. However, these therapies do not reduce the incidence of future epilepsy and almost two-thirds of these infants continue to have seizures that do not respond to existing therapies [6]. Unfortunately, at present there is no consistent way of predicting who will respond to these treatments. Moreover, the optimal therapy would not only acutely arrest seizure activity but would also possess a “permanent” disease-modifying effect and perhaps even reverse any cognitive decline that had already taken place.

More severe and most frequent causes of IS stem from structural abnormalities in specific regions of the brain [2]. To understand the underlying biology of this form of IS and identify effective treatments, Dr. Aristea Galanopoulou, a member of CURE Epilepsy’s Infantile Spasms Initiative [8], at the Albert Einstein College of Medicine, and colleagues Drs. Solomon Moshé and Morris Scantlebury, developed a rat model known as the “multiple-hit model.” This model has brain lesions that closely mirror those observed in the brains of infants with IS, along with more visible traits such as developmental delay, behavior problems, poor social skills, drug resistance, EEG abnormalities, and potential emergence of other seizure types [1].

Using this model, Dr. Galanopoulou’s team created a platform for screening the potential for various drugs to treat IS. The investigators first used the model to test the ability of the drug rapamycin, an inhibitor of a neuronal signaling pathway linked to epilepsy, to affect IS symptoms [9]. Importantly, rapamycin was given in a 3-day pulse (as opposed to continuous administration) and only after the onset of spasms. This strategy of drug delivery is meaningful since it mimics what happens in clinical practice. A previous study from this group [9] had shown that the rapamycin stopped the spasms and was able to partially restore learning and memory deficiencies, which suggests that the rapamycin was able to modify the progression of IS. However, rapamycin did not diminish any of the other seizure types or reduce the size of the structural lesions.

To better understand the long-term effects of the pulse rapamycin treatment, the researchers then examined [10] whether it reduced the rate of epilepsy in adult rats with IS. The same 3-day pulse of rapamycin was given to the “multiple-hit” rats and investigated in greater detail. In the absence of rapamycin, and similar to the clinical picture of some severe cases of IS in humans, rats eventually exhibited LGS-like features such as motor seizures during sleep and a distinct EEG pattern termed “slow spike-wave discharges”. Importantly, the pulse rapamycin treatment that had been used to stop spasms early in life significantly reduced the rate of epilepsy with motor seizures in adult rats with IS. Furthermore, rapamycin also reversed the sleep disorder seen in these rats, suggesting an interesting relationship between sleep and epilepsy. These preclinical findings raise hope that drugs like rapamycin may be developed for treatment of IS, to both stop spasms and prevent lifelong epilepsy and associated comorbidities, filling a current gap in the clinical management of IS.

Literature Cited

1. Scantlebury, M.H. et al. A model of symptomatic infantile spasms syndrome. Neurobiol. Dis. 2010; 37(3): 604-612. 
2. Pellock, J.M et al. Infantile spasms: a U.S. consensus report. Epilepsia 2010; 51: 2175-2189. 
3. D’Alonzo et al. West syndrome: a review and guide for paediatricians. Clin. Drug. Investig. 2018; 38: 113-124. 
4. Nelson, J.A. et al. Evolution of infantile spasms to Lennox-Gastaut Syndrome: what is there to know J. Child Neurol. 2021; 36(9): 752-759. 
5. Riikonen, R. Recent advances in the pharmacotherapy of infantile spasms. CNS Drugs 2014; 28(4): 279-290. 
6. Riikonen, R. Infantile spasms: outcome in clinical studies. Pediatr. Neurol. 2020; 108: 54-64. 
7. Knupp, K.G. et al. Response to treatment in a prospective national infantile spasms cohort. Ann. Neurol. 2016; 79(3): 475-484 
8. CURE Infantile Spasms Consortium, Lubbers, L., & Iyengar, S.S. A team science approach to discover novel targets for infantile spasms. Epilepsia Open 2020; 6(1): 49-61. 
9. Raffo, E. et al. A pulse rapamycin therapy for infantile spasms and associated decline.Neurobiol. Dis. 2011;43: 322-329. 
10. Akman, O. et al. Antiepileptogenic effects of rapamycin in a model of infantile spasms due to structural lesions. Epilepsia 2021; 62(8): 1985-1999. 

