Appendix 1
History of Epilepsy
Misunderstandings about epilepsy can be found throughout history and still exist in many cultures around the world. Epilepsy has been depicted in literature for centuries with the first reports occurring around 2000 BC (Magiorkinis 2010). The explanation of epilepsy has ranged from a religious, sacred experience to one of demonic possession or a curse.
The first scientific explanation of epilepsy generating from the brain was detailed in a text titled On the Sacred Disease, written around 400 BC and included in the Hippocratic Corpus.* This piece of literature is thought to have started the understanding of epilepsy as scientific, rather than religious or spiritual. It depicts epilepsy as a medical condition, noting the “sacred disease” has no relation with the divine, but is explained instead by the accumulation of phlegm in the brain.
Despite the description in the Hippocratic Corpus, explanations of epilepsy tied to religion persisted (Magiorkinis 2014), as shown in a review of epilepsy during the Middle Ages, the Renaissance, and the Enlightenment (Diamantis 2010). The review notes that the primary view of epilepsy during the Middle Ages was one of superstition, most notably endorsed by some religious authorities. The predominant theory was that those with epilepsy were possessed and a religious intervention was the only cure. Epilepsy in the Middle Ages was also thought to be contagious, leading to those with epilepsy being shunned and facing social discrimination. An isolation hospital for people with epilepsy opened in France in 1486, named St. Valentin, after Saint Valentine, the patron saint of epilepsy (Diamantis 2010).
In the 18th and 19th centuries, the broader acceptance of epilepsy as being a medical condition helped to create an understanding of its pathology and dissolved the idea that it was a religious or spiritual condition. This led to the introduction of medical treatment with some of the first therapies for epilepsy. A review of epilepsy research from the same time noted several treatment options, including ingesting substances such as bromides, indigo, belladonna, mistletoe, zinc oxide, and chloroform (Sidiropoulou 2010). Intentionally causing fevers, bloodletting, and surgical procedures involving creating holes in the skull also occurred during this time.
Medical advancements and research have come a long way since the early history of epilepsy, but it is still not completely understood, leading to the continued stigma of the disease, even today. (“Stigma” refers to negative and unfair beliefs people have about something.) In 2019, the World Health Organization, in partnership with various epilepsy organizations, published a comprehensive report, “Epilepsy: a public health imperative,” noting this stigma and discrimination. This report encourages improving knowledge and raising awareness in schools, workplaces, and communities. Enacting legislation to uphold human rights standards can help prevent discrimination in this group of individuals (World Health Organization 2019).
Addressing the stigma often associated with epilepsy can be best done through education. Knowing what to say to others about epilepsy, particularly for children, can help empower them to not be embarrassed or ashamed of their condition. This education should be provided not just to the individual with epilepsy but the entire family (Guilfoyle 2017). Increasing education is shown to decrease negative attitudes toward epilepsy. Still, misconceptions and myths exist today (Beghi 2019).
* A collection of Ancient Greek medical works associated with Hippocrates and his teachings. The exact authorship of these books is largely unknown.
References
Beghi E (2019) Social functions and socioeconomic vulnerability in epilepsy. Epilepsy Behav, 100, 1–4.
Diamantis A, Sidiropoulou K, Magiorkinis E (2010) Epilepsy during the Middle Ages, the Renaissance and the Enlightenment. J Neurol, 257, 691–698.
Guilfoyle SM, Wagner JL, Modi AC, et al. (2017) Pediatric epilepsy and behavioral health: The state of the literature and directions for evidence-based interprofessional care, training, and research. Clinical Practice in Pediatric Psychology, 5, 79–90.
Magiorkinis E, Diamantis A, Sidiropoulou K, Panteliadis C (2014) Highights in the history of epilepsy: The last 200 years. Epilepsy Res Treat, 2014, 1–13.
