Epilepsy – A Lifelong Companion of Human Existence

1. Introduction

Epilepsy represents a significant public health challenge, both today and throughout human history.¹ Key questions frequently arise when discussing epilepsy: What is epilepsy, and how does it develop? Why do some individuals respond exceptionally well to treatment, becoming seizure-free, while others experience only partial relief with fewer seizures? Why do some patients derive no benefit from medication, continuing to experience seizures with the same frequency and severity? These questions are often accompanied by another: Why do similar types of epileptic seizures—essentially similar conditions—respond to treatment in some individuals but not in others?² Can we predict which cases of epilepsy will respond to treatment? Is epilepsy a lifelong condition, or can it be cured? Is it hereditary?³

Let us begin by addressing these questions systematically.

1.1. What Is Epilepsy?

Epilepsy is a neurological disorder characterized by the occurrence of epileptic seizures.⁴ Without seizures, there is no epilepsy.

1.2. What Are Epileptic Seizures?

Epileptic seizures are sudden, involuntary, uncontrolled, and excessive events that manifest as abnormal movements, sensations, or psychological activities.⁵ These phenomena can occur in isolation—solely as movement, sensation, or psychological activity—or as any combination of the three. Additionally, they may present with fully preserved, partially preserved, or entirely lost consciousness.⁶

These unwanted episodes typically arise abruptly, last for a limited duration, resolve spontaneously, and leave the individual in a state of full recovery as if nothing had occurred.⁷

1.3. Why Do These “Epileptogenic Phenomena” Occur?

These phenomena result from sudden, uncontrolled, and spontaneous hyperactivity in a specific area of the brain that acts as the epileptogenic focus.⁸

Examples:

• If the hyperactivity occurs in the motor area responsible for the right hand, the seizure will manifest as uncontrolled movements of the right hand.⁹

• If the hyperactivity involves the sensory area responsible for sensation in the right hand, such as heat perception, the seizure will involve a sensation of warmth in the right hand, even in the absence of an actual heat source.¹⁰

• If both the motor and sensory areas for the right hand are simultaneously hyperactive, the seizure will consist of uncontrolled movements of the right hand accompanied by a sensation of warmth.¹¹

These episodes are a direct consequence of localized brain dysfunction, with the type and nature of the seizure determined by the specific brain region affected.¹²

2. Seizure Classification

2.1. Focal Onset Seizures

Focal onset seizures originate in a specific region or network in one hemisphere of the brain. They are categorized based on the individual’s awareness and the presence of motor or non-motor symptoms¹³:

1. Focal Aware Seizures

   • Previously referred to as “simple partial seizures.”

   • Awareness is preserved, even if the individual experiences unusual sensory, motor, autonomic, or emotional phenomena (e.g., auditory hallucinations, tingling, or déjà vu).¹⁴

2. Focal Impaired Awareness Seizures

   • Previously referred to as “complex partial seizures.”

   • Awareness is impaired, either during the seizure or post-ictally. These seizures may involve automatisms, such as lip-smacking or repetitive hand movements.¹⁵

3. Focal to Bilateral Tonic-Clonic Seizures

   • Seizures that start in one hemisphere and spread to involve both hemispheres. These often result in generalized motor symptoms, including tonic (stiffening) and clonic (jerking) movements, with a loss of consciousness.¹⁶

2.2. Generalized Onset Seizures

Generalized onset seizures begin in and rapidly engage networks in both hemispheres of the brain. These are divided into motor and non-motor categories¹⁷:

1. Generalized Motor Seizures

   • Tonic-Clonic Seizures (formerly “grand mal”)

     • Loss of consciousness with tonic stiffening followed by clonic jerking movements. May include incontinence, tongue-biting, and postictal confusion.¹⁸

   • Other Motor Seizures

     • Includes myoclonic (brief, shock-like jerks), tonic (stiffening), atonic (sudden loss of muscle tone), and clonic (rhythmic jerking) seizures.¹⁹

2. Generalized Non-Motor Seizures (Absence Seizures)

   • Typical Absence: Brief lapses in awareness, often with staring and subtle motor signs like eyelid fluttering.²⁰

   • Atypical Absence: Similar but with slower onset and resolution, often associated with more pronounced motor features and atypical EEG findings.²¹

2.3. Unknown Onset Seizures

When the onset of the seizure is not observed or cannot be determined, it is categorized as unknown.²² These seizures can later be reclassified if additional information becomes available.

• Examples:

  • Tonic-clonic seizure of unknown onset.

