The word “epilepsy” comes from the Greek epilambanein, meaning “to seize, take hold of, or attack” (Baloyannis, 2013). As evidenced by historical accounts and works of art, epilepsy has existed since the beginning of recorded history, and has been the subject of myth and prejudice ever since. It was identified and described early on by ancient Mesopotamian civilizations. Akkadian texts (circa 2000 BC) contain the first description of an epileptic seizure: “…his neck turns left, his hands and feet are tense and his eyes wide open, and from his mouth froth is flowing without his having any consciousness” (Magiorkinis et al., 2010).
Assyrian and Babylonian texts associated seizures with “evil” or “sin,” and perpetuated the notion that epilepsy embodies demonic possession (Ali et al., 2016). During the Homeric era (1200 – 800 BC), epilepsy was considered a gift from the gods (Baloyannis, 2013) and some believed those with seizures were endowed with supernatural powers (Magiorkinis et al., 2010). Hippocrates (c. 400 BC) and his followers were the first to consider epilepsy as a physical disorder of natural origin, although this scientific conceptualization was discarded in the Middle Ages. In 1870, Dr. John Hughlings Jackson first established its anatomical and pathological basis when he defined epilepsy as “occasional, sudden, excessive, rapid and local discharges of gray matter” (Jackson, 1873).
We all have electrical activity in our brains. The combined electrical activity of thousands of brain cells (aka neurons) determines how your coffee tastes, how alert you feel, and how focused you are as you read this article. This electrical activity is caused by a complex series of chemical changes that occur when neurons communicate with each other. The synapse is the gap between two neurons, and is the key point of neuron-to-neuron communication (Kandel et al., 2021). Based on the signals reaching the synapse, neurons can either excite (i.e., prompt) or inhibit (i.e., stop) other neurons from sending messages (Kandel et al. 2021; Vaughn, 1998). Healthy brain function relies on a balance of cells stimulating and inhibiting messages. This balance is lost during a seizure: too many excitatory signals (i.e., too much activity) or a loss of inhibitory signals (i.e., the inability to dampen or “cancel” activity) throws the brain’s electrical activity out of balance and out of control (Scharfman, 2007). Surges of abnormal electrical activity cause the behavioral changes (e.g., uncontrolled movements) and clinical manifestations (e.g., altered olfactory, visual and auditory function) of seizures, and can be recorded with an electroencephalogram (EEG) (Scharfman, 2007; Falco-Walter et al., 2018; Wolf, 2016).
A single seizure does not mean a person has epilepsy. In fact, one in ten people will experience a seizure at some point in their life (World Health Organization – Epilepsy [Fact Sheet]). Seizures can be triggered by viral infections, brain injury, stroke, diabetes/metabolic disorders and more (Bhalla et al., 2011). Patients with epilepsy have a persistent predisposition to spontaneous, unprovoked seizures (Fisher et al., 2014). In focal epilepsy, these electrical disturbances appear in one part of the brain, like a small brush fire in a large forest (Falco-Walter et al., 2018). In generalized epilepsy, this fire spreads throughout the forest, causing abnormal electrical discharges throughout the brain (Falco-Walter et al., 2018). Focal seizures can generalize in this way, but they can also start in several places at the same time (e.g., multifocal epilepsy) (Falco-Walter et al., 2018).
“In fact, one in ten people will experience a seizure at some point in their life “
WE STILL DON’T FULLY UNDERSTAND EPILEPSY
Science has made great strides to understand and treat epilepsy, but many mysteries remain. Scientists have yet to fully understand how a normal brain transforms into one capable of producing unprovoked seizures, a process known as epileptogenesis (Goldberg and Coulter, 2013; Pitkänen et al., 2015). Epileptogenesis can be triggered by genetic or acquired factors, the latter including known (TBI, stroke, infection, etc.) or unknown brain injury (Goldberg and Coulter, 2013; Pitkänen et al., 2015). The epileptogenicity of a brain injury (i.e., its ability to induce epileptogenesis) depends on several factors, including but not limited to: 1) the cause, location, and severity of the inciting injury; 2) genetic and epigenetic factors; 3) age; 4) health history; 5) comorbidities (Klein et al., 2018). For example, while only 2 – 4 % of patients develop epilepsy after mild to moderate TBI, the incidence increases to 15 – 50 % in patients with severe TBI and/or neurological comorbidities (Hauser et al., 1993; Banerjee et al., 2009; Pitkänen et al., 2017).