Magiorkinis E, Sidiropoulou K, Diamantis A (2010) Hallmarks in the history of epilepsy: Epilepsy in antiquity. Epilepsy Behav, 17, 103–108.
Sidiropoulou K, Diamantis A, Magiorkinis E (2010) Hallmarks in 18th- and 19th-century epilepsy research. Epilepsy Behav, 18, 151–161.
World Health Organization (2019) Epilepsy a public health imperative [pdf], Geneva, Available at: <https://www .who.int/publications/i/item/epilepsy-a-public-health-imperative> [Accessed September 13 2024].
Appendix 2
Seizure Mimics
Not all events that look like a seizure are in fact a seizure. A seizure is often obvious, but sometimes an event characterized by a change in consciousness, physical movement, behavior, sensation, or feeling appears to be a seizure but is not; rather, it is due to another condition. This is referred to as a “seizure mimic” or a “nonepileptic event.” To differentiate between seizures and seizure mimics, the medical professional uses the process of differential diagnosis. Meticulously eliminating seizure mimics is done before diagnosing the event as a seizure.
Common seizure mimics are presented in Tables A2.1 to A2.3 of the PDF, by the age group in which they most often occur or start to be noticed. These lists are not exhaustive.
Appendix 3
Seizure and epilepsy terminology
The terminology for seizures and epilepsy has changed over the years, and both “old” and “new” terms can be found in the literature. Table A3.1 shows common terms in both their old and new forms (Fisher 2016, Sarmast 2020) This book uses the new terms, listed in the table in the order they are discussed in the text.
Table A3.1 Old and new terms for seizures and epilepsy
New Term
Old Term
Focal onset seizure
Partial seizure
Focal aware seizure
Simple partial seizure
Focal impaired awareness seizure
Complex partial seizure
Focal to bilateral tonic-clonic seizure
Focal seizure with secondary generalization
Generalized tonic-clonic seizure
Grand mal seizure
Absence seizure
Petit mal seizure
Atonic
Akinetic or drop attacks
Hyperkinetic
Hypermotor
Epileptic spasm
Infantile spasm
Nonepileptic psychogenic seizure (PNES)
Psychogenic seizure, pseudoseizure
References
Fisher R, Shafer PO, D’Souza C (2016) 2017 Revised classification of seizures. [online] Available at: <https://www .epilepsy.com/stories/2017-revised-classification-seizures> [Accessed December 16 2024]
Sarmast ST, Abdullahi AM, Jahan N (2020) Current classification of seizures and epilepsies: Scope, limitations and recommendations for future action. Cureus, 12, 1–13.
Appendix 4
Neurons and seizures
Neurons are the smallest unit of the nervous system, and there are billions of them in the brain and spinal cord. They are electrically excitable cells and carry information (signals) between the central nervous system and the rest of the body as electrical impulses through a web-like structure from neuron to neuron, or from neurons to other cells in the body (Sirven 2013).
Electrical activity moves through and out of a neuron to the next neuron or cell via a complex process, known as an “action potential.”
The inside of a neuron at rest (not sending or receiving any signals) is negatively charged compared to the fluid surrounding it (containing ions). This is referred to as the “resting membrane potential” and is a measurement of the difference in electrical charge (voltage) between the inside and the outside of the neuron.
Figure A4.1 illustrates this concept for a typical resting membrane potential for a neuron.
Figure A4.1 Resting membrane potential in a neuron. The plus (+) and minus (–) signs represent the net electrical charges of the ions inside and outside the cell. The barrier between the two spaces is the plasma, or cell, membrane. The net electrical charge outside the cell is positive, while net electrical charge inside the cell is negative. The resting membrane potential (–70 mV on the voltmeter*) is the difference between the inside of the cell relative to the outside of the cell.