  • Other motor or non-motor seizures with unclear onset characteristics.²³

2.4. Special Considerations for Children

In children, certain generalized seizures, such as absence seizures, may manifest with minimal motor activity but significant impacts on learning and behavior.²⁴ Other syndromes like infantile spasms (characterized by brief, symmetric spasms) or Lennox-Gastaut syndrome involve mixed seizure types and developmental implications.²⁵

3. Etiological Framework

Modern classification also emphasizes identifying the underlying cause of epilepsy²⁶:

• Genetic: Resulting from known or presumed genetic defects (e.g., Dravet syndrome).²⁷

• Structural: Associated with visible brain abnormalities (e.g., cortical dysplasia).²⁸

• Metabolic: Due to metabolic disorders (e.g., mitochondrial diseases).²⁹

• Immune: Related to autoimmune conditions (e.g., autoimmune encephalitis).³⁰

• Infectious: Caused by infections such as neurocysticercosis or encephalitis.³¹

• Unknown: Etiology remains unidentified.³²

3.1. Pathophysiology of Seizures

The human brain contains approximately 86 billion neurons forming intricate networks.³³ These neurons are broadly classified into:

1. Excitatory neurons, which promote the activity of connected neurons through neurotransmitters like glutamate.³⁴

2. Inhibitory neurons, which suppress neural activity via neurotransmitters like gamma-aminobutyric acid (GABA).³⁵

The balance between excitatory and inhibitory activity underpins the brain’s ability to function cohesively. Disruptions in this balance—such as excessive excitation, insufficient inhibition, or network hypersynchrony—can result in epileptic seizures.³⁶ Advances in molecular biology and neuroimaging have identified genetic mutations, structural abnormalities, and dysfunctional ion channels or synaptic mechanisms as contributors to these imbalances.³⁷

3.2. Contemporary Understanding

Epilepsy is no longer viewed as a singular disorder but rather as a spectrum of syndromes with diverse etiologies, ranging from genetic predispositions to acquired conditions, such as brain injuries or infections.³⁸ Modern treatment approaches include tailored pharmacological regimens, neuromodulation techniques (e.g., vagus nerve stimulation),³⁹ and surgical interventions targeting seizure foci, all aimed at restoring neural network stability and improving quality of life.⁴⁰

3.3. Organization and Functionality of Neurons in the Brain

Neurons typically organize into functional networks, with each group responsible for a specific function. A group of neurons dedicated to controlling a particular function is referred to as the brain center for that function.⁴¹ Everything we do, think, or feel is governed by specific neural centers within the nervous system, which initiate and terminate actions or thoughts. In healthy individuals, this system operates harmoniously, forming a well-coordinated psychophysical unit.⁴²

For this harmony to exist, each motor, sensory, or psychological function must be active at the appropriate “time and place,” and equally important, inactive when its activation is unnecessary. In neurological terminology, this is referred to as spatial and temporal referencing, which also establishes a logical (or functional) reference.⁴³ A disruption occurs when a function is either inactive when required or active at inappropriate times or places, creating imbalance in the human organism’s functions.⁴⁴

3.4. What Is Epilepsy in This Context?

Epilepsy represents a condition where brain activity occurs when it should not or fails to occur when it should.⁴⁵ This leads to the question: Why does a group of neurons in the brain suddenly lose control and begin to act in an unregulated, unnecessary, or undesired manner?

3.5. Main Causes of Epilepsy

3.5.1. Brain Damage and Neuronal Loss

Damage to the brain disrupts the delicate balance between excitatory and inhibitory neural activity, leading to a predisposition for seizures.⁴⁶ This damage may result from trauma, stroke, infections, tumors, neurodegenerative diseases, or even the natural aging process.⁴⁷

1. Pathophysiology:

   • Neuronal loss may disproportionately affect inhibitory (GABAergic) neurons or excitatory (glutamatergic) neurons.⁴⁸

   • Regions with an overactive excitatory network or insufficient inhibitory control can generate hypersynchronous neuronal discharges, characteristic of epileptic seizures.⁴⁹

2. Clinical Outcomes:

   • Post-injury epilepsy (e.g., after traumatic brain injury or stroke) often responds to antiepileptic drugs (AEDs).⁵⁰

   • In some cases, epilepsy resolves spontaneously through mechanisms like neuroplasticity, including:

     • Synaptic Reorganization: Neural circuits may adapt by strengthening inhibitory pathways or reducing excitatory signaling.⁵¹

     • Glial Modulation: Astrocytes and microglia can influence synaptic activity and help restore homeostasis.⁵²

