In this discussion, we go over a basic overview of epilepsy, different types of epilepsy, pharmacologic agents, and status epilepticus.
Epilepsy Overview
Epilepsy is prevalent in 1.2% of the population in the U.S. This makes it somewhat rare, but can be very debilitating. The onset is usually in childhood or older adults.
Mortality is 2-3x higher than the general population.
Remember that not all seizures are epilepsy. Seizures can occur with substance use, alcohol/BZD withdrawal, febrile seizures, acute systemic illness. These are referred to provoked seizures. This type of seizures is not usually treated long-term.
Etiology of Epilepsy
Multiple etiologies have been proposed for epilepsy. Patients who develop epilepsy later in life usually got epilepsy from an injury (TBI, stroke, brain tumors.)
Some other etiologies are genetic predisposition, acquired injury, infectious sources, metabolic abnormalities, immune disorders, and idiopathic.
Pathophysiology
Seizures start with neuronal hyperexcitability and hyper-synchronization. These lead to excessive neuro-activity and a large spike in activity.
Focal seizures are seizures that occur in one specific area of the brain. Focal seizures can propagate to other areas and become generalized seizures.
Generalized seizures occur across a wide area all at once, and they generally start in the thalamus or cortex.
Risk Factors
Risk factors include some genetic components in addition to environmental issues, such as perinatal injury, small gestational weight, and alcohol withdrawal seizures.
Epilepsy can be triggered by various types of stimulation, such as stress, flashing light, hormonal change, and sleep deprivation.
Medications that Lower Seizure Threshold
- Theophylline
- Bupropion
- Alcohol
- Substance Use
These medications can put patients at risk.
Types of Epilepsy
As mentioned before, there are focal onset epilepsy and generalized epilepsy. Focal onset epilepsy can be further categorized into focal aware (no loss of consciousness) seizure and focal impaired awareness (loss of consciousness) seizure. The other two types of epilepsy are focal onset epilepsy that spread to become generalized seizures and seizures with unknown etiology.
Symptoms of epilepsy can be separated into those with motor symptoms and those with no motor symptoms.
- Motor symptoms: tonic-clonic, myoclonic, atonic, etc.
- Nonmotor: absence, autonomic, cognitive, emotional, and sensory
Epilepsy Diagnosis
In general, a patient needs to either have at least two unprovoked seizures occurring at least 24 hours apart or have one unprovoked seizure with a greater than 60% chance of having another seizure as seen on EEG.
It is recommended that EEG is utilized each time to detect suspected epilepsy. While EEG abnormality might not be detectable in some patients, it still can be present in some.
CT/MRI can be used to detect structural lesions.
There is no lab to identify epilepsy, but the result can be used to rule out other abnormalities, such as hypoglycemia.
It is important to identify a specific type of epilepsy if possible, but this can be difficult. Generally, a specific type of epilepsy is easier to diagnose in childhood and adolescence.
Specific Epilepsy Syndromes
Childhood Absence Epilepsy (CAE) or Juvenile Absence Epilepsy (JAE)
This is characterized by generalized clonic-tonic onset seizures and unresponsiveness (10-45 seconds).
Juvenile Myoclonic Epilepsy (JME)
This type is characterized by myoclonic jerks, limb moving, and an uncontrollable movement usually when waking up to falling asleep. It is often clonic-tonic and can be accompanied by absence seizures.
Lennox-Gastaut Syndrome (LGS)
This is characterized by multiple seizure types and intellectual disability prior to the development of seizures. The onset is generally between 3-5 years. The types of symptoms are tonic, atypical absence, and atonic.
Dravet Syndrome
This can be a focal or generalized onset that begins in infancy or early childhood. These patients are at a higher risk of status epilepticus and developmental delay after the first few years caused by repetitive seizure activity.
West Syndrome
This is characterized by infantile spasms and intellectual disability
It is important to note that this is not an all-inclusive list, but it is a good start.
Goals of Treatment
There is no cure for epilepsy unless you count surgery, which only a few patients are qualified for. The goal of the treatment is to have complete seizure freedom. This is generally attained in 65-80% of the patients.
Anti-seizure medications (ASMs) are a mainstay of the treatment. These medications only treat symptoms, and they usually come with various adverse effects. This is why it is important to have a balance between good seizure control and minimizing adverse effects. We need to be realistic about the goal.
A patient with two or more unprovoked seizures should always be started on pharmacologic therapy.
Non-Pharmacologic Therapy
Non-pharmacologic therapy can help those who cannot achieve seizure control with ASM alone.
The ketogenic diet is a diet that is low in carbs and high in fat. It is very poorly tolerated, which is why patients tend to do better on the Atkins diet. It is unsure how this works, but it seems like when the body is put on a ketogenic diet, there is an effect on the hyperexcitability state of the brain.
