A new peptide administered through a nasal spray shows promising results as an anticonvulsant and could ultimately be further developed as a treatment to prevent seizures in both epilepsy and Alzheimer’s disease (AD).
A study published in The American Society for Clinical Investigation outlines work conducted by researchers to develop a peptide called A1R-CT that disrupts the signaling between the molecule neurabin and the adenosine 1 receptor (A1R). A1R sits on the outside of the neuron and responds to adenosine, whereas neurabin binds to the receptor and blocks it from use.
It has previously been established that A1R has neuroprotective effects and that, when activated by adenosine, it mediates an anti-convulsant response. This, however, is often blocked by neurabin.
“Neurabin is a brake, so it doesn’t do too much,” Dr. Qin Wang, neuropharmacologist and founding director of the program for Alzheimer’s therapeutics discovery at the Medical College of Georgia at Augusta University, told Science News. “But now we need to remove it to unleash A1’s power.”
Surgery can cure or significantly improve both the frequency and intensity of seizures in patients with medication-refractory epilepsy. The set of diagnostic and therapeutic interventions involved in the path from initial consultation to definitive surgery is complex and includes a multidisciplinary team of neurologists, neurosurgeons, neuroradiologists, and neuropsychologists, supported by a very large epilepsy-dedicated clinical architecture. In recent years, new practices and technologies have emerged that dramatically expand the scope of interventions performed: stereoelectroencephalography has become widely adopted for seizure localization; stereotactic laser ablation has enabled more focal, less-invasive, destructive interventions; and new brain stimulation devices have unlocked treatment of eloquent foci and multifocal-onset etiologies. This article articulates and illustrates the full framework for how epilepsy patients are considered for surgical intervention, with particular attention given to stereotactic approaches.
Voltage-gated sodium and potassium channels regulate the initiation and termination of neuronal action potentials. Gain-of-function mutations of sodium channel Scn8a and loss-of-function mutations of potassium channels Kcna1 and Kcnq2 increase neuronal activity and lead to seizure disorders. We tested the hypothesis that reducing expression of Scn8a would compensate for loss-of-function mutations of Kcna1 or Kcnq2. Scn8aexpression was reduced by administration of an antisense oligonucleotide (ASO). This treatment lengthened survival of the Kcn1a and Kcnq2 mutants, and reduced seizure frequency in the Kcnq2 mutant mice. These observations suggest that reduction of SCN8Amay be therapeutic for genetic epilepsies resulting from potassium channel mutations.
John Swann, PhD, and his team explored an underlying cause of infantile spasms (IS), a devastating epileptic encephalopathy (an epilepsy syndrome that can lead to deterioration of the brain) that typically begins within the first year of life.This new research, funded by the National Institutes of Health (NIH), was a direct result of Dr. Swann’s findings from his work as a member of the CURE Epilepsy Infantile Spasms Initiative, conducted from 2013-2017.
Standard treatments for IS work in only approximately 50% of patients and can have severe side effects. The need for additional effective therapies drove Dr. Swann and his team to explore a more effective treatment with fewer or, ideally, no side effects.
Through extensive experimentation with an established rat model of IS and parallel studies in human tissue removed during epilepsy surgery, Dr. Swann observed very low levels of an important growth factor in the brain which has the potentialto be a promising new treatment for this severe form of epilepsy.
Deep Dive:
Infantile spasms (IS) is a rare catastrophic form of epilepsy with approximately 90% of the cases beginning within the first year of life [1,2].The condition is characterized by seizures with sudden brief jerking movements of the arms and legs or head bobs and often, though not always, an atypical, chaotic pattern of brain waves on the electroencephalogram (EEG) known as hypsarrhythmia [3]. The seizures are accompanied by significant development delays as well as cognitive and physical deterioration [2]. Standard treatments include adrenocorticotropic hormone (ACTH)or prednisone,and the antiseizure medication vigabatrin [4]. Unfortunately, only approximately 50% of children with IS respond to these treatments and there remains no reliable way of predicting who will respond favorably [4]. Even if these treatments diminish IS symptoms for a specific patient, they can have serious side effects. Therefore, scientists have been searching for other drug targets with the ultimate goal of developing alternative therapies.
