Science One Step Closer to Turning Off Seizures, Sleep Disturbances Linked to Intellectual Disability

Article published in Science Daily

Science is one step closer to developing targeted drug therapies that may reduce seizures, sleep disorders, and related symptoms common in people with intellectual disabilities.

Research led by a team of UNLV neuroscientists has shown the potential to zero in on the root-level cause of a host of adverse symptoms associated with unique subtypes of neurodevelopmental disorders, work that could one day improve the lives of millions worldwide.

The study, published Feb. 15 in the Nature journal Molecular Psychiatry, builds on previous research by UNLV neuroscientist Rochelle Hines and collaborators, which discovered that two key proteins — collybistin and the GABAA receptor ?2 subunit — control the firing of brain cells and contribute to epileptic seizures, learning and memory deficiencies, sleep disturbances, and other symptoms frequently associated with various forms of intellectual disability including Down syndrome, autism, and ADHD.

The team’s newest findings unveiled that mutations in ARHGEF9 — the gene that codes for collybistin — lead to intellectual disability through impaired ?2 subunit function. The team further showed that ?2 is a central hub for many of the adverse neurological symptoms characteristic of multiple intellectual disability subtypes.

In addition to patients with neurodevelopmental disorders, researchers said their study has the potential to improve the quality of life more broadly for people who grapple with sleep dysfunction, epilepsy, anxiety, hyperactivity, and other neurological abnormalities.

Surgical Outcome of Temporal Plus Epilepsy is Improved by Multilobar Resection

Abstract found in PubMed and originally published in Epilepsia

Objective: Temporal plus epilepsy (TPE) represents a rare type of epilepsy characterized by a complex epileptogenic zone including the temporal lobe and the close neighboring structures. We investigated whether the complete resection of temporal plus epileptogenic zone as defined through stereoelectroencephalography (SEEG) might improve seizure outcome in 38 patients with TPE.

Methods: Inclusion criteria were as follows: epilepsy surgery performed between January 1990 and December 2001, SEEG defining a temporal plus epileptogenic zone, unilobar temporal operations (“temporal lobe epilepsy [TLE] surgery”) or multilobar interventions including the temporal lobe (“TPE surgery”), magnetic resonance imaging either normal or showing signs of hippocampal sclerosis, and postoperative follow-up of at least 12 months. For each assessment of postoperative seizure outcome, at 1, 2, 5, and 10 years, we carried out descriptive analysis and classical tests of hypothesis, namely, Pearson ?2 test or Fisher exact test of independence on tables of frequency for each categorical variable of interest and Student t-test for each continuous variable of interest, when appropriate.

Results: Twenty-one patients underwent TPE surgery and 17 underwent TLE surgery with a follow-up of 12.4 ± 8.16 years. In the multivariate models, there was a significant effect of the time from surgery on Engel Class IA versus IB-IV outcome, with a steadily worsening trend from 5-year follow-up onward. TPE surgery was associated with better results than TLE surgery.

Significance: This study suggests that surgical outcome in patients with temporal plus epilepsy can be improved by a tailored, multilobar resection and confirms that SEEG is mandatory when a temporal plus epilepsy is suspected.

