Inside the seizure spectrum: insight into the epileptic pathways

Epilepsy is a chronic, non-communicable brain disorder characterised by recurrent seizures due to excessive electrical discharges in neurons. However, experiencing a seizure does not necessarily mean having epilepsy: up to 10% of people worldwide have a seizure during their lifetime without being diagnosed with the condition.¹

The International League Against Epilepsy (ILAE) defines epilepsy as a persistent predisposition to epileptic seizures and their neurobiological, cognitive, psychological, and social consequences.² Since 2014, ILAE experts have proposed considering epilepsy as a brain disease when any of the following conditions occur:³

• At least two unprovoked (or reflex) seizures occurring more than 24 hours apart;³
• One unprovoked (or reflex) seizure and a probability of further seizures (at least 60%) after two unprovoked seizures over the next 10 years;³
• Diagnosis of an epilepsy syndrome.³ 

Globally, epilepsy affects about 50 million people, particularly in low- and middle- income countries.¹ Epilepsy can manifest at any age, although its incidence follows a U-shaped pattern, with higher rates in young children and older adults.²  

In about half of the cases, the cause of epileptic seizures is unknown.¹ In some instances, seizures may be due to various types of brain damage (stroke, tumours, trauma, infections).⁴ Among the elderly, the increase in epileptic seizures appears to be linked to the rising incidence of cerebrovascular diseases.² 

The symptoms of an epileptic seizure depend on the type of seizure. These can be primarily classified into two groups:⁵  

• Generalised seizures, which affect both sides of the brain and are divided into: 
  • Absences or “petit mal” characterized by brief loss of consciousness; 
  • Bilateral Tonic-clonic seizures, or “grand mal,” which may be accompanied by loss of consciousness, falls, and uncontrolled spasms or tremors.⁵  
• Focal or partial seizures, which affect only one part of the brain and are divided into: 
  • Focal Aware Seizures, which affect a small area and may cause changes in taste and smell; 
  • Focal Impaired Aware seizures, which lead to confusion or a dazed feeling; 
  • Focal to Bilateral Tonic Clonic Seizures, where a focal seizure evolves into a generalised one.⁵ 

Seizures can last for several minutes⁵ and can vary in frequency, from less than one per year to several per day.¹  

Stigma and mental health associated with epilepsy 

Epilepsy is one of the oldest known diseases.¹ However, fear of the condition, lack of awareness, discrimination, and stigma continue to surround those who suffer from it.¹ It is estimated that up to 50% of people with epilepsy experience stigma related to the condition and that more than 40% do not discuss their condition with others.⁶ Stigma, in turn, is a risk factor for developing psychiatric disorders, such as anxiety and depression: people with epilepsy have rates of depression two to three times higher than the general population and are more likely to suffer from depression compared to individuals with other chronic illnesses. About one in five adults with epilepsy suffers from generalised anxiety disorder. Additionally, epilepsy negatively impacts health-related quality of life, increasing stress, sleep problems, and pain.⁷ In young people with epilepsy, anxiety and depression are associated with poor academic performance, increased suicidal ideation, and reduced quality of life.⁸  

Families are also negatively affected by epilepsy: parents of children with the condition often fear seizures and constantly monitor their children’s health, having to forgo daily activities.⁹ Consequently, nearly half of the parents of children with epilepsy develop psychopathological symptoms, including post-traumatic stress disorder, depression, anxiety, high levels of stress, and sleep problems.⁹ 

Pathophysiology of seizures and epilepsy 

Epileptic seizures result from an imbalance between excitation and inhibition in neurons, which exhibit high, coordinated, and sustained excitability.¹⁰ Epileptogenesis, on the other hand, is the process by which the brain undergoes changes, predisposing it to the development of epilepsy. This process involves gradual changes in neuronal excitability, leading to alterations in brain connections and structure.¹⁰ Various neurotransmitters, such as glutamate, aspartate, acetylcholine, and adrenaline, increase neuronal excitability, while others, like dopamine and gamma-aminobutyric acid (GABA), limit it.¹⁰ Additionally, ions and ion channels, which are normally responsible for transmitting impulses between neurons, also play a role in the mechanism that triggers excitation.¹⁰ 