Key Points:

• Taking Flight grantee Dr. Ankit Khambhati and colleagues at the University of California – San Francisco sought to understand why some people with drug-resistant epilepsy respond better than others to responsive neurostimulation (RNS) therapy.

• After examining the pattern of brain waves of approximately 50 patients, the investigators identified a new biomarker that could predict which people would most benefit from RNS therapy.

• This important finding has the potential to help neurologists decide which patients would benefit the most from an RNS device before it is actually implanted in the brain.

Deep Dive:

Of the millions of people who are impacted by epilepsy, approximately one-third do not respond to currently available antiseizure medications [1], adversely affecting their quality of life. Among those with drug-resistant focal epilepsy (seizures that start from a single area in the brain, formerly known as partial seizures), one of the more effective treatment options involves brain stimulation [2], including the Neuropace Responsive Neurostimulation System® (RNS) [3]. The RNS is a ‘smart’ device implanted on the surface of the brain, with two thin wires placed where the seizures begin. It monitors brain waves recorded from the wires to produce what is called an intracranial electroencephalogram (iEEG). When the RNS device senses abnormal neural activity, it responds with subtle electrical pulses to either terminate or suppress an emerging seizure. The iEEG data can also be mined for research purposes to identify changing patterns in the brain waves as a patient’s condition improves.

The RNS is effective at reducing seizures in many patients with focal epilepsy, but it does not work for every patient, and it is not clear why. Dr. Khambhati and his colleagues, Drs. Edward Chang and Vikram Rao, thought that the lack of response in some people may be related to some seemingly inconsistent observations from numerous clinical trials of the RNS System. As mentioned above, the RNS device was designed to send electrical pulses to terminate a developing seizure only when abnormal electrical activity was detected, but the researchers found actual stimulation often occurred more than 1,000 times a day. This did not correlate with the actual number of seizures reported suggesting a significant amount of abnormal activity between seizures. In addition, clinically significant improvements, i.e., reduction in seizure frequency, occurred gradually over time, often years rather than just immediately after electrical stimulation by RNS [4]. Together, these observations suggested that there is abnormal electrical activity that occurs between seizures, possibly exacerbating them, and that the RNS device both terminates seizures and may also slowly modify how they are generated.

To explore this possibility, Dr. Khambhati and colleagues capitalized on the availability of many years’ worth of iEEG data from approximately 50 patients with an implanted RNS device [5]. Upon close examination of the data, they found a wide range of RNS response effectiveness among these patients and categorized them in three separate groups: super, intermediate, and poor responders based on the percent reduction in seizures.

Comparing the iEEG patterns from each of these groups allowed the researchers to conclude that RNS therapy, in addition to suppressing an emerging seizure, was also inducing a rewiring of the epileptic network, essentially disrupting it. This, in turn, dramatically decreased the brain’s tendency to generate excessive excitatory electrical activity sufficient to trigger a seizure. More importantly, the researchers found that much of this rewiring was a result of stimulation that occurred between seizures rather than just before the “buildup” of electrical activity indicative of seizure onset. Furthermore, since each of the three responder groups exhibited different iEEG “fingerprints”, the researchers were also able to consolidate these data to generate a powerful algorithm that could examine iEEG patterns and pinpoint unique biomarkers reflecting a prospective patient’s likely response to an implanted RNS device.

With this critical advancement, clinical care of patients with focal epilepsy being treated with RNS therapy may be improved beyond the typical adjustment of stimulation parameters. Neurologists may now be able to predict how a patient will respond to RNS, better counsel patients on their prognosis, and adjust stimulation parameters accordingly. Ideally, this discovery will help determine if a patient will even benefit from RNS therapy before the device is even implanted in the brain, thereby reducing unnecessary treatment risks for patients with focal epilepsy.

Literature Cited
1. Chen, Z. et al. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal cohort study. JAMA Neurol. 2018; 75: 279-286.
2. Foutz, T. & Wong, M. Brain stimulation treatments in epilepsy: basic mechanisms and clinical advances. Biomed. J 2021; in press
3. 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.
4. Nair, D.R. et al. Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy. Neurology 2020; 95: e1244-e1256.
5. Khambhati, A.N. et al. Long-term brain network reorganization predicts responsive neurostimulation outcomes for focal epilepsy. Sci. Transl. Med. 2021; 13(608): eabf6588.