Incidence and Prevalence of Major Epilepsy-Associated Brain Lesions

Abstract found in ScienceDirect and originally published in Epilepsy & Behavior

Epilepsy surgery is an effective treatment option for drug-resistant focal epilepsy patients with associated structural brain lesions. However, little epidemiological data are available regarding the number of patients with these lesions. We reviewed data regarding (1) the prevalence and incidence of epilepsy; (2) the proportion of epilepsy patients with focal epilepsy, drug-resistant epilepsy, and drug-resistant focal epilepsies; and (3) the number of epilepsy presurgical evaluations and surgical resections. We also assessed the relative proportion of brain lesions using post-surgical histopathological findings from 541 surgical patients from the Cleveland Clinic and 9,523 patients from a European multi-center cohort. Data were combined to generate surgical candidate incidence and prevalence estimates and the first lesion-specific estimates for hippocampal sclerosis (HS), low-grade epilepsy-associated brain tumors (LEAT), malformations of cortical development (MCD), glial scars, vascular malformations, and encephalitis. The most frequently diagnosed brain lesions were HS (incidence = 2.32 ± 0.26 in 100,000, prevalence = 19.40 ± 2.16 in 100,000) for adults and MCD (incidence = 1.15 ± 0.34 in 100,000, prevalence = 6.52 ± 1.89 in 100,000) for children. Our estimates can guide patient advocacy groups, clinicians, researchers, policymakers in education, development of health care strategy, resource allocation, and reimbursement schedules.

Standardization of Seizure Response Times and Data Collection in an Epilepsy Monitoring Unit

Abstract found in PubMed

Objective: We sought to improve seizure response times in the epilepsy monitoring unit (EMU), improve the accuracy and reliability of seizure response time data collection, and develop a standardized and automated approach for seizure response data collection in the EMU.

Methods: We used Quality Improvement (QI) methodology to understand the EMU workflow involved in responding to seizures (a process map); to create a theory of change that stated the desired aim, potential drivers/barriers and interventions (i.e., key driver diagram) and perform iterative interventions to address some of the drivers plan-do-study-act (PDSA) cycles. We performed three PDSA cycles with a focus on improving the seizure alert system in our EMU. Adjustments were made to the methodology as it became clear that this was a systems issue, and our project would need to focus on improving the system rather than iteratively improving a functioning (stable) system.

Results: Over a 6-month period, 252 seizure response times were recorded and analyzed. We performed 3 interventions. The first was initiating twice monthly meetings with nursing and EEG techs to discuss the project and provide feedback on response times. The second was the implementation of a new Hill-Rom seizure alert system to reduce alert times and automate data tracking. The third was implementing a new alert deactivation system to reduce variability in the data. Following these 3 interventions, variation, and data collection methods were improved while also maintaining improvements in seizure response times.

Significance: We identified and implemented an alert system in our epilepsy monitoring unit which led to more efficient and accurate data collection while maintaining improved response times that resulted from the first intervention. This lays the groundwork for future quality improvement initiatives and has created a framework for standardizing seizure response time recording and data collection that can be replicated at other centers with similar infrastructure, personnel and workflows.

Substantial Early Changes in Bone and Calcium Metabolism Among Adult Pharmacoresistant Epilepsy Patients on a Modified Atkins Diet

Abstract appeared in Wiley Online Library

Objective: The aim of this study was to investigate whether the modified Atkins diet (MAD), a variant of the ketogenic diet, has an impact on bone- and calcium (Ca) metabolism.

Methods: Two groups of adult patients with pharmacoresistant epilepsy were investigated. One, the diet group (n = 53), was treated with MAD for 12 weeks, whereas the other, the reference group (n = 28), stayed on their habitual diet in the same period. All measurements were performed before and after the 12 weeks in both groups. We assessed bone health by measuring parathyroid hormone (PTH), Ca, 25-OH vitamin D (25-OH vit D), 1,25-OH vitamin D (1,25-OH vit D), phosphate, alkaline phosphatase (ALP), and the bone turnover markers procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide collagen type 1 (CTX-1). In addition, we examined the changes of sex hormones (estradiol, testosterone, luteinizing hormone, follicle-stimulating hormone), sex hormone-binding globulin, and leptin.

Results: After 12 weeks of MAD, we found a significant reduction in PTH, Ca, CTX-1, P1NP, 1,25-OH vit D, and leptin. There was a significant increase in 25-OH vit D. These changes were most pronounced among patients <37 years old, and in those patients with the highest body mass index (?25.8 kg/m²), whereas sex and type of antiseizure medication had no impact on the results. For the reference group, the changes were nonsignificant for all the analyses. In addition, the changes in sex hormones were nonsignificant.