Persistent gaps in our understanding of how epileptic brains generate and sustain unprovoked seizures have hampered the development of drugs that disrupt, reverse, or prevent the underlying mechanism. Currently available anti-seizure drugs can only reduce seizure symptoms (frequency and severity) by targeting the activity of voltage-gated and ligand-gated ion channels involved in promoting neuronal hyperexcitability (e.g., sodium channel blockers) (Rho and White, 2018; Rogawski et al, 2016). As a result, two-thirds of epilepsy patients can control their seizures with anti-seizure drugs, but one-third cannot control seizures with any combination of drugs and are said to have treatment-resistant epilepsy (TRE) (Laxer et al., 2014; Kwan et al., 2010). Epileptogenesis is progressive and indeterminate, particularly in TRE patients. As a result, seizure-producing brain tissue (aka, the seizure onset zone or ictal onset zone) slowly expands, encompassing a larger region as seizures persist (Goldberg and Coulter, 2013; Jehi, 2018). Over time, uncontrolled seizures damage brain cells, affecting memory, attention, language and more (Laxer et al., 2014; Traynelis et al., 2020; Kent et al., 2006; Black et al., 2010). Patients with uncontrolled seizures report more severe depressive and anxiety symptoms than patients with controlled seizures (Devinsky et al., 2005). This may be due in part to the loss of independence caused by uncontrolled epilepsy, which can impair social and occupational functioning (Laxer et al., 2014). For example, most states do not legally allow patients with uncontrolled seizures to drive, although the minimum time patients must be seizure-free varies from state to state. In addition to a significant reduction in quality of life, uncontrolled seizures dramatically increase the likelihood of epilepsy-related death (Lhatoo et al., 2001; Szaflarski and Szaflarski, 2004). For treatment-resistant patients with focal epilepsy, surgical removal of epileptic tissue is promising but also very challenging due to the inability to precisely delineate all brain tissue responsible for a patient’s seizures without removing tissue vital for other cognitive functions.
“Over time, uncontrolled seizures damage brain cells, affecting memory, attention, language and more.”
BRAIN INFLAMMATION: EXCITING FINDINGS
Based on evidence from animal model studies and resected human epileptic tissue, brain inflammation – or neuroinflammation – is a key factor in the onset and maintenance of seizures in epilepsy and may initiate epileptogenesis (Aronica et al., 2010; Maroso et al., 2010). But what is neuroinflammation, what triggers it, and is it always bad? If you’ve ever been bit by a bug, you’ve experienced the heat, redness, swelling, pain, and loss of function that bodily inflammation causes. The same process takes place in your brain and is mediated by cells called microglia. Microglia are the brain’s doctors and caretakers. In healthy brains, microglia hibernate when not needed, but become active when signaled to come to the rescue. Once active, they orchestrate inflammation to repair tissue damage and eliminate dead cells when the brain is damaged or infected (Amor et al., 2010; Devinksy et al., 2013). Neuroinflammation is healthy when it helps repair damage, but causes disease when it persists when it is no longer needed (Amor et al., 2010; Devinksy et al., 2013; Vezzani et al., 2013). Once inflammation becomes cyclical and enduring, it slowly destroys healthy brain tissue and eventually makes neurons more excitable and thus more likely to cause seizures (Vezzani et al., 2011; Vezzani et al., 2013). Unfortunately, once-normal brain activity will eventually be abnormal when examined with an EEG.