One of these scientists is Dr. John Swann, Professor of Pediatrics at the Baylor College of Medicine, Director of the Gordon and Mary Cain Pediatric Neurology Research Foundation, and Principal investigator at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, who leveraged findings from his work as part of the CURE Epilepsy Infantile Spasms Initiative(2013-2017). With additional funding from NIH, Dr. Swann and his team used a previously developed rat model of IS [5] that mirrors many of this disorder’s symptoms, to investigate spasms that result from pediatric brain injuries, such as those suffered during a traumatic birth.
He and the team wanted to determine if the level of a substance known as insulin-like growth factor-1 (IGF-1) was altered in the injuredbrains of both their rat model and in IS patients, the latter using brain tissue from IS patients who had undergone neurosurgery to stop their seizures. The rationale behind this experiment was based on two observations. The first is that the level of IGF-1 in the cerebrospinal fluid of IS patients with preexisting brain damage is low [6], and second is that IGF-1 activates a biological pathway crucial for proper brain development and neuronal function [7]. As hypothesized, data revealed that IGF-1 levelswere lower in brain tissue from both the rat model and from infants with IS. Data also showed that reduced expression of IGF-1 in the rat model affected the biological pathways critical for neurodevelopmental processes [8].
These promising findingssuggested that increasing the amount of IGF-1 in the brains of the rat model might alleviate at least some of the symptoms of IS. To test this idea, the researchers employed a shorter version of IGF-1 called (1-3)IGF-1 which is a natural breakdown product of IGF-1 that can cross the blood-brain barrier with much higher efficiency than the full-length IGF-1 [9].
After confirming that (1-3)IGF-1 could activate the same biological pathways responsible for regulating the processes involved in early brain developmentas full-length IGF-1, the researchers administered it to their rat model and successfully eliminated both the spasms as well as the hypsarrhythmia in most rodents. This exciting finding suggests that this smaller (1-3)IGF-1 or perhaps an IGF-1-like drug may one day be used to treat IS patients immediately after the condition is diagnosed. This new approach could potentially reduce or even eliminate the associated neurodevelopmental and cognitive effects of this devastating disorder without the side effects of the currently available treatments. Dr. Swann states that this research and subsequent additional funding from NIH to continue the work would not have been possible without his participation in the CURE Epilepsy Infantile Spasms Initiative.
Literature Cited:
Pellock, JM et al. Infantile spasms: a US consensus report. Epilepsia 2010; 51: 2175-2189
Cowan, L.D. & Hudson, L.S. The epidemiology and natural history of infantile spasms. Child Neurol. 1991; 6(4): 355-364.
Gibbs, E.L., Fleming, N.M, & Gibbs, F.A. Diagnosis and prognosis of hypsarrhythmia and infantile spasms. Pediatrics 1954; 13(1): 66-73.
Knupp, K.G. et al. Response to treatment in a prospective national infantile spasms cohort. Neurol. 2016; 79(3): 475-484.
Lee, C.L. et al. A new animal model of infantile spasms with unprovoked persistent seizures. Epilepsia 2008; 49(2): 298-307.
Riikonen, R.S. et al. Insulin-like growth factor-1 is associated with cognitive outcome in infantile spasms. Epilepsia 2010; 51(7): 1283-1289.
O’Kusky, J. & Ye, P. Neurodevelopmental effects of insulin-like growth factor signaling. Neuroendrocrincrinol. 2012; 33(3): 230-251.
Ballester-Rosado, C.J. et al. A role for insulin-like growth factor 1 in the generation of epileptic spasms in a murine model. Neurol. 2022; 92(1): 45-60.
Yamamoto, H. & Murphy, L.J. Enzymatic conversion of IGF-1 to des(1-3)IGF-1 in rat serum and tissues: a further potential site of growth hormone regulation of IGF-1 action. Endocrinol. 1995; 146(1): 141-148.