Vagal nerve stimulation may be effective, but the effects take time to see the improvement.
Surgery is the treatment of choice in refractory and focal seizures, but only a few patients would qualify for this. Additionally, there may be some negative effects on learning and memory post-surgery.
Efficacy of ASMs
There are many anti-seizure medications, but only a few are approved as monotherapy. This is because it can be difficult to conduct a controlled trial to study monotherapy because we don’t want patients to be at risk of having seizures. It is important to note that many agents are used off-label as monotherapy.
Currently (2023), there is no direct comparison study, as such, most ASMs are considered to be equally efficacious. Gabapentin is the exceptive. It has been shown to be less efficacious than most.
Some ASMs can worsen certain seizure types.
Adverse medication reactions affect effectiveness.
Adverse Effects
There are two main types of ASM ADRs: Dose-dependent and idiosyncratic
Dose-dependent ADRs include CNS effects (sedation, dizziness, impaired cognition, blurred vision) and GI effects (nausea, vomiting, appetite loss, and diarrhea).
Idiosyncratic ADRs include rash (phenytoin, phenobarbital, carbamazepine, lamotrigine), blood dyscrasia (phenytoin, phenobarbital, carbamazepine, and VPA), suicidal behavior (all ASMs), osteoporosis (phenytoin, phenobarbital, carbamazepine, oxcarbazepine, felbamate)
Patients can be put on vitamin D supplements to help with osteoporosis.
Pharmacokinetic Concerns
This is a large factor when considering what agent for a patient. Due to many of the pharmacokinetic factors, titration and taper should be conducted carefully.
Most of these medications are CYP450 agents and are metabolized through the liver (with an exception of levetiracetam, gabapentin, pregabalin, and vigabatrin),
Phenytoin displays a Michellis-Menten kinetic. This makes phenytoin difficult to monitor over time.
Phenytoin, phenobarbital, primidone, and carbamazepine are strong inducers.
VPA is a strong inhibitor.
Agents, such as phenobarbital, phenytoin, carbamazepine, oxcarbazepine, and topiramate, may affect estrogen efficacy.
First-Generation ASMs
First-generation ASMs are probably the most effective at controlling seizures, but they have a lot of ADRs and complex pharmacokinetics.
In general, they are used as a second-line agent, but the exception of ethosuximide, which is the first-line for absence seizures.
Carbamazepine (Na inactivation) – mono/adjunct
Carbamazepine is indicated for focal-onset seizures.
It can worsen other seizure types and should not be avoided in patients with generalized onset, juvenile myoclonic, and absence seizures.
Carbamazepine and phenytoin are medications that are indicated for generalized seizures even though they can worsen the symptoms. This should be determined patient by patient.
Carbamazepine is a potent inducer and autoinducer, which is why it can take up to 28 days to reach a steady state.
Carbamazepine reduces estrogen potency.
Common ADRs: Hyponatremia and rash.
Longterm ADRs: Osteoporosis, agranulocytosis
Caution is used in patients of Asian descent and must check for the HLA-B*1502 allele.
This medication is teratogenic.
Helpful in migraine or bipolar disorder
Ethosuximide (T-type calcium inhibition) – mono/adjunct
This is the drug of choice in the absence seizure.
It can worsen other seizure types, especially mixed epilepsy.
It is used most often in kids and can cause behavioral changes with long-term use.
Ethosuximide is a CYP3A4 substrate.
Phenobarbital, Primidone (GABA-A potentiator)
Phenobarbital is a class IV controlled substance that is so old that it has no FDA approval.
Both phenobarbital and primidone are used in focal and generalized seizures.
Primidone is used in essential tremor.
They can worsen other seizure types, such as absence and myoclonic seizures.
They have A LOT of drug interactions and also are potent inducers of everything.
They also lower estrogen potency.
ADRs: paroxysmal irritability, connective tissue disorders, anemia, osteoporosis.
These agents are used worldwide, but tolerance and dependence can occur. Taper slowly.
Phenytoin (Na channel inactivation) – mono/adjunct
Phenytoin is used for focal onset seizures.
It may worsen generalized onset, JME, and absence seizures.
Phenytoin is a potent inducer, highly protein-bound, with non-linear pharmacokinetics.
It also lowers estrogen potency.
ADRs: insomnia, hair loss, neuropathy, blood dyscrasia, gingival hyperplasia, and osteoporosis.
It is available as fosphenytoin, which can be loaded in patients with significant seizure activity who need a fast serum level. Fosphenytoin is a prodrug.
Phenytoin can be done once daily as ER formulation.
Valproic Acid (GABA potentiate) – mono/adjunct
VPA is a broad-spectrum ASM that can be used in any seizure type, but it is indicated for both focal and generalized.
It is by far the most effective and useful drug that we have.
VPA is a potent inhibitor and highly protein-bound.
Estrogen can LOWER the serum level of VPA.