Significance: Twelve weeks of modified Atkins diet (MAD) treatment leads to significant changes in bone and Ca metabolism, with a possible negative effect on bone health as a result. A reduced level of leptin may be a triggering mechanism. The changes could be important for patients on MAD, and especially relevant for those patients who receive treatment with MAD at an early age before peak bone mass is reached.

The Effect of Epilepsy Surgery on Productivity

Abstract appeared in Wiley Online Library

 Objectives: An important but understudied benefit of resective epilepsy surgery is improvement in productivity; that is, people’s ability to contribute to society through participation in the workforce and in unpaid roles such as carer duties. Here, we aimed to evaluate productivity in adults with drug-resistant epilepsy (DRE) pre- and post-resective epilepsy surgery, and to explore the factors that positively influence productivity outcomes.

Methods: We conducted a systematic review and meta-analysis using four electronic databases: Medline (Ovid), EMBASE (Ovid), EBM Reviews – Cochrane Central Register of Controlled Trials (CENTRAL), and Cochrane Library. All studies over the past 30 years reporting on pre- and post-resective epilepsy surgical outcomes in adults with DRE were eligible for inclusion. Meta-analysis was performed to assess the post-surgery change in employment outcomes.

Results: A total of 1005 titles and abstracts were reviewed. Seventeen studies, comprising 2056 unique patients, were suitable for the final quantitative synthesis and meta-analysis. Resective epilepsy surgery resulted in a 22% improvement in overall productivity (95% confidence interval [CI]: 1.07–1.40). The factors associated with increased post-surgery employment risk ratios were lower pre-surgical employment in the workforce (relative risk ratio [RRR] =0.34; 95% CI: 0.15–0.74), shorter follow-up duration (RRR = 0.95; 95% CI: 0.90–0.99), and lower mean age at time of surgery (RRR= 0.97; 95% CI: 0.94–0.99). The risk of bias of the included studies was assessed using Risk Of Bias In Non-randomised Studies – of Interventions and was low for most variables except ”measurement of exposure.”

Significance: There is clear evidence that resective surgery in eligible surgical drug-resistant epilepsy (DRE) patients results in improved productivity. Future work may include implementing a standardized method for collecting and reporting productivity in epilepsy cohorts and focusing on ways to reprioritize health care resource allocation to allow suitable candidates to access surgery earlier. This will ultimately benefit individuals with DRE, their families, our communities, and the wider health care system.

Effectiveness of Zonisamide (Zonegran®) in Childhood Refractory Epilepsy

Abstract appeared in PubMed

Introduction: Zonisamide (ZNS) is a new generation antiepileptic drug (AED) used in refractory epilepsy. This study assessed the effectiveness and reliability of ZNS in childhood refractory epilepsy.

Method: Sixty-eight epilepsy patients who were followed up in the paediatric neurology clinic, between 2013 and 2019, and in whom add-on therapy ZNS had been added as their seizures had continued despite multiple drugs being used, were included in this retrospective study. Their demographic findings, seizure aetiology, pre-treatment and post-treatment electroencephalography findings, treatment responses and any side effects of the drugs given were assessed in these patients.

Results: There were 46 (67.6%) patients in the refractory generalized epilepsy (RGE) group using multiple AEDs and 22 (32.35%) patients in the refractory focal epilepsy (RFE) group. Of these patients, 12 (17.65%) were being followed up for idiopathic epilepsy and 8 (11.76%) were being followed up for epilepsy of unknown aetiology. Twenty-two (32.36%) patients were followed up for structural abnormality, 8 patients (11.77%) were followed up for genetic disease, 4 patients (5.88%) were followed up for infectious sequel, 14 patients (20.59%) were followed up for metabolic reasons. In the RGE group, a more than 50% reduction was found in the seizures of 26 (56.5%) patients, while the seizures of 7 (15.2%) patients were found to have terminated completely. In the RFE group, a more than 50% reduction was found in the seizures of 19 (86.4%) patients, while the seizures of 2 (9.1%) patients were found to have terminated completely. The termination or a more than 50% reduction in seizures in 4 of the 6 patients followed up for a diagnosis of tuberous sclerosis complex (TSC) was significant.