Objective: To discuss the results of the KETASER01 trial and the reasons for its failure, particularly in view of future studies.
Methods: KETASER01 is a multicenter, randomized, controlled, open-label, sequentially designed, non-profit Italian study that aimed to assess the efficacy of ketamine compared with conventional anesthetics in the treatment of refractory convulsive status epilepticus (RCSE) in children.
Results: During the five-year recruitment phase, a total of 76 RCSEs treated with third-line therapy were observed in five of the ten participating Centers; only ten individuals (five for each study arm; five females, mean age 6.5 ±?6.3?years) were enrolled in the KETASER01 study. Two of the five patients (40%) in the experimental arm were successfully treated with ketamine and two of the five (40%) children in the control arm, where successfully treated with thiopental. In the remaining six (60%) enrolled patients, RCSE was not controlled by the randomized anesthetic(s).
Significance: The KETASER01 study was prematurely halted due to low eligibility of patients and no successful recruitment. No conclusions can be drawn regarding the objectives of the study. Here we discuss the KETASER01 results and critically analyze the reasons for its failure in view of future trials.
The National Institute of Neurological Disorders and Stroke (NINDS) has awarded Emory neuroscientists a three-year, $2 million grant to develop new anti-inflammatory drugs for the prevention of comorbidities related to epilepsy.
Thota Ganesh, PhD, and Ray Dingledine, PhD, have been investigating the potential for EP2 antagonists, which inhibit signals from inflammatory prostaglandins, to prevent the development of comorbidities associated with epilepsy. Ganesh says EP2 antagonists act as a sort of “fire extinguisher,” interrupting the chain of events occurring in the brain in response to an initial injury by seizures.
“In animal models, we have shown EP2 receptor activation is responsible for blood-brain barrier leakage and much of the inflammatory reaction, neuronal injury and cognitive deficits that follow seizure-provoked induction of the enzyme cyclooxygenase 2,” Ganesh says.
The researchers will conduct further studies to identify EP2 antagonist candidate compounds for eventual study in human clinical trials. They hope to develop the first preventative treatment for cognitive deficits related to epilepsy through this research.
Featuring the work of CURE Epilepsy grantee Dr. Pavel Klein
Long-term use of Xcopri was safe and reduced seizures by more than 90% in adults with uncontrolled focal seizures, according to results of an open-label extension study published in Neurology.
“The findings show that the notable improvement in seizure control that was seen in patients with uncontrolled focal epilepsy is sustained over long term,” Pavel Klein, MD, lead study author and epileptologist and neurologist at Mid-Atlantic Epilepsy and Sleep Center in Bethesda, Md., told Healio. “The study shows that a significant proportion of patients with uncontrolled epilepsy continue to remain seizure-free or have at least 90% reduction for a period of time that sustained over the duration of the study — for years.”
Klein and colleagues conducted a randomized, double-blind, placebo-controlled study of Xcopri (cenobamate, SK Life Science Inc.) and assessed data from 355 adult patients with focal seizures that were uncontrolled despite being treated with up to three antiseizure medications.
According to a press release about the study findings from SK Life Science, participants, who had at least eight seizures during the 8-week baseline period, completed the 18-week, double-blind phase and continued into the open-label extension.
The development of seizures is associated with many changes in the brain; one of these changes is alterations in the white matter (the deep part of the brain) composed of axons covered in myelin. Myelin is a substance that acts as a nerve insulator and is critical for communication between neurons.
Dr. Juliet Knowles at Stanford University was granted both a CURE EpilepsyTaking Flight and a CURE EpilepsyResearch Continuity Fund award to investigate whether changes in myelin might play a role in the development of epilepsy. Through her research, the team discovered that abnormal neuronal activity during absence seizures may lead to changes in myelination. The changes in myelin, in turn, lead to seizure progression.
This research paves the way for future studies that may identify ways to prevent harmful changes in myelination to treat some forms of epilepsy.