The action potential process can be divided into stages. The neuron starts at the resting membrane potential phase and is then activated, causing a brief change from negative to positive, and then back to negative again. These stages are shown in Figure A4.2 and described below (Grider 2023):
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Depolarization: An event where a neuron’s membrane potential briefly becomes less negative (for about 1 millisecond, or 1,000th of a second). This results when the cell body of a neuron receives enough signals to activate (when the threshold is met), causing a portion of the axon nearest the cell body to depolarize—becomes less negative for a moment (in about 1 millisecond).
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Repolarization: This occurs after the firing of the axon reaches the peak positive value and switches back to a more negative state by the movement of ions.
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Hyperpolarization: This is when the membrane falls below the resting potential based on movement of ions. While brief, this action is notable because the amount of stimulus needed to reactivate (or depolarize) this same neuron would be more than what triggered it to begin with, making it less likely that this same neuron would be immediately triggered again (within the next few milliseconds).
Additional terms related to action potentials and depicted in Figure A4.2 include:
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Resting potential: When no impulse is being received or sent and the neuron is “at rest.” The voltage of the resting membrane potential is –70mV in the figure.
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Threshold: The voltage at which the signals are of a large enough intensity to produce the effect (–55 mV in the figure).
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Failed initiations: The result of signals being insufficient to cause the membrane potential to reach the threshold, so depolarization does not occur. The action potential is an all-or-nothing process; that is, if the threshold is not reached, an action potential does not result, and no message is sent. Some failed initiations are depicted in the figure. Notice the peaks are below the threshold, so no depolarization occurs.
Figure A4.2 Stages of an action potential. Na+ = sodium; K+ = potassium.
The action potential process continues down the axon of the neuron with the changes from one segment of the axon triggering depolarization in the next section and so on until it reaches the end of the axon.
Many ions exist in the body and in and around the neurons, and the movement of these ions (traveling in the impulse) across the axon’s membrane (the outer surface) creates the action potential. Action potentials allow neurons to communicate signals rapidly and efficiently. However, during a seizure, neurons fire excessively and uncontrollably, and the ability of the neurons to regulate signals is disrupted. This leads to uncontrolled electrical activity, seen as a seizure.
Most often, sodium and potassium ions generate the action potentials. A “sodium-potassium pump” is an energy-consuming mechanism within cells that moves these ions in and out of the cells, changing the net electrical charge, allowing the membrane to return to the resting potential and prepare for another action potential. The action potential process is illustrated in Figure A4.3.
Figure A4.2 Action potential traveling down a neuron’s axon. Potassium (K+) and sodium (Na+) ions move into and out of the neuron (the double lines represent the plasma, or cell, membrane, with the inside of the cell located between the lines) as the electrical charge changes. The three images along the bottom represent a sequence at three time points: the curved arrows indicate the movement of the ions, and the color of the plasma membrane signifies the specific ion moving. In this way, the message, or impulse, moves down the length of the axon from left to right.
* An instrument that measures voltage. The unit of measurement for a membrane potential is a millivolt (1/1000th of a volt), expressed
as mV.
References
Grider MH, Jessu R, Kabir R (2023) Physiology, Action Potential. [e-book] Treasure Island (FL), StatPearls. Available at: <https://www.ncbi.nlm.nih.gov/books/NBK538143/> [Accessed December 16 2024].
Sirven JI, Osborne Shafer P, Fisher R (2013) Staying safe. [online] Available at: <https://www.epilepsy.com/ preparedness-safety/staying-safe> [Accessed September 25 2024].
Appendix 5
Genetic testing and epilepsy
Genetic testing may be recommended for individuals with epilepsy. Having an overview of DNA, genes, and chromosomes, and their relationship to one another is helpful to understanding the process of genetic testing.
This relationship is depicted in Figure A5.1 and terms are described below (Medline Plus 2021):
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DNA: The building block of genes.
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Gene: A segment of DNA.