     • Reduction of Excitotoxicity: Over time, adaptive processes may downregulate excessive excitatory activity.⁵³

3.5.2. Epileptogenic Neurons

Epileptogenic neurons are hypothesized to exhibit intrinsic abnormalities that predispose them to hyperexcitability. However, modern research emphasizes that epilepsy often involves network-level dysfunction rather than isolated neuronal anomalies.⁵⁴

1. Characteristics:

   • Epileptogenic neurons may have altered ion channel expression, synaptic receptor function, or intracellular signaling pathways that promote hyperexcitability.⁵⁵

   • These neurons may fail to respond to inhibitory inputs, leading to unregulated bursts of high-frequency firing.⁵⁶

2. Current Understanding:

   • Epilepsy is less about “rogue neurons” and more about disrupted networks. For example:

     • Paroxysmal Depolarization Shifts (PDS): Seen in epilepsy models, these reflect a pathological interplay between excitatory and inhibitory activity at the network level.⁵⁷

     • Neuronal Microcircuits: Dysfunctional communication between neurons and glia (e.g., astrocytes regulating extracellular potassium) can create a permissive environment for seizures.⁵⁸

   • Advances in imaging and electrophysiology have demonstrated that epileptogenesis often involves maladaptive changes across broader networks, not just individual neurons.⁵⁹

4. Epilepsy mechanisms

4.1. Epileptogenic Neurons and Neural Network Dysfunction

Epilepsy arises from complex dysfunctions in neuronal networks, where hyperexcitability and hypersynchrony develop due to genetic, structural, or functional abnormalities. These abnormalities disrupt the balance between excitatory and inhibitory signaling, leading to localized or widespread seizure activity.⁶⁰

1. Spread of Hyperexcitability:

   • While seizure activity can propagate from one brain region to another, this reflects network-level dynamics rather than the “conversion” of healthy neurons into epileptogenic ones.

   • Such propagation depends on synaptic connectivity, ion channel dysfunction, and the state of surrounding neural circuits.⁶¹

2. Pharmacoresistant Epilepsy:

   • In some individuals, particularly those with structural brain abnormalities (e.g., cortical dysplasia, hippocampal sclerosis), seizures become resistant to antiepileptic drugs (AEDs).

   • These cases often benefit from surgical interventions targeting seizure foci, although widespread or multifocal epileptogenic zones may complicate surgical treatment.

3. Familial Epilepsy:

   • Genetic predispositions can increase the likelihood of developing epilepsy, but these are linked to mutations in specific genes (e.g., ion channelopathies, synaptic protein dysfunction) rather than the spontaneous emergence of epileptogenic neurons.⁶²

4.2. Reflex Epilepsies and Stimulus Sensitivity

Certain types of epilepsy, such as reflex epilepsies, are triggered by specific external stimuli (e.g., flashing lights, reading, certain sounds).⁶³

1. Neuronal Network Instability:

   • These epilepsies arise from hypersensitive neuronal networks that overreact to normal sensory inputs.

   • Reflex epilepsies are rare and often respond to AEDs, lifestyle modifications, or avoiding known triggers.⁶⁴

2. Treatment Outcomes:

   • While some individuals find success in avoiding triggers, these strategies are not universally effective, as reflex epilepsy is a distinct subset of epilepsy types.⁶⁵

4.3. Epilepsy Induced by External Factors

Epileptic seizures can be provoked in healthy brains by external factors that lower the seizure threshold, such as toxins, sleep deprivation, or stress.

1. Provoked Seizures:

   • These are not considered epilepsy unless seizures recur without the presence of a provoking factor.

   • Removing the external cause (e.g., drug withdrawal, toxin clearance) typically resolves provoked seizures.

2. Clinical Relevance:

   • Understanding and addressing these external factors are critical in preventing secondary epilepsy, especially in vulnerable populations.⁶⁶

4.4. Combination of Mechanisms

Many individuals with epilepsy exhibit overlapping mechanisms, such as structural brain abnormalities combined with environmental triggers.

• Multifactorial Nature:

  • Epileptogenesis often involves a combination of genetic predispositions, structural brain damage, and network-level changes.

  • These combined mechanisms underscore the heterogeneity of epilepsy and the need for personalized treatment approaches.⁶⁷

4.5. Subclinical Seizures and Normal Neural Oscillations

While subclinical or unnoticed seizures may occur, the claim that nearly everyone has experienced an epileptic seizure is inaccurate. Instead:

1. Normal Neural Oscillations:

   • Oscillatory feedback mechanisms are a natural part of brain function and are not inherently pathological.