Deep Dive:
Some types of epilepsy are progressive, and the disease progression may manifest in the form of more frequent seizures, worsened control of seizures, or decline of cognition.[1] Progression of seizures has a direct correlation to the severity of epilepsy as time progresses.[2] Multiple factors may contribute to how seizures progress, but one factor that had not been investigated is a change, (known as plasticity), in the white matter or myelin of the brain. Myelin is a substance that acts as a form of insulation around the nerve cells of the brain and is essential for the conduction of electrical impulses between neurons and for the proper functioning of the brain. In fact, this white coating of myelin is what gives the collection of axons deep inside the brain the name “white matter”. Plasticity or changes in myelination can occur in response to neuronal activity and are important in the non-epileptic brain for functions such as learning, memory, and attention.[3,4] The team found that seizures in newborn infants with genetic forms of epilepsy may be associated with abnormalities in myelination.[5] These findings suggested that myelin plasticity might also occur in response to seizures.
With her CURE Epilepsy Taking Flight Award, generously funded by the Ravichandran Foundation, Dr. Knowles and her colleagues sought to determine whether changes in myelination caused by a type of seizure called an absence seizure (formerly known as a petit mal seizure) contribute to the progression of epilepsy.[6] And when COVID-19 forced this study to be put on a temporary hold, the CURE Epilepsy Research Continuity Fund award, generously funded by the Cotton Family in memory of Vivian Cotton, helped Dr. Knowles’ team to finish these experiments when laboratories reopened. For her study, Dr. Knowles hypothesized that changes in myelin might influence seizure severity in absence seizure spreading.
Absence seizures are characterized by the abrupt stopping of behavior (“behavioral arrest”) and a specific pattern of brain activity. Even though absence seizures are typically brief, an individual can have an extremely high number of seizures in a day.[7, 8] Absence seizures originate in connections between two parts of the brain called the thalamus and cortex, after which seizure activity is transmitted through a large brain network by myelin-coated axons in white matter.[9, 10]
The team used rodent models which had specific genetic mutations in their neurons that produce absence seizures. The pattern of seizure progression in these animals is similar to what is found in children with progressive forms of epilepsy.[2, 8] Electroencephalogram (EEG) was used to study electrical activity in the brain and the structure of neurons was examined using sophisticated microscopy techniques.[6] Additional techniques used to investigate the role of seizures in myelination included genetic interventions to block myelination (the process by which layers of myelin are produced) and drugs that decreased seizures.[6]
By using these methods, Dr. Knowles’ team first observed that there was an increase in myelination within the seizure network in seizure-prone animals, but this was seen only once seizures had started. This suggests that there is something unique and specific about the seizure activity that impacts myelination. Additionally, when Dr. Knowles’ team blocked seizures either genetically or using drugs, the increase in myelination was prevented. When the team blocked this abnormal myelination, the number of seizures decreased, and neuronal hypersynchrony decreased as well.[6] Neuronal hypersynchrony is the process by which networks of neurons fire together in an extremely organized and coordinated but abnormal way and is thought to underlie some aspects of seizure onset and spreading.[11]
The current study by Dr. Knowles’ group is the first that clearly shows that abnormal neuronal activity (in this case, due to absence seizures) can lead to harmful changes in myelination, which contribute to the continued progression of epilepsy.[6] Future work in the field will look at the exact molecules and neurotransmitters involved to better characterize this change in myelination. Although more studies are necessary, the current work suggests that developing treatments that address both abnormal neuronal activity and the associated abnormal myelination could more effectively prevent seizures and cognitive difficulties.[12]
Literature Cited:
Coan AC, Cendes F. Epilepsy as progressive disorders: what is the evidence that can guide our clinical decisions and how can neuroimaging help? Epilepsy Behav. 2013 Mar;26:313-321.
Brigo F, Trinka E, Lattanzi S, Bragazzi NL, Nardone R, Martini M. A brief history of typical absence seizures – Petit mal revisited Epilepsy Behav. 2018 Mar;80:346-353.
McKenzie IA, Ohayon D, Li H, de Faria JP, Emery B, Tohyama K, et al. Motor skill learning requires active central myelination Science. 2014 Oct 17;346:318-322.
