Here are 4 summary statements, supported by research, that hopefully will provide a useful overview of epilepsy medication for persons with epilepsy (PWE) and parents of children with epilepsy.  This blog will expand on each statement and indicate why this information is important to know.

1.  There are no drugs that treat the root cause of epilepsy; there are more than 25 FDA approved drugs that treat seizures, the symptoms of epilepsy.

2.  Drug selection should be based on seizure type but in many cases, seizure type is unknown.  Generally, in both instances, physicians prescribe drugs based on their familiarity with a specific drug.

3.   Drugs in clinical use act to suppress seizures in one of four ways.  Thus, when a drug fails to work, an alternative drug with a different mechanism of action would be a reasonable next step.

4.  No drug has a single action and all drugs used to treat PWE produce adverse drug reactions, many of which reduce quality of life.

1.  Epilepsy Drugs versus Seizure Drugs

Previous blogs (Assessments 3,4,5) discussed prescription drugs that induce seizures either during treatment of epilepsy and other conditions or on withdrawal of therapy.  This blog will discuss prescription drugs that control seizures and hence are the pharmacological treatment of epilepsy.  These drugs, of which there are more than 25, are termed anti-epileptic drugs (AED) but as noted by Sills and Rogawski, (2020), since they have no ameliorating effect on the disease of epilepsy but solely inhibit seizures, a better name is anti-seizure drugs (ASDs).  None of the drugs in clinical use correct the main cause of epilepsy.  Thus, at present, there is no cure for epilepsy, only possible relief from its symptoms.

It is important to know that only the symptoms of epilepsy are treated with medication and rarely will the disease go away.  It is truly sad that epilepsy which has been diagnosed since the Middle Ages (Brigo et al., 2018) remains, today, without a cure!

2.  Anti-Seizure Drug (ASD) Selection 

Seizures are categorized as focal, generalized, unknown or unclassifiable.  This is according to the International League Against Epilepsy (ILAE) guidelines (Scheffer et al., 2017).   Correct identification of a seizure is essential because data for drug efficacy is based on results of randomized controlled clinical trials in which a specific drug is evaluated against a specific seizure type.  A mismatch between seizure type and appropriate drug leads to inadequate therapy.  As noted by Kim (2020), “the diagnosis of the patient must first be accurate, in terms of the cause, seizure type, and epilepsy syndrome.”  Unfortunately, many seizure types are difficult to diagnose and unlike most other diseases, diagnosis of epilepsy relies on the patient’s history of the seizure.  Additionally, ASDs are not efficacious for all type of seizures and some, such as absence seizures are more difficult to treat (Kim, 2020).

Anti-seizure drugs (ASDs) as a monotherapy (single drug use) are effective in about half of all patients with epilepsy (PWE).  Twenty percent of PWE require additional drugs (polytherapy) and the remaining 30% are ASD-resistant, in which none of the available drugs suppress seizures (Verrotti et al., 2020). 

Selection of ASDs should be based  on drug “efficacy, tolerability and safety provided by solid evidences from well-designed randomized clinical trials (RCTs)” (Santulli, 2016).  However, survey results of PWE and their physicians (Groenewegen et al., 2014) imply that drug choice, in addition to safety and efficacy is based on the physician’s knowledge and experience with a specific drug.  This represents a possible source of bias (Santulli (2016). 

Persons wih epilepsy should ask their neurologist why they are taking a specific drug.  Ideally, for example, they should hear a discussion of the clinical trial results such that this drug suppresses their seizure type and not that their physician has considerable  experience with this ASD.

3.  Familiarity with anti-seizure drugs aids in successful treatment

Anti-seizure drugs  are divided into 4 groups according to the way in which they block seizures.  Scientists have worked hard from 1938 (advent of first clinically tested drug, phenytoin) to the present to understand the pathology of the seizure and develop ways to effectively interrupt them (Perucca, 2019).  They have successfully identified 25+ drugs with variable degrees of success in preventing seizures.  Additionally, they have developed a number of animal models with reproducible seizures to test novel anti-seizure drugs (Perucca, 2019).

Scientists have learned that seizures are identical to normal nerve activity except that seizures break loose of biological controls.  The result is unleashed neuronal activity and disruption of normal brain function.

Thus, anti-seizure drugs act to restore normal neuronal activity by restraining excessively high abnormal nerve function.  They essentially dampen this run-away nerve action and let alone the underlying normal nerve function.