ADRs: weight gain, PCOS, osteoporosis, and blood dyscrasias.
VPA is also useful in bipolar and migraine. It can be rapidly dosed with IV or orally.
It is the most teratogenic medication.
ALL first-generation ASMs have narrow therapeutic index. Because of this, all of them need serum monitoring. The main purpose of this is to prevent toxicity. This monitoring can be used to guide therapy, but not to be used alone to justify dose adjustment. We must consider the patient’s symptoms as well. If the seizure is well-controlled, there may be no reason to adjust the dose.
Second-Generation ASMs
Second-generation ASMs are first-line for most epilepsies.
Lamotrigine (Na channel inactivation) – mono for focal/adjunct for generalized
Lamotrigine is a broad-spectrum ASM that is used as monotherapy for many epilepsies off-label.
Lamotrigine needs to be titrated slowly. The dose needs to be reduced by 50% with administered with VPA, and increased by 50% if given with carbamazepine, phenytoin, and phenobarbital.
Like VPA, the serum concentration of lamotrigine is lowered by estrogen.
ADRs: tremor, GI, rash
The extended-release can be dosed once daily.
Levetiracetam (T-type SV2-A Ca channel) – adjunct
Levetiracetam is a broad-spectrum ASM and is often used as monotherapy off-label.
It is renally eliminated, but must still be adjusted in renal impairment.
It has minimal drug interaction.
ADR: CNS effects, anxiety, anger, emotional lability, and psychosis (rare)
Levetiracetam used to be marketed as a miracle drug, but psychiatric ADRs are becoming more and more recognized and more common than previously thought. Careful with comorbid psychiatric disorders.
This medication may be loaded rapidly both IV and orally.
Oxcarbazepine (Na channel inactivation) – Mono/adjunct
This is an analog of carbamazepine, but there is no autoinduction. This means that there are not as many drug-drug interactions.
This medication is used in focal onset seizures.
It may worsen JME or absence.
Like carbamazepine, it may decrease estrogen potency.
Like carbamazepine, it has a high risk of hyponatremia, even higher than carbamazepine.
Patients of Asian descent should be genetically screened prior to use.
Topiramate (Na channel inactivation, carbonic anhydrase, GABAnergic, and AMPA antagonism) – mono/adjunct
This is a broad-spectrum ASMs, but it is NOT the first-line agent due to the many drug-drug interactions. Topiramate can be used in LGS, JME, absence, and Dravet.
It is an inducer and substrate of CYP3A4.
It may decrease estrogen potency.
It’s lovingly referred to as ‘DOPAMAX’ due to the number of ADRs, which are CNS effects, cognitive clouding, trouble speaking, trouble to find words, paresthesias, renal stone, glaucoma, anxiety, nervousness, and hepatotoxicity.
Topiramate can be helpful in comorbid migraine or obesity.
Cognitive effects are more common with rapid titration.
Topiramate is also teratogenic.
Zonisamide (Na channel inactivation and carbonic anhydrase inhibitor) – Adjunct
Zonisamide is very similar to topiramate but has fewer ADRs than topiramate.
It is only indicated for focal onset seizure as an adjunct.
ADRs: CNS effects, sedation, cognitive slowing, renal stones, rash, blood dyscrasias.
Zonisamide has a sulfa moiety, which is why it is contraindicated in sulfa allergy.
This medication has one of the longest half-lives and is dosed once daily.
Gabapentin (Ca channel) – adjunct
Gabapentin is weakly efficacious and only indicated as adjunctive for focal onset.
This medication can worsen generalized onset seizures.
This medication must be dose-adjusted in renal impairment.
Gabapentin is also used for post-herpetic neuralgia, chronic pain, and neuropathy.
Tiagabine (GABA reuptake inhibitor) – Adjunct
This medication is not commonly seen except in patients with refractory epilepsy that requires further control.
It is indicated as adjunctive for focal onset.
This medication may worsen generalized onset seizures and may cause status epilepticus.
It may cause long-term ophthalmologic effects.
Felbamate (NMDA antagonism)
This is broad-spectrum ASM indicated in most seizure types, but it is used only in severe refractory epilepsy.
This is because it can cause fatal irreversible aplastic anemia and liver failure (BBW). Patients must sign a contract prior to taking this medication.
Third-Generation ASMs
Many of these agents are controlled substances and brand-name only.
Focal Onset Seizures
Brivaracetam (Briviact – CV – SV2a Ca channel) – Mono/adjunct. Unlike levetiracetam, it is not renally eliminated. It is used when the patient doesn’t tolerate levetiracetam.
Cenobamate (Xcopri – Na channel inactivation and GABA-A modulator) – Mono/adjunct. It has a weird QT interval and memory effect. It must be slowly titrated like lamotrigine due to rash.