Pan S, Mayoral SR, Choi HS, Chan JR, Kheirbek MA. Preservation of a remote fear memory requires new myelin formation Nature Neuroscience. 2020 2020/04/01;23:487-499.
Musgrave J, Gloor P. The role of the corpus callosum in bilateral interhemispheric synchrony of spike and wave discharge in feline generalized penicillin epilepsy Epilepsia. 1980 Aug;21:369-378.
Fogerson PM, Huguenard JR. Tapping the Brakes: Cellular and Synaptic Mechanisms that Regulate Thalamic Oscillations Neuron. 2016 Nov 23;92:687-704.
Jiruska P, de Curtis M, Jefferys JGR, Schevon CA, Schiff SJ, Schindler K. Synchronization and desynchronization in epilepsy: controversies and hypotheses J Physiol. 2013;591:787-797.
Li MCH, Cook MJ. Deep brain stimulation for drug-resistant epilepsy Epilepsia. 2018 Feb;59:273-290.
Neuromodulation is a key therapeutic tool for clinicians managing patients with drug-resistant epilepsy. Multiple devices are available with long-term follow-up and real-world experience. The aim of this review is to give a practical summary of available neuromodulation techniques to guide selection of modalities, focusing on patient selection for devices, common approaches and techniques for initiation of programming, and outpatient management issues.
Vagus nerve stimulation (VNS), deep brain stimulation of the anterior nucleus of the thalamus (DBS-ANT), and responsive neurostimulation (RNS) are all supported by randomized controlled trials that show safety and a significant impact on seizure reduction, as well as a suggestion of reduction in the risk of sudden unexplained death from epilepsy (SUDEP). Significant seizure reductions are observed after 3 months for DBS, RNS, and VNS in randomized controlled trials, and efficacy appears to improve with time out to 7-10?years of follow-up for all modalities, albeit in uncontrolled follow-up or retrospective studies. A significant number of patients experience seizure-free intervals of 6 months or more with all three modalities. Number and location of epileptogenic foci are important factors affecting efficacy, and together with co-morbidities such as severe mood or sleep disorders, may influence choice of modality. Programming has evolved – DBS is typically initiated at lower current/voltage than used in the pivotal trial while charge density is lower with RNS, but generalizable optimal parameters are yet to be defined. Non-invasive brain stimulation is an emerging stimulation modality, although currently not widely used.
Clinical practice has evolved from those established in pivotal trials. Guidance is available for clinicians wishing to expand their approach, and choice of neuromodulation technique may be tailored to individual patients based on their epilepsy characteristics, risk tolerance, and preferences.
CURE Epilepsy Award grantee Dr. Nuria Lacuey and her team sought to identify specific parts of the brain essential for regulating breathing, a fundamental function whose failure following a seizure is primarily responsible for Sudden Unexpected Death in Epilepsy (SUDEP).
The team recruited patients who were being evaluated for epilepsy surgery and who formally agreed to enroll in a study that had them perform various breathing exercises while having different areas of their brain electrically stimulated with varying intensities.
Quantitative analyses of the data revealed that four specific areas of the cortex of the brain affected the patients’ breathing responses, depending on the strength and frequency of the electrical stimulation. Two of these areas resulted in enhanced respiratory activity.
Additional data from more patients is needed, but Dr. Lacuey hopes to use these valuable results to develop a device that will stimulate critical areas of the brain following seizures to enhance breathing and avoid its cessation, thereby preventing SUDEP.
Deep Dive:
SUDEP is the most frequent cause of death among people with drug-resistant epilepsy [1,2]. Although different biological processes may contribute to SUDEP, the most prominent appears to be a phenomenon known as centralapnea, a condition in which breathing repeatedly stops and starts, usually while sleeping, during or immediately after a severe seizure [3,4]. There is compelling evidence that breathing irregularities are an underlying cause of SUDEP. Research to date has almost exclusively concentrated on the role of an area of the brain called the brainstem [5], which ultimately connects higher cortical regions of the brain to the spinal cord. Although the brainstem plays a crucial role in maintaining respiratory activity, it may not be the only contributing area. Indeed, areas of the cortexhave also been implicated [6], but the specific roles different areas of the cortex play in modulating breathing is unclear. Most importantly, there are currently no strategies for directly improving respiratory function during the dangerous period between seizure-induced central apnea and death.