Anti-seizure drugs target aspects of basic neuronal physiology.   Some anti-seizure drugs block ion channels that carry information throughout the nerve; others act to enhance the inhibitory neurotransmitter, gamma-amino-butyric acid (GABA) or inhibit an excitatory neurotransmitter, glutamate.  Anti-seizure drugs are listed below, grouped according to the way they act in the brain, called their mechanism of action. 

It is important to know that if an anti-seizure drug with a specific mechanism of action fails to suppress seizures, there exist other drugs with different mechanisms of action that would be the appropriate next anti-seizure drug to try.

4.  Adverse drug reactions (ADRs)

No drug has a single action.  All drugs have undesirable side effects termed adverse drug reactions (ADRs) and anti-seizure drugs are no exception.  Results of a 3 year prospective, cross-sectional, observational study of ~1000 patients with epilepsy found that ADRs occurred at a rate of ~2 per patient (Kumar et al., 2020).  ADRs increase with use of more than one anti-seizure drug.  Interestingly, Kumar et al., (2020) found no correlation between ADRs and the mechanism of the anti-seizure drug.  Thus, all anti-seizure drugs produce ADRs.  It remains unresolved as to the origin of ADRs but considering they target basic nerve activity in the brain and elsewhere, the existence of ADRs with use of anti-seizure drugs is not surprising.

ADRs that are least tolerated relate to behavioral/psychiatric side effects.  These ADRs include somnolence, ataxia (instability in standing/walking), sedation, aggression, depression, mood swings, psychosis, anxiety, suicidal thoughts, irritability, aggression, tantrums  and cognitive impairment (memory loss) (Chen et al., 2017; Kumar et al., 2020).  Other ADRs of lesser concern but still serious, are physiological or physical side effects such as diarrhea, nausea, skin disorders, and eye disorders (Witt, 2013; Kumar et al., 2020; Verrotti et al.,.2020). 

ADRs reduce quality of life and remains a major reason patients with epilepsy stop taking their medication.  This outcome is especially evident when seizure suppression is less than 100% (Chen et al., 2017).

Summary

On the one hand, considerable progress has been made in development of many efficacious anti-seizure drugs that target seizures in specific ways.  However, on the other hand, 30 % of patients with epilepsy receive no benefit from these drugs and 20% require use of more than one anti-seizure drug, elevating the risk of intolerable adverse drug reactions.  Furthermore,  none of the anti-seizure drugs in clinical use treat the root cause of the epilepsy.  Although current investigations seems interested in drug discovery and development to cure epilepsy, additional effort is needed in this direction (Perucca 2019).

Anti-seizure Drugs – Grouped according to how they work in the brain

Inactivators of sodium channels include the following drugs:

• Phenytoin (Phenytek, Dilantin),
• Carbamazepine (Tegretol),
• Lamotrigine (Lamictal),
• Fosphenytoin (Cerebyx),
• Eslicarbazepine acetate prodrug – S-licarbazepine active metabolite (Aptiom, Zebinix),
• Cenobamate (Xcopri),
• Rufinamide (Banzel),
• Lacosamide (Vimpat),
• Topiramate (Topamax, Trokendi XR),
• Oxcarpazepine (Trileptal)

Inactivators of calcium channels include the following drugs:

• Ethosuximide (Zarontin),
• Zonisamid (Zonegran),
• others with multiple targets: Levetiracetam (Keppra XR, Spritam broad spectrum),
• Gabapentin (Gralise, Horizant, Neuraptine), Pregabalin (Lyrica)

Activator of potassium Kv7channels include the following drug: 

Retigabine (Trobalt, Potiga) discontinued 2017 due to limited use and toxicities.

Enhancement of inhibitory neurotransmission

• benzodiazepines: Diazepam (Diastat),  Lorazepam (Ativan), Clonazepam (Klonopin),  Clobazam (Onfi)
• Tiagabine (Gabitril)
• Vigabatrin (Sabril)

Attenuation of excitatory neurotransmission

Perampanel (Fycompa) 

Modulation of neurotransmitter release

• Levetiracetam (Keppra XR, Spritam broad spectrum),
• Brivaracetam (Briviact),
• Gabapentin (Gralise, Horizant, Neuraptine),
• Pregabalin (Lyrica)