The balance between neuronal excitation and inhibition can be disrupted in many ways, leading to different causes of seizures and epilepsy.¹¹ Besides the unknown etiology, the ILAE has defined five etiological categories that may overlap:¹¹ 

• Structural, resulting, for example, from hypoxic-ischemic encephalopathy, stroke, and trauma; 
• Genetic, when there is a specific known or presumed variant causing the disease, and seizures are a common manifestation; 
• Metabolic, arising from a known or presumed metabolic imbalance where seizures are a primary symptom; 
• Infectious, representing the most common identifiable etiology in some regions of the world; 
• Immune, accounting for 5-7% of all epilepsies, suspected in people with specific antibodies and nervous system inflammation mediated by autoimmune components.¹¹ 

Treatment of epileptic seizures 

Up to 70% of people with epilepsy could become seizure-free with the appropriate use of antiepileptic drugs (AEDs), to the extent that after two years, discontinuation of drug therapy may be considered based on clinical, social, and personal factors.¹ The goal of seizure treatment is to enable people with epilepsy to live as unrestricted a life as possible.¹¹ Antiepileptic drugs work by reducing neuronal excitability, thereby stopping or preventing the onset or spread of seizures. AEDs can act on the channels that regulate the passage of ions responsible for transmitting nerve impulses or on neurotransmitters.¹¹ Based on their mechanism of action, antiepileptic drugs are often classified into:¹¹ 

• Sodium (Na)-dependent action potential inhibitors; 
• Calcium (Ca2+) channel inhibitors; 
• Drugs that open potassium channels; 
• Blockers of the excitatory neurotransmitter glutamate; 
• Drugs that directly enhance the activity of the inhibitory neurotransmitter GABA; 
• Drugs that indirectly enhance GABA activity by inhibiting its reuptake.¹¹ 

Antiepileptic drugs are effective in nearly 80% of people with epilepsy, while the remaining 20% are drug-resistant.¹¹ Newer antiseizure medications may offer more specific and effective treatment in some cases. Where area of seizure onset is clear, and there has been no adequate drug response the possibility of surgically removing or disconnecting a specific brain region to control seizures is considered.¹¹ The percentage of individuals who become seizure-free after surgery ranges from 50% to 80%.¹¹ Finally, for those with drug-resistant epilepsy who cannot undergo surgery or for whom surgery has failed, neurostimulation can be used. This technique uses electrical impulses to counter the generation or propagation of epileptic seizures.¹¹ With this method, at least 50% of people with epilepsy can achieve a 50% or greater reduction in seizure frequency.¹¹ 

In recent years, new therapeutic possibilities have been under investigation.¹¹ Gene therapy, which aims to restore physiological functions in target cells, could be a future  alternative for the treatment of drug-resistant epilepsy.¹¹ Additionally, an innovative therapeutic approach involves the injection of compounds into the brain that inhibit certain microRNAs (miRNAs) believed to be responsible for seizures.¹¹ 

References 

1. World Health Organization. Epilepsy. 
2. Lang J. D. & Hamer H. M. Epidemiology of epilepsy in old age – English version. Zeitschrift fur Epileptologie (2022); 35:78-81 
3. Fischer R. S. et al., A practical clinical definition of epilepsy. Epilepsia (2014); 55(4):475-482.
4. National Health Service. Epilepsy
5. Centers for Disease Control and Prevention (CDC). Types of seizures 
6. Mao L. et al., Felt stigma and its underlying contributors in epilepsy patients. Frontiers in Public Health (2022); 10:879895
7. Malik N. I. et al., Perceived stigma, discrimination and psychological problems among patients with epilepsy. Frontiers in Psychiatry (2022); 13:1000870
8. Temple J. et al., Psychosocial factors associated with anxiety and depression in adolescents with epilepsy: A systematic review. Epilepsy & Behavior (2023); 149:109522
9. Yu Z. et al., The experiences of caregivers of children with epilepsy: A meta-synthesis of qualitative research studies. Frontiers in Psychiatry (2022); 13:987892
10. Sumadewi K. T. et al., Biomolecular mechanisms of epileptic seizure and epilepsy: a review. Acata Epidemiologica (2023); 5:28 
11. Vera-Gonzalez Alejandro. Pathophysiological mechanisms underlying the etiologies of seizures and epilepsy. Epilepsy. Chapter 1