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Chromosomes: Units of packaged genetic materials made up of DNA and proteins. Chromosomes exist in pairs,* with both males and females† having 23 pairs of chromosomes (46 total, in each cell‡); one pair in the set are sex chromosomes, differing males from females. Males have both an X and a Y sex chromosome while females have two X sex chromosomes. A child will inherit one copy of each chromosome from the female parent and one copy of each chromosome from the male parent, thereby inheriting 50 percent of the genetic material from the female parent and 50 percent from the male parent. Since females do not have a Y chromosome, males always inherit the Y chromosome from the male parent.
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Nucleus: Found in the center of the cell and contains most of the genetic material; responsible for controlling and regulating the activities of the cell.
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Mitochondria: The structure that surrounds the nucleus of the cell and contains some genetic material; responsible for supplying the cell with energy. Genetic material from the mitochondria is primarily inherited by a child from the female parent (National Human Genome Research Institute 2024a).
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Nucleotides: The building blocks of DNA. The order of nucleotides in DNA is examined (called sequencing) in genetic testing (National Human Genome Institute 2023). Multiple nucleotides are found in DNA (listed in the figure).
Figure A5.1 DNA, genes, and chromosomes
Genetic tests used in individuals with epilepsy include:
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Karyotype: Produces a picture of the pairs of chromosomes in an individual. Karyotypes are useful in identifying missing, extra, or large structural changes in chromosomes (American Academy of Pediatrics 2022).
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Chromosomal microarray analysis (CMA, also known as comparative genomic hybridization): Produces a high resolution molecular karyotype and helps detect atypical, small changes related to the number of chromosomes, the shape of the chromosomes, or extra or missing segments of chromosomes (Haeri 2016). CMA detects changes known as copy number variants on stretches of DNA. CMA has replaced karyotype as a first-line genetic test in most genetic settings.
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Gene panel: A test that targets and investigates specific genes known to be involved in specific conditions (Centers for Disease Control and Prevention 2024): for example, epilepsy. An epilepsy gene panel is used when a specific type of epilepsy known to be associated with a particular gene is suspected.
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Whole exome sequencing: A test sequencing all the protein-coding regions of genes in the genome, known as the exome. The exome makes up only about 1.5 percent of the entire genome, but is associated with 85 percent of all variants (National Human Genome Research Institute 2024b, Rabbani 2014, Perucca 2020).
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Mitochondrial DNA sequencing: A genomic technique for sequencing the genes located on the mitochondrial DNA.
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Whole genome sequencing: A technique involving sequencing of all the protein-coding regions and nonprotein-coding regions of genes in a genome (American Academy of Pediatrics 2022)
Genetic testing typically produces one of the following results:
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No abnormalities detected: This result is also known as normal, negative, or benign (not harmful). In an individual with epilepsy, this means a genetic cause of epilepsy was not identified using the genetic test performed. It does not completely rule out the possibility of genetic cause, however, and more testing may be recommended. (Wojcik 2020)
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Pathogenic variants detected: This result is also known as abnormal, positive, or as diseasecausative. In an individual with epilepsy, this means the genetic change is identified as the cause of epilepsy. (Wojcik 2020)
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Variant of uncertain significance detected: This result is also known as genetic variant of uncertain significance (VUS) and means a genetic change was detected, but the meaning of the finding is not fully understood. In this situation, it may be recommended that other family members be tested, other in-depth testing be done, and/or the results be reevaluated later (in one to two years). With ongoing research, genetic causes may be identified in the future. A VUS today might later be reclassified as normal, as a genetic epilepsy, or another condition. (Wojcik 2020)
* In this description, the sex chromosomes are considered a pair; although the male has two different chromosomes (X and Y), which are not an exact pair. Another way to describe the number of chromosomes is to state that humans have 22 sets of autosomes (nonsex chromosomes) and one set of sex chromosomes.
† “Male” and “female” refer to biologic sex, not gender.
‡ Sperm cells and egg cells contain only half the genetic material (just one copy of each chromosome) as other cells in the human body.