NON-EPILEPTIC SEIZURES: NOT ALL “ATTACKS” ARE EPILEPTIC
What happens when patients experience seizures, but their EEGs show normal brain activity? The puzzling condition is referred to as a “pseudo-seizure”, but has other names such as psychogenic non-epileptic seizure (PNES) or “attack” (Perez and LaFrance, 2016). Unlike epileptic seizures, the types of seizures these patients experience are not caused by abnormal electrical discharges in the brain or by any currently measurable disease process (Reuber and Brown, 2017). Patients with PNES undergo extensive medical evaluations consisting of brain imaging, blood tests, and long-term monitoring, only to be told that “nothing is wrong”. The attacks resemble epileptic seizures to the untrained (and sometimes the trained) eye, but there are subtle differences that can be used to distinguish them from epileptic seizures (Reuber et al., 2011). For example, a PNES often lasts several minutes or hours longer than epileptic seizures, and patients are much less likely to inadvertently injure themselves during a PNES episode because motor control is partially preserved (Reuber & Elger, 2003). The condition is frightening for patients and family members, and equally interferes with school, work, and social interactions, since PNES usually recur if left untreated. Worse, those diagnosed with PNES must contend with the notion that there is no known cause or effective medication for their condition.
BRAIN INFLAMMATION: A PHENOMENON SEEN IN BOTH DISEASES?
Based on recent study results, brain inflammation could also play a role in PNES. Advances in understanding PNES have been limited by controversy among experts as to whether these attacks are due to psychological distress or neurobiological mechanisms. Fortunately, research is currently being conducted that could change the outlook for PNES patients. The neurobiological processes underlying PNES are now being explored using brain imaging (Szaflarski and LaFrance, 2018). Some scientists are investigating neuroinflammatory processes as a possible culprit (Gledhill et al., 2021; Sharma and Szaflarski, 2021). Based on evidence from neuroimaging and biomarker studies, Sharma & Szaflarski recently proposed a two-hit disease model for PNES that relies on two significant predisposing factors: previous TBI and history of early-life stress (including childhood trauma, abuse, and/or neglect) (LaFrance et al., 2013; Popkirov et al., 2018; Mökleby et al., 2002; Bowman and Markand, 1996). Similar to treatment-resistant patients with focal epilepsy, patients with PNES often have a history of brain injury. In fact, up to 83% had a history of TBI prior to the onset of PNES (LaFrance et al., 2013; Popkirov et al., 2018). This hypotheses posits that chronic stress in early-life causes neuroinflammatory changes that prime the brain’s stress response system to be less resilient when faced with additional injury/trauma later in life. These two “hits” create fertile ground for the development of PNES.
“Similar to treatment-resistant patients with focal epilepsy, patients with PNES often have a history of brain injury. In fact, up to 83% had a history of TBI prior to the onset of PNES…”
Low-levels of inflammation in the brain, possibly due to previous injuries (e.g., traumatic brain injury) or high levels of stress hormones can remain in the brain for a long time, and slowly damage delicate neuronal processes. The result is suboptimal performance, and wires sometimes get crossed as the brain works to repair itself. The process just described also takes place in healthy brains. Most of us experience nausea when smelling (or just thinking about) a food that previously made us sick. In the case of severe food poisoning, we refrain from consuming the offending food even after several years. Our immense ability to learn from past experiences means our brain can produce physical symptoms (nausea) based on a single past experience with an object (food). It does this by strengthening the structural and functional connections between stored memories. In the case of PNES, behavioral theories suggest that the brain has learned to associate a prior experience with seizure-like symptoms. In practice, any physical symptom can be triggered by this mechanism. There are cases of stuttering, blindness, paraplegia, and even pain caused by this phenomenon (Fobian and Elliott, 2019). Medical professionals refer to these disorders collectively as functional neurological disorders because they involve abnormalities in brain function rather than a physical defect. New interventions based on cognitive behavioral therapy (CBT) are being developed, with the aim of restructuring faulty brain connections by creating new memories to replace them (Fobian et al., 2020). In addition, researchers are testing whether medications could be helpful.