One possible approach would be to electrically stimulate specific areas of the brain to maintain respiratory function during this critical period. As a first step, it is vital to assess the role of specific areas of the brain and what intensity and frequency of the electrical current might have beneficial or detrimental effects on breathing. Developing such an innovative method requires a detailed understanding of the relationship between brain electrical activity and breathing responses, specifically how brain regions are structurally and functionally linked through their neuronal connections, collectively known as the connectome [7,8].
Research on this approach was conducted by Dr. Lacuey and her team in the Department of Neurology at the University of Texas Health Science Center in Houston, TX. Nineteen patients who suffered from drug-resistant epilepsy and who were being evaluated for epilepsy surgery consented to be enrolled in the study [9]. Pinpointing the exact seizure focus without damaging surrounding healthy tissue necessitated placing electrodes directly on the brains of these patients and then, electrically stimulating various brain regions for clinical mapping.
Electrodes were implanted in seven brain regions common to all 19 participants, and thus, these were the regions selected for comprehensive investigation. The goal was to ascertain whether electrical stimulation of each of these seven regions would affect breathing responses and, if so, whether the resulting respiratory activity would be enhanced or inhibited. Equally important was to determine the stimulation intensity as well as frequency necessary to elicit such responses. Electrical stimulation was carried out at a current of 1-10 milliamps (mA) and a frequency of 50 Hertz for 0.2 milliseconds [9].
Quantitative analyses of the data showed that electrical stimulation affected breathing responses in four of the seven different brain regions tested. Stimulation of two of these regions, specifically within the frontal portions of areas calledthe temporal lobe and cingulate gyrus, promoted breathing enhancementat a relatively low current (less than 3 mA) but not at the higherelectrical current conditions tested [9]. Future experiments will require a larger group of patients, finer mapping of the identified brain regions, and exploration of brain regions other than the seven examined in the current study. Subsequent experiments will also include an evaluation of electric current and frequency as well as how any observed changes in respiratory control interact with the breathing mechanisms of the brainstem.
The fact that electrical stimulation of four cortical regionsaffected respiration, and that two of these areas enhanced breathing is an exciting finding. Significantly, this CURE Epilepsy funded research supports the idea that an implantable device capable of electrically stimulating pre-identified cortical regions of the brain to enhance breathing at critical times to prevent SUDEP may eventually be possible.
Literature Cited:
Jones, L.A. & Thomas, R.H. Sudden unexpected death in epilepsy: insights from the last 25 years. Seizure 2017; 44: 232-236.
Devinsky, O. et al. Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention. Lancet Neurol. 2016; 15(10): 1075-1088.
Vilella, L. et al. Postconvulsive central apnea as a biomarker for sudden unexpected death in epilepsy (SUDEP). Neurology 2019; 92(3): e171-e182.
So, E.L., Sam, M.C., & Lagerlund, T.L. Postictal central apnea as a cause of SUDEP: evidence from near-SUDEP incident. Epilepsia 2000; 41(11): 1494-1497.
Patodia, S. et al. The ventrolateral medulla and medulla raphe in sudden unexpected death in epilepsy. Brain 2018; 141(6): 1719-1733.
Herrero, J.L. Breathing above the brain stem: volitional control and attentional modulation in humans. J. Neurophysiol. 2018; 119(1): 145-159.
Bethlehem, R.A.J. et al. Brain charts for the human lifespan. Nature 2022; 604(7906): 525-533.
Fan, Q. et al. Mapping the human connectome using diffusion MRI at 300 mT/m gradient strength: Methodological advances and scientific impact. Neuroimage 2022; 254:118958.
Ganne, C. et al. Limbic and paralimbic respiratory modulation: from inhibition to enhancement. Epilepsia 2022; Epub
within the first year of life.
communication between neurons.