The mainstay treatment strategy for seizures is medication management. However, much like the prescription of any other pharmaceutical agent, a clinician must balance efficacy with adverse events, and provide consideration for cost, drug interactions, patient preference, and availability. This article is intended to provide a general overview of seizure medications and the current knowledge base for optimal utilization.
The American Academy of Neurology (AAN) and the American Epilepsy Society offered recent guidelines on initiation of seizure medications after a first unprovoked seizure in an adult. The focus is predominantly on an individualized approach, with patient autonomy at the forefront. Before making any decisions, factors that may increase risk should be identified and include abnormal brain imaging, abnormal EEG, and the presence of nocturnal seizures. Patients should understand that the risk of recurrence is greatest within the first 2 years (21% to 45%) and that this risk may be mitigated with the initiation of medications. However, adverse events of anti-seizure medications, though most frequently mild and reversible, should be reviewed and discussed in detail.
Of note, certain seizure medications have been used off-label for a variety of other indications including but not limited to:
Anti-epileptic drugs (AEDs) are numerous, with different mechanisms of action, and some AED's with multiple mechanisms of action.
Some AEDs act on the sodium channels by either blocking their repetitive activation (phenytoin, carbamazepine) or by enhancing their slow inactivation (lacosamide). Others work on calcium channels by blocking either T-calcium channels (ethosuximide, valproic acid) or the N and L calcium channels (zonisamide). Lamotrigine works by blocking sodium channels, N and L calcium channel, and modulating H-current. Topiramate works by blocking sodium channels, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, and by inhibiting carbonic anhydrase. Other mechanisms through which AEDs act are by enhancing gamma-aminobutyric acid (GABA)–A receptors (phenobarbital, benzodiazepines), blocking N -methyl-D-aspartic acid (NMDA) receptors (felbamate), and opening neuronal potassium channels (ezogabine).
After the diagnosis of epilepsy, choosing of an AED is largely dependent on the classification of the seizure type. In the most general sense, seizures can be classified as either partial or generalized. Partial seizures can be further broken down into those that do not affect awareness (simple partial) or those that do (complex partial).
Simple partial seizures affect focal areas of the brain that, in turn, cause focal neurological findings like loss of motor function in one limb, sensory dysfunction in a specific body region, or changes to vision or speech, without affecting awareness of the event. Complex partial seizures are similar but do include brief moments of confusion that quickly resolve once the seizure has ended.
Generalized seizures affect the entire body and can exist as tonic-clonic seizures (where muscles stiffen initially, which is followed by jerking and spasming of the body), absence seizures (where individuals may stare off into space, and there is a brief lapse in awareness, often confused with daydreaming), and atonic seizures (where there is a sudden loss of muscle tone, frequently resulting in falls).
The International League Against Epilepsy recommends that epilepsy be diagnosed when any of the following exist: a history of two unprovoked seizures at least 24 hours apart, or an unprovoked seizure when the risk for a subsequent seizure is greater than 60% after two unproved seizures over the subsequent 10 years, or seizures that are part of an epilepsy syndrome.
Initiation of Antiepileptic Drugs
AEDs can be broken down into two categories: broad-spectrum and narrow-spectrum. Broad-spectrum AEDs treat a wide variety of seizure types, as the name suggests, and are a good initial choice, especially when the classification of seizure type is uncertain. These AEDs include but are not limited to levetiracetam, lamotrigine, zonisamide, topiramate, valproic acid, clonazepam, perampanel, clobazam, and rufinamide.
Narrow spectrum AEDs primarily are for the treatment of focal or partial seizures. These include but are not limited to lacosamide, pregabalin, gabapentin, carbamazepine, oxcarbazepine, ezogabine, phenytoin, and vigabatrin.
Monotherapy is the ideal pathway for the treatment of seizures, but newer AEDs have had difficulty obtaining FDA approval as a monotherapy agent due to the difficulty of achieving approval requirements. However, anecdotally, and by examining the current evidence base, second-generation AEDs appear to be an appropriate choice, as they have demonstrated similar efficacy when compared to older AEDs and may be better tolerated.
One large randomized trial, the Standard and New Antiepileptic Drugs (SANAD) trial, demonstrated some comparative advantages of certain AEDs when treating focal or generalized epilepsy. In the end, when comparing valproate, lamotrigine, or topiramate for generalized seizures, they recommended valproic acid as their first line choice. Additionally, when comparing carbamazepine, gabapentin, lamotrigine, oxcarbazepine, and topiramate for focal seizures, lamotrigine was cited as the first line choice.
Of note, regarding partial onset seizures specifically, perampanel, lacosamide, brivaracetam, and eslicarbazepine acetate are a few of the recently FDA-approved seizure medications for monotherapy.
When to discontinue AEDs is less clear. In children, consensus recommendations appear to be after two years of remaining seizure free. However, in adults, some research has estimated the risk of seizure recurrence immediately after cessation of AEDs at the 2-year mark at 30%. The risk appears to diminish with time if an individual continues without further seizures. Taking this into account, it is apparent why guidelines in adults are more conservative and recommend a seizure-free period of 2 to 5 years while advising against driving for three months after AED cessation.