Why do we need these tools for epilepsy? Until recently, we could only detect neuroinflammation by examining post-mortem brains or by probing surgical tissue samples. Targeted imaging of key players involved in neuroinflammation can complement the cocktail of imaging tools currently used to delineate the borders of epileptic tissue in potential surgical candidates (Koepp et al., 2017; Sharma et al., 2020). If neuroinflammation is indicative of epileptogenesis, imaging neuroinflammation may also allow clinician to monitor disease progression and determine optimal treatment. Although we have several tools to study neuroinflammation in humans, they are still in their infancy and require further technological advances before they are reliable and accurate enough to influence clinical decision-making.
Neuroinflammation is well-studied in epilepsy, but this line of research is only beginning to explore the neurobiology of PNES. Therefore, the development of advanced neuroimaging tools and anti-neuroinflammatory medications may be crucial for both diseases. As the field advances, it will be exciting to see how early childhood stress, neuroinflammation, brain injury – and factors that have yet to be considered (or discovered) influence the development of PNES.
Perhaps one day, in the distant future, we will know enough to prevent patients from having these seizures in the first place!
Written by Ayushe Sharma and Christina Mueller
Illustrated by Sumana Shrestha
Edited by Caitlin Goodpaster and Talia Oughourlian
Ali, R., Connolly, I. D., Feroze, A. H., Awad, A. J., Choudhri, O. A., and Grant, G. A. (2016). Epilepsy: A Disruptive Force in History. World Neurosurg. 90, 685–690. doi:10.1016/J.WNEU.2015.11.060.
Amor, S., Puentes, F., Baker, D., & Van Der Valk, P. (2010). Inflammation in neurodegenerative diseases. In Immunology (Vol. 129, Issue 2, pp. 154–169). https://doi.org/10.1111/j.1365-2567.2009.03225.x
Aronica E, Fluiter K, Iyer A, Zurolo E, Vreijling J, van Vliet EA, et al. (2010). Expression pattern of miR-146a, an inflammation-associated microRNA, in experimental and human temporal lobe epilepsy. Eur J Neurosci, 31:1100–7. https://doi.org/10.1111/j.1460-9568.2010.07122.x.
Black, L. C., Schefft, B. K., Howe, S. R., Szaflarski, J. P., Yeh, H. shain, and Privitera, M. D. (2010). The effect of seizures on working memory and executive functioning performance. Epilepsy Behav. 17, 412–419. doi:10.1016/j.yebeh.2010.01.006.
Bowman, E. S., & Markand, O. N. (1996). Psychodynamics and psychiatric diagnoses of pseudoseizure subjects. American Journal of Psychiatry, 153(1), 57–63. https://doi.org/10.1176/ajp.153.1.57
Devinsky O, Barr WB, Vickrey BG, Berg AT, Bazil CW, Pacia SV, Langfitt JT, Walczak TS, Sperling MR, Shinnar S, Spencer SS. (2005). Changes in depression and anxiety after resective surgery for epilepsy. Neurology, 65(11):1744-9. doi: 10.1212/01.wnl.0000187114.71524.c3.
Devinsky, O., Vezzani, A., Najjar, S., De Lanerolle, N. C., & Rogawski, M. A. (2013). Glia and epilepsy: Excitability and inflammation. In Trends in Neurosciences (Vol. 36, Issue 3, pp. 174–184). https://doi.org/10.1016/j.tins.2012.11.008
Fisher, R. S., Acevedo, C., Arzimanoglou, A., Bogacz, A., Cross, J. H., Elger, C. E., et al. (2014). ILAE Official Report: A practical clinical definition of epilepsy. Epilepsia 55, 475–482. doi:10.1111/epi.12550.