Eslicarbazepine (Aptiom – Na ch inactivation) – Mono/adjunct. This is another analog of carbamazepine with fewer ADRs and is better tolerated than oxcarbazepine. It is renally eliminated. It is dosed once daily.
Lacosamide (Vimpat – C-V – Na ch inactivation) – Mono/adjunct. This should be dose adjusted in both renal and hepatic impairments. Avoid in heart block/cardiac conduction abnormalities.
Perampanel (Fycompa – CIII – AMPA antagonism) – Mono for focal, adjunct for generalized. It is a substance, inducer, and highly protein bound. It can worsen estrogen potency. It has a BBW for aggression – avoid in active psychosis. Dosed once daily.
Pregabalin (Lyrica – CV – calcium channels) – Adjunct. It is renally eliminated.
Epilepsy Syndromes
Clobazam (BZD) – Adjunct for LGS. It is less sedating than other BZD. It shouldn’t be used alone due to ADR.
Stiripentol (GABA-A receptor) – Adjunctive with clobazam for Dravet. This medication increases the clobazam effect by increasing clobazam’s concentration. The is a risk of neutropenia and thrombocytopenia.
Cannabidiol (unknown MoA) – Mono/Adjunct for LGS and Dravet. It is metabolized through the liver and has a lot of drug-drug interactions.
Rufinamide (Na ch inactivation) – Adjunct for LGS. This medication has complex pharmacokinetics and is contraindicated in severe liver impairment. Do NOT use in short QT syndrome. It reduces estrogen potency.
Fenfluramine (5-HT2 agonist) – Mono for LGS and Dravet (refractory). It has a BBW for valvular heart disease and pulmonary hypertension.
Vigabatrin (GABA transaminase inhibition) – Mono for infantile spasms. It medication is only to be used if the benefits outweigh the risks. This medication may worsen absence or JME. There is a REM program for permanent vision loss (monitor every 3 months).
Epilepsy Therapeutic Process
The treatment is initiated at an appropriate starting dose. The medication is, then, titrated over a few weeks. A loading dose is sometimes used if needed.
The optimal dose is based on response and the patient’s tolerability.
Mono-therapy should be the goal, but patient management is the most important. 65% of the patient will achieve control with monotherapy.
10% of the 35% monotherapy failure will respond to polytherapy and 20% will have unsatisfactory control, which is when we look toward non-pharmacologic treatments.
Medication-resistant epilepsy is when a trial of 2 medications, either monotherapy or polytherapy, fails to achieve adequate control.
In monitoring the treatment, it is important to know that non-adherence is the most common reason for treatment failure.
ASMs can be stopped if patients are seizure-free for several years and if the patients only have a single type of seizure with a low risk of recurrence. Most patients are on ASMs long-term.
Pregnancy
Any ASMs can present a risk during pregnancy with neural tube defects, which is why patients should take a folic supplement to prevent neural tube defects until after giving birth.
Remember that VPA has the highest risk for birth defects.
Status Epilepticus
Status epilepticus is a prolonged seizure (longer than 5 minutes or repeated seizures with no return to clinical baseline). The longer a seizure lasts, the less likely it is to stop.
It is also associated with irreversible brain damage.
It is further classified into generalized convulsive status epilepticus (GCSE) and nonconvulsive status epilepticus (NCSE).
GCSE looks like a seizure, and NCSE has no physical symptoms, but the brain is going through a seizure. Patients with NCSE generally are unconscious and non-responsive.
The course of treatment approach starts with how long they’ve been seizing, then emergent treatment, then urgent control, and then AMS or refractory treatment.
The first step: stabilize the patients.
- Don’t stick something in their mouth
- Get them in an area that is safe for thrashing
- Oxygenation
- EEG
- Basic labs
- IV access
This is where you also try to identify a secondary reason if there is one, such as a glucose stick.
Thiamine and dextrose are also important.
These patients will be admitted to the ICU.
The second step: Initial therapy
This is where you give them a dose of a benzodiazepine (lorazepam, diazepam, midazolam). A second dose may be given after 5-10 minutes if there is no improvement.
The third step: a control therapy
Once the patient is stabilized, a loading dose of ASM (fosphenytoin VPA, levetiracetam) is given to continue seizure control. If there is a response, continue doing ASM normally. If there is no response, you can consider a second dose. If still no response, continue with refractory treatment.
The fourth step: a refractory therapy
This is a full pharmacologic coma where the patient is on a continuous IV drip of benzodiazepine and ASM. The goal is the shut the brain off completely to restart the brain circuit over.
There is a lot less evidence guiding this treatment.
The fifth step: Post-Ictal Recovery
Most patients will recover responsiveness within 10-20 minutes. Upon recovery, the patient should get a full neurologic assessment because many complications can occur during this process, such as neurologic and cognitive defects. Most patients develop epilepsy if they don’t have the diagnosis already.