Patients should be taught that adverse events with anti-seizure medications, according to the AAN, may range from 7% to 31%, but are mostly mild and reversible. In general, it is important to review the specific medication insert for a complete list of adverse events.
Of the more mild and common side effects, patients should be advised to monitor for headaches, fatigue, dizziness, blurry vision, nausea, weight gain or loss, mood disorders and neurocognitive problems. The potential for allergic reactions is present amongst all medications and should be monitored with initiation.
With chronic use, many AEDs carries a side effect of osteoporosis, and general recommendations are to supplement diets with calcium and vitamin D, as well as to encourage routine exercise habits.
Of the more serious side effects, Stevens-Johnson syndrome, agranulocytosis, aplastic anemia, hepatic failure, pancytopenia, multiorgan hypersensitivity, psychosis, and lupus syndrome have all been reported. Although the risk for suicidality is low, the FDA has required all AEDs to carry a suicide warning.
Also of concern are drug-drug interactions, which occur most commonly with the older generation of AED’s, as they can affect hepatic enzymes. If these hepatic enzymes are induced, it can lead to rapid metabolism of other medications, potentially leading to their subtherapeutic levels in the body. If, on the other hand, hepatic enzymes are inhibited, toxic levels of medications can be reached due to impaired breakdown through the liver.
Both are inducing and inhibiting medications can raise significant concern when managing certain comorbid conditions where therapeutic doses of medications are of the utmost importance, including HIV, cancer, endocrine disorders, and cardiovascular disease.
A contraindication to most medications, in general, is a prior history of hypersensitivity or allergic reaction to that medication. Other contraindications exist but are more drug-specific, including hepatic failure, certain blood diseases, narrow-angle glaucoma, and familial short QT syndrome to name a few.
Valproic acid and felbamate are associated with hepatotoxicity, and therefore, contraindicated in patients with hepatic failure. The liver metabolizes many others, and dosage adjustments need to be made before initiation.
Similarly, those with renal impairments need to adjust dosing with AEDs excreted by the kidneys, primarily by using the glomerular filtration rate. Hemodialysis also may require dosing adjustment to ensure the medication remains in the respective therapeutic range.
Likewise, because of variability in metabolism and excretion rates, caution must be exercised in children and the elderly.
While in pregnancy, guidelines proffered by the American Academy of Neurology in 2009 report that women should remain on their current AED, as switching medications increase the risk of breakthrough seizure, and adding another AED increases the risk of congenital disabilities. Folic acid should be supplemented for any woman of childbearing age, and especially those considering becoming pregnant. If possible, optimization of the medication regimen, by identifying the lowest effective dose with the least amount of medications, is ideal. Women who experience their first seizure during pregnancy should follow the same management strategy as if she was not pregnant.
Through the duration of the pregnancy, serum drug levels should regularly be monitored, and dosages titrated or adjusted to within therapeutic ranges.
Unfortunately, there is insufficient research into comparative efficacy and teratogenicity for recommendations of specific AEDs in pregnancy. However, valproic acid deserves special mention as it is contraindicated in pregnancy due to consistent evidence of teratogenicity, including dose-dependent effects on IQ, adaptive functioning, increased risk of ADHD, and increased risk of major congenital malformations.
As benefits are believed to outweigh risks, the consensus remains that AEDs can continue to be taken while breastfeeding. However, measurable levels can be found in breastmilk, and available research has not determined what risk this poses to newborns.
Once administered, monitoring of serum medication levels is recommended to establish a therapeutic baseline and assess for toxicity. If the patient remains stable, these levels can be checked yearly, along with a complete blood count, a comprehensive metabolic panel, and liver function testing.
Toxic symptoms in AEDs are idiosyncratic and are believed to occur more frequently in the first-generation AEDs. One such example is carbamazepine, a commonly implicated first-generation AED in acute or chronic toxicity. Possible symptoms may include ataxia, dystonia, sinus tachycardia, hyperthermia, coma, arrhythmias, respiratory depression, and death. Another example is valproic acid, which can have toxic effects that include metabolic and hematological disruption, pancreatitis, central nervous system (CNS) depression, optic nerve atrophy, respiratory depression, cardiopulmonary arrest, brain edema, and coma.
Treatment can range from supportive measures to high-flow hemodialysis, plasmapheresis, or charcoal hemoperfusion.
Patients should be educated before initiating any AED to alert treating physicians when adverse events are encountered. It is also important to note that therapeutic reference ranges are considered guidelines, and levels outside of the range do not necessarily indicate toxicity or a need to adjust dosing. However, if clinical picture correlates with elevated serum drug levels, then, indeed, treatment is warranted.
Once a patient has been started on anti-seizure medications, education of the patient is vital. Both the nurse and pharmacist should educate the patient on adherence on medication compliance. Further, the injury is not uncommon during a seizure, and the family has to be educated about seizure precautions. Patients with a diagnosis of seizures should not undertake unsupervised activities in the water or work at heights. Depending on the frequency of seizures, some patients may not be allowed to drive. Because most anti-seizure medications have side effects, the patient must be told to follow up with the primary caregiver and be monitored closely. Finally, patients should be cautioned against changing the dose frequency or timing, without first speaking to the healthcare provider. (Level V)
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