References
American Academy of Pediatrics (2022) Genetic testing for epilepsy. [online] Available at:< www.aap.org/en/ patient-care/epilepsy/diagnosing-pediatric-epilepsy/genetic-testing-for-epilepsy/ > [Accessed December 24 2024].
Berkovic SF (2020) The genetics of epilepsy. Annual Review of Genomics and Human Genetics, 21, 205–230.
Centers for Disease Control and Prevention (2024) Genetic testing. [online] Available at: <https://www.cdc.gov/ genomics-and-health/about/genetic-testing.html> [Accessed September 20 2024].
Genetic Alliance District of Columbia Department of Health (2010) Genetic Alliance Monographs and Guides. Washington (DC): Genetic Alliance.
Haeri M, Gelowani V, Beaudet AL (2016) Chromosomal microarray analysis, or comparative genomic hybridization: A high throughput approach. MethodsX, 3, 8–18.
Medline Plus (2021) What is a chromosome? [online] Available at: <https://medlineplus.gov/genetics/understanding/ basics/chromosome/> [Accessed December 16 2024].
National Human Genome Research Institute (2023) DNA sequencing fact sheet. [online] Available at: <https:// www.genome.gov/about-genomics/fact-sheets/DNA-Sequencing-Fact-Sheet> [Accessed December 16 2024].
National Human Genome Research Institute (2024a) Mitochondrial DNA. [online] Available at: <https://www .genome.gov/genetics-glossary/Mitochondrial-DNA> [Accessed December 16 2024].
National Human Genome Research Institute (2024b) Exome. [online] Available at: <https://www.genome.gov/ genetics-glossary/Exome> [Accessed December 16 2024].
Rabbani B, Tekin M, Mahdieh N (2014) The promise of whole-exome sequencing in medical genetics. J Hum Genet, 59, 5–15. 10 Perucca P, Bahlo M,
Wojcik A (2020) Genetic testing for epilepsy. [online] Available at: <https://www.epilepsy.com/causes/genetic/ testing> [Accessed December 16 2024].
Appendix 6
Epilepsy syndromes
An epilepsy syndrome is a group of symptoms that consistently occur together and are associated with the diagnosis of epilepsy. Epilepsy syndromes are classified by age of onset:
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Onset in the neonatal period and infancy
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Onset in childhood
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Onset in adolescence and adulthood
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Onset at a variable age
Tables A6.1-A6.4 in the PDF contain information about epilepsy syndromes within each age of onset.
Appendix 7
Mechanism of action of antiseizure medications
“Mechanism of action” is how a medication works in the body to achieve a desired effect. As it relates to antiseizure medications, it is what the medication does to reduce, prevent, or stop seizures.
The mechanism of action of antiseizure medications often occurs in the area of the synapse, which is the space between neurons in which neurotransmitters carry messages (for chemical synapses). Seizures result when too many excitatory neurotransmitters cause excessive firing of neurons, or too few inhibitory neurotransmitters exist to stop excessive firing of neurons. Figure A7.1 depicts neuron-to-neuron communication in the area of a chemical synapse and the general mechanism of action of various antiseizure medications.
Antiseizure medications may work to manage or control the imbalance of excitatory and inhibitory neurotransmitters (Sheffler 2023) They may also work by altering the ion channels (in the axon terminal) and postsynaptic channel receptors (in the dendrite), and by blocking the ions from moving in and out of the neurons, stopping the neuron from excessively firing. NMDA receptors, AMPA receptors, and GABA receptors are postsynaptic channel receptors that act as control centers within the neurons and are targets for antiseizure medications.
Figure A7.1 Mechanism of action of antiseizure medications. Na+ = sodium; Ca+ = calcium.
References
Sheffler MF, Reddy V, Pillarisetty LS (2023) Physiology, Neurotransmitters. [e-book] Treasure Island (FL), StatPearls. Available at: <https://www.ncbi.nlm.nih.gov/books/NBK539894/> [Accessed December 16 2024].