   • Epileptiform activity (e.g., interictal spikes) differs significantly from the transient, non-synchronous activity seen in healthy brains.⁶⁸

2. Preclinical Seizure Activity:

   • Subclinical seizures or interictal discharges may occur in individuals predisposed to epilepsy without progressing to overt clinical seizures. These are studied using advanced neuroimaging and electrophysiology.⁶⁹

6. How is epilepsy diagnosed?

Epilepsy is confirmed by demonstrating the occurrence of epileptic seizures. This process can be straightforward in cases where seizures have a clear clinical presentation, such as generalized tonic-clonic seizures, or when they occur frequently. However, when seizures have a subtle clinical manifestation or are infrequent, diagnosis can be challenging and sometimes even impossible to establish definitively.⁷⁰

The primary diagnostic tool for epilepsy is the recording of the brain’s electrical activity through electroencephalography (EEG). EEG results, ranging from standard recordings to extended multi-day continuous monitoring, are analyzed for epileptogenic patterns and their correlation with suspected epileptic phenomena. The goal is to establish a high likelihood of connection between EEG findings and clinical events suspected to be epileptic. This often requires multiple EEG sessions for confirmation.⁷¹

7. How is epilepsy treated?

Epilepsy is primarily treated with medications designed to reduce neuronal excitability. These drugs are administered continuously following a diagnosis and are not reserved solely for seizure occurrences. Antiepileptic drugs (AEDs) act as chemical agents that “saturate” the brain, reducing the excitability of all neurons (an unintended effect) to also suppress the hyperexcitability of those involved in seizures (the desired effect).

This approach raises questions:

• Do AEDs suppress all brain cells to include those involved in seizures? Yes, that is accurate.

• Could a drug be developed to selectively inhibit only the neurons involved in seizures without affecting others? As of now, such a drug does not exist.

In cases where suspicion of epilepsy persists without definitive proof, clinicians may resort to the ex juvantibus approach. This involves administering an antiepileptic medication and monitoring whether the suspected phenomena diminish significantly or resolve. If they do, the likelihood of epilepsy is considered high.

However, this method is complicated by the fact that antiepileptics can also alleviate a wide range of symptoms unrelated to epilepsy, particularly in psychiatry, pain syndromes, and organ dysfunctions. Distinguishing whether such symptoms are epileptic in origin remains a complex issue.⁷²

8. Are there alternative treatment methods?

Surgical treatment is an option when an epileptogenic focus can be identified based on seizure type and EEG findings. This focus is often associated with an abnormal structural or morphological change in the brain, though not always. When a focus is identified, it can be surgically removed.

However, surgical intervention presents a dilemma:

• Does surgery risk creating new epileptogenic areas by damaging the brain? Yes, this is a possibility. The decision to operate involves presenting patients with a trade-off: the removal of a focus causing refractory seizures versus the potential creation of a new, less problematic epileptogenic focus. Based on clinical experience, the new focus is often less severe, potentially eliminating or significantly reducing seizures, which constitutes progress in treatment.

Surgical recommendations are supported by decades of evidence. Over 70 years of operative experience have provided robust biostatistical data on the success of such interventions for specific types of epilepsy and brain abnormalities. Despite this, less than 1% of patients with drug-resistant epilepsy are candidates for surgical treatment.

In recent decades, vagus nerve stimulation (VNS) has emerged as another treatment modality. This involves implanting a pacemaker-like device that delivers electrical impulses to the vagus nerve, which modulates certain brain centers critical for seizure propagation. While VNS can be effective in carefully selected patients, it is not a definitive treatment and has not fulfilled its initial high expectations.^73,74

9. Why is epilepsy challenging to treat?

The core issue lies in excitability, which is not only fundamental to epilepsy but also essential for normal brain function. Drastically reducing excitability would prevent seizures but also compromise the brain’s ability to function normally.

Even primitive animals with relatively simple neural systems exhibit uncontrolled activity akin to seizures. Epileptic seizures have been observed in reptiles, including crocodiles and monitor lizards.

10. Prognosis and treatment outcomes

The treatment of epilepsy is inherently uncertain. In some cases, achieving seizure control remains elusive, while in others, seizures can be completely suppressed. At the onset of treatment, it is crucial to avoid overly optimistic or pessimistic prognoses.

11. Final Remarks

Epilepsy’s enigmatic nature and its interplay with the fundamental excitability of neural cells highlight the complexity of its diagnosis and treatment. Continued research and innovation remain imperative to better understand and manage this pervasive neurological condition.

Conflict of interest

The author declares no conflict of interest related to this manuscript.