Conclusion: ZNS is an effective and reliable option as an add-on therapy in paediatric refractory epilepsy, especially in focal epilepsy. It can also be considered for treatment in TSC patients.

The Beneficial Effect of Probiotics Supplementation on Penicillin-Induced Focal Seizure in Rats

Abstract published in PubMed

The focal epilepsy is a chronic neurological brain disorder which affects millions of people in the world. There is emerging evidence that changes in the gut microbiota may have effects on epileptic seizures. In the present study, we examined the effect of probiotics on penicillin-induced focal seizure model in rats. Male Wistar Albino rats (n: 21) were randomly divided into three groups: control (no medication), penicillin and penicillin + probiotic. Probiotic VSL#3 (12.86 bn living bacteria/kg/day) was given by gavage for 30 days. The seizures were induced by intracortical injection of penicillin G (500 IU) into the cortex. An ECoG recordings were made for 180 min after penicillin G application. The spike frequency and the amplitude were used to assess the severity of seizures. Tumor necrosis factor (TNF-?), nitric oxide (NO) and interleukin (IL-6) levels in the brain were studied biochemically. Our results indicated that probiotic supplementation improved focal seizures through increasing the latency (p < 0.001) and decreasing the spike frequency (p < 0.01) compared to the penicillin group. Penicillin-induced seizure in rats significantly enhanced TNF-? (p < 0.01), NO (p < 0.01) and IL-6 (p < 0.05) compared to the control. Probiotic supplementation significantly decreased IL-6 (p < 0.05), TNF-? (p < 0.01) and NO (p < 0.001) compared to the penicillin group. When the body weights were compared before and after the experiment, there was no difference between the control and penicillin groups, but it was observed that the body weight decreased after probiotic supplementation in the penicillin + probiotic group.

Probiotic supplementation may have anti-seizure effect by reducing proinflammatory cytokine and nitric oxide levels in epileptic rat brain.

Yale Researchers Receive Grant to Develop Novel Epilepsy Brain-Computer Chip Treatment

Article appeared in Yale Daily News

An interdisciplinary team of Yale researchers has designed brain-machine interface chips that, when implanted in humans, can reduce the rate of epileptic seizures.

More than three million people experience epileptic seizures in the United States, with 60 to 70 percent of patients able to successfully treat the condition with medicine. For the remaining individuals, surgically removing the parts of the brain where seizures arise, regardless of their role in everyday function, has been the only path toward mitigating the issue. A team of Yale computer scientists, engineers and surgeons have found that short-circuiting the path neurons fire during an epileptic seizure can successfully reduce the rate of seizures in patients. The Swebilius Foundation recently awarded the team a grant to continue its research.

“When the signature traits of a seizure are observed, the device stimulates that part of the brain, and it is not curative, but over time 60 percent of patients will get 50 percent fewer seizures than they had before,” said Dennis Spencer, professor emeritus of neurosurgery, who implants these brain-computer interface chips in patients.

The team is still working to increase the success rate. Currently, each chip contains two electrodes with four contacts. When attempting to short-circuit a seizure, a surgeon can only stimulate the brain on the linear path between those two electrodes.

The chips are uniquely targeted, both spatially and temporally, making them superior to medication or surgery for seizures that extend into critical regions of the brain. However, the chips’ targeted nature makes them inadequate in many cases when seizures follow a network of connections, moving quickly around the brain.

CURE Epilepsy Impact: Investing in Early-Stage Investigators Advances Careers & Leads to Groundbreaking Epilepsy Treatments

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.