Fobian, A. D., and Elliott, L. (2019). A review of functional neurological symptom disorder etiology and the integrated etiological summary model. J. Psychiatry Neurosci. 44, 8. doi:10.1503/JPN.170190.
Fobian AD, Long DM, Szaflarski JP. (2020). Retraining and control therapy for pediatric psychogenic non-epileptic seizures. Ann Clin Transl Neurol, 7(8):1410-1419. doi:10.1002/ACN3.51138
Gledhill, J. M., Brand, E. J., Pollard, J. R., Clair, R. D. St., Wallach, T. M., and Crino, P. B. (2021). Association of Epileptic and Nonepileptic Seizures and Changes in Circulating Plasma Proteins Linked to Neuroinflammation. Neurology 96, e1443–e1452. doi:10.1212/WNL.0000000000011552.
Goldberg EM, Coulter DA. (2013). Mechanisms of epileptogenesis: A convergence on neural circuit dysfunction. Nat Rev Neurosci, 14:337–49. https://doi.org/10.1038/nrn3482.
Hauser WA, Annegers JF, Kurland LT. (1993). Incidence of Epilepsy and Unprovoked Seizures in Rochester, Minnesota: 1935-1984. Epilepsia, 34:453–8. https://doi.org/10.1111/j.1528-1157.1993.tb02586.x.
Jackson, J. H. On the anatomical, physiological and pathological investigation of epilepsies. West Riding Lunatic Asylum Medical Reports. 1873; 3: 315-339.
Kandel, E. R., Schwartz, J., Jessell, T., Siegelbaum, S., and Hudspeth, A. Principles of Neural Science.
Kent, G. P., Schefft, B. K., Howe, S. R., Szaflarski, J. P., Yeh, H. S., and Privitera, M. D. (2006). The effects of duration of intractable epilepsy on memory function. Epilepsy Behav. 9, 469–477. doi:10.1016/j.yebeh.2006.07.005.
Klein P, Dingledine R, Aronica E, Bernard C, Blümcke I, Boison D, et al. (2018). Commonalities in epileptogenic processes from different acute brain insults: Do they translate? Epilepsia, 59:37–66. https://doi.org/10.1111/epi.13965.
Koepp, M. J., Årstad, E., Bankstahl, J. P., Dedeurwaerdere, S., Friedman, A., Potschka, H., Ravizza, T., Theodore, W. H., & Baram, T. Z. (2017). Neuroinflammation imaging markers for epileptogenesis. Epilepsia, 58, 11–19. https://doi.org/10.1111/epi.13778
Kwan, P., Arzimanoglou, A., Berg, A. T., Brodie, M. J., Hauser, W. A., Mathern, G., et al. (2010). Definition of drug resistant epilepsy: Consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 51, 1069–1077. doi:10.1111/j.1528-1167.2009.02397.x.
LaFrance, W. C., Deluca, M., MacHan, J. T., & Fava, J. L. (2013). Traumatic brain injury and psychogenic nonepileptic seizures yield worse outcomes. In Epilepsia (Vol. 54, Issue 4, pp. 718–725). Epilepsia. https://doi.org/10.1111/epi.12053.
Laxer, K. D., Trinka, E., Hirsch, L. J., Cendes, F., Langfitt, J., Delanty, N., et al. (2014). The consequences of refractory epilepsy and its treatment. Epilepsy Behav. 37, 59–70. doi:10.1016/J.YEBEH.2014.05.031.
Lhatoo, S. D., Johnson, A. L., Goodridge, D. M., MacDonald, B. K., Sander, J. W. A. S., and Shorvon, S. D. (2001). Mortality in epilepsy in the first 11 to 14 years after diagnosis: Multivariate analysis of a long-term, prospective, population-based cohort. Ann. Neurol. 49, 336–344. doi:10.1002/ana.70.
