Epilepsy: A Diagnostic and Treatment Update

Epilepsy can be a challenging disease to understand and treat given the various types of seizures that can occur, the evolving language around the condition, and a lack of available resources that facilitate anti-seizure medication prescribing. Herein is a brief overview of the condition as it is defined today, as well as current treatment recommendations.

Epileptic Seizures and Pathophysiology

Typical communication between neurons and other cells starts with the opening and closing of positive and negative ion channels, generating an action potential that propagates across a neural network. If a group or large area of neurons generate an “abnormal,” synchronous, and oscillating excitatory discharge, a seizure occurs. Here, the group action builds to a threshold either through an increase in excitatory activity (the influx of positive ions) or when inhibitory activity is blocked (exchange of negative ions). Different cell groups within areas of the cortex, hippocampus, and cerebellum have lower excitable thresholds and are where many seizures originate.¹

In epilepsy – a condition defined by re-occurring seizures – there appears to be a state of neural hyper-excitability and hyper-synchronicity.^1,2

New Terminology and ICD-11 Codes for Epilepsy

For some clinicians, the terms grand mal or petit mal may sound familiar, as well as the terms partial, simple, or complex when referring to epileptic seizures, however, the International League Against Epilepsy (ILAE) has suggested that these older terms are inadequate for categorizing and, ultimately, diagnosing epilepsy.³

In 2017, the ILAE proposed the following for describing and categorizing seizures:

1. State the origination of the seizure: focal (formerly a partial), focal to bilateral (formerly a secondary generalized seizure), or generalized.

Seizures that start and remain in one brain hemisphere are called focal seizures. If the electrical imbalance propagates to include the other hemisphere, it is called a focal to bilateral seizure. Some seizures originate in both hemispheres simultaneously, called generalized seizures.³

Further, “unknown” onset has been added to the description to allow for seizures where the onset was unobserved or when the person with epilepsy was unaware of what happened. Even with an unknown onset, seizures can be classified using the most dominant or first-noticed symptoms as described below.³

2. State the level of awareness: is the person aware of what is happening to them, or is there impaired awareness?

Older terms such as simple partial or complex partial would be reclassified by ILAE as focal-awareness seizure or focal-impaired awareness respectively.

3. State the first major symptom of the seizure, whether it is motor or non-motor in nature.³

Many of the descriptive changes suggested by ILAE have been adopted into the World Health Organization’s International Classification of Diseases 11^th Revision (ICD-11); the ICD-9 and ICD-10 use the older terminologies (ie, grand mal, petit mal, partial, simple, complex).³ The ICD-11 was implemented worldwide in January 2022, although universal application of the codes is expected to take several years.⁴ Using the ICD-11 coding tool, terms such as grand mal are now coded as “generalised tonic-clonic seizure” (8A68.4). The term “complex partial seizure” is now coded as “focal unaware seizure” (8A68.0). See Figure 1.

Anti-Seizure Medication Classes

Antiseizure medication (ASM) classes fall into several mechanistic categories that can often be used to treat the spectrum of seizure types.⁵ Traditional ASMs modulate ion channels directly whereas others have indirect effects via a ligand-gated receptor. They all work to move the neuronal membrane away from an instigating excitatory discharge, thus reducing the risk of seizures.

Voltage-Gated Sodium Ion Channel Modulators

Voltage-gated sodium ion channel (VGSC) modulators have been frontline ASMs for decades. These prevent the influx of positively charged sodium ions by:⁶

• blocking the ion channel (phenytoin, carbamazepine, valproate)

• promoting the fast-inactivation during an action potential (oxcarbazepine, lamotrigine, zonisamide)

• prolonging the slow-inactivation period (lacosamide, eslicarbazepine)⁷

Voltage-Gated Calcium Ion Channel Blockers

Voltage-gated calcium channel (VGCC) blockers also prevent the influx of positive ions, mostly calcium, often by working on the low threshold or T-type calcium channel. The VGCC blockers, such as ethosuximide, zonisamide, and trimethadione, may also have some neuroprotective effects through antioxidant modulations.⁸

GABAergic Modulators

GABA and its receptors produce most of the nervous system’s inhibitory functions, and several ASMs work to enhance these actions. Vigabatrin reduces the enzymes that metabolize GABA and tiagabine blocks the re-uptake of GABA, resulting in more of this ligand in the synaptic cleft between neurons.⁶ Clonazepam and levetiracetam indirectly affect GABA receptors through their action on the positive or negative allosteric modulation of GABA receptors, respectively.

Full agonist drugs that affect the GABA receptors directly can result in physical dependence and tolerance.⁶ These include phenobarbital and benzodiazepines.

Glutamatergic Modulators

The glutamatergic system is the primary excitatory system. ASMs that interact with this system often do so by blocking the ionotropic receptors: AMPA, kainate, and NMDA. Felbamate blocks the passage of calcium and sodium channels connected to NMDA receptors. Lacosamide and zonisamide inhibit both kainate and AMPA receptors, while perampanel affects only AMPA receptors.⁶ These last three ASMs can also pass into breastmilk so, their use with pregnant people should be carefully thought out.^9,10

Anti-Seizure Medication Use by Seizure Onset

First-line ASMs are broadly separated into those for focal seizures and those for generalized and unknown-origin seizures.^6,11,12 For example, carbamazepine, oxcarbazepine, and lacosamide are often prescribed as monotherapies when a patient first presents with a focal seizure. Ethosuximide has been shown to be beneficial for generalized absence seizures while perampanel has been indicated for initial generalized tonic-clonic seizures. Valproate and lamotrigine are widely used in both focal and generalized seizure management, as well as for unknown onset seizures.^6,11,12

There is substantial overlap in how ASMs are used to manage seizures, and since more than 50% of people with epilepsy fail to respond to their initial drug, which one to start with can become a guessing game.¹³ However, in choosing the second ASM, the physician can make a more rational choice. Understanding the mechanism of action of the first ASM and knowing that many of the side effects, drug interactions, and the exacerbation of comorbid disorders are related to those actions, the second ASM to try is made with more insight.^6,11-13 After trying two ASMs, the percentage of people with controlled seizures increases to 60%, unfortunately, this still leaves 40% with medically refractory seizures.¹³

Anti-Seizure Medications in Development

Newer ASMs in development attempt to avoid drug-to-drug interactions, increase tolerability, and/or better treat medically refractory seizures by indirectly influencing the neuronal membrane potential. The synaptic vesicles that release receptor ligands from the neuron are one such target. Levetiracetam and its analogs, brivaracetam and padsevonil, work through the synaptic vesicle protein 2A (SVP2A).^6,14,15

All the drugs currently in use and approved by the FDA are seizure-preventing drugs. None address the mechanisms behind epilepsy. Several lines of research are underway with this in mind. They are targeting structural proteins in the neuronal membranes, transcription factors that regulate cell proliferation, autophagy, and apoptosis, or interact with stress-activated proteins.^6,16

Additional Resources

Physicians interested in CME or additional training on epilepsy may find these useful:

• Anti-seizure medication modules from the American Epilepsy Society

• Tools and guidelines from the American Academy of Neurology

• CME credits on therapeutic advances from the CME Institute