Maroso M, Balosso S, Ravizza T, Liu J, Aronica E, Iyer AM, et al. (2010). Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures. Nat Med 2010;16:413–9. https://doi.org/10.1038/nm.2127.
Perez, D. L., and LaFrance, W. C. (2016). Nonepileptic seizures: An updated review. CNS Spectr. 21, 239–246. doi:10.1017/S109285291600002X.
Mökleby, K., Blomhoff, S., Malt, U. F., Dahlström, A., Tauböll, E., & Gjerstad, L. (2002). Psychiatric comorbidity and hostility in patients with psychogenic nonepileptic seizures compared with somatoform disorders and healthy controls. Epilepsia, 43(2), 193–198. https://doi.org/10.1046/j.1528-1157.2002.20901.x
Pitkänen A, Lukasiuk K, Edward Dudek F, Staley KJ. (2015). Epileptogenesis. Cold Spring Harb Perspect Med, 5. https://doi.org/10.1101/cshperspect.a022822.
Pitkänen A, Kyyriäinen J, Andrade P, Pasanen L, Ndode-Ekane XE. (2017). Epilepsy After Traumatic Brain Injury. Models of Seizures and Epilepsy, 2: 661–81. https://doi.org/10.1016/B978-0-12-804066-9.00046-8.
Popkirov, S., Carson, A. J., & Stone, J. (2018). Scared or scarred: Could ‘dissociogenic’ lesions predispose to nonepileptic seizures after head trauma? In Seizure (Vol. 58, pp. 127–132). W.B. Saunders Ltd. https://doi.org/10.1016/j.seizure.2018.04.009.
Reuber, M., and Brown, R. J. (2017). Understanding psychogenic nonepileptic seizures—Phenomenology, semiology and the Integrative Cognitive Model. Seizure 44, 199–205. doi:10.1016/J.SEIZURE.2016.10.029.
Rogawski MA, Löscher W, Rho JM. (2016). Mechanisms of action of Antiseizure Drugs and the Ketogenic diet. Cold Spring Harb Perspect Med, 6:28. https://doi.org/10.1101/cshperspect.a022780.
Scharfman, H. E. (2007). The Neurobiology of Epilepsy. Curr. Neurol. Neurosci. Rep. 7, 348. doi:10.1007/S11910-007-0053-Z.
Sharma, A. A., and Szaflarski, J. P. (2021). Neuroinflammation as a pathophysiological factor in the development and maintenance of functional seizures: A hypothesis. Epilepsy Behav. Reports 16, 100496. doi:10.1016/J.EBR.2021.100496.
Sharma, A. A., Szaflarski, J. P., & Sharma, Ayushe; Szaflarski, J. (2020). In Vivo Imaging of Neuroinflammatory Targets in Treatment-Resistant Epilepsy. Current Neurology and Neuroscience Reports, 20(4). https://doi.org/10.1007/s11910-020-1025-9.
Szaflarski, J. P., and LaFrance, W. C. (2018). Psychogenic Nonepileptic Seizures (PNES) as a network disorder – Evidence from neuroimaging of functional (psychogenic) neurological disorders. Epilepsy Curr. 18, 211–216. doi:10.5698/1535-75188.8.131.52.
Traynelis, S. F., Dlugos, D., Henshall, D., Mefford, H. C., Rogawski, M. A., Staley, K. J., et al. (2020). Epilepsy Benchmarks Area III: Improved Treatment Options for Controlling Seizures and Epilepsy-Related Conditions Without Side Effects. Epilepsy Curr. 20, 23S-30S. doi:10.1177/1535759719895279.
Vaughn, B. (1998). Epilepsy: A Comprehensive Textbook. J. Clin. Neurophysiol. doi:10.1097/00004691-199805000-00039.
Vezzani A, Friedman A, Dingledine RJ. (2013). The role of inflammation in epileptogenesis. Neuropharmacology, 69:16–24. https://doi.org/10.1016/j.neuropharm.2012.04.004.