Optimal use of antiepileptic drugs (AEDs) is one of the most challenging tasks in clinical neurology because the epilepsies are exceedingly heterogeneous as to etiology, natural history, and response to treatment. It is an advantage that many different agents are available, but this makes the clinician’s task of choosing and using these drugs more complex. A rational, stepwise approach is required.

When to start AEDs

After a first seizure, the decision to initiate medications is based on the risk of future seizures. This risk depends on the circumstances of the seizure and the results of diagnostic testing (Chapter 4). The 10-year risk of a subsequent spontaneous seizure is 19% after an acute symptomatic seizure due to traumatic brain injury, stroke, or CNS infection, but the risk is more than three times higher after a first spontaneous unprovoked seizure. Among those with a first unprovoked seizure, predictors of a higher risk of recurrence are evidence of a possible causal neurological condition (remote symptomatic seizure), status epilepticus, or generalized spike-and-wave activity on EEG. Risk of recurrence is even higher after multiple seizures, with about 75% of those with two or three unprovoked seizures having further seizures within 4 years. The most common approach is not to start long-term AEDs after acute symptomatic seizures or a single unprovoked seizure in patients without status epilepticus and with normal MRI and EEG, but to do so after a remote symptomatic seizure or any recurrent unprovoked seizures.

Choosing the AED

If AEDs are prescribed, the goal is a medication that is rapidly effective and without adverse effects, although this certainly cannot always be achieved in the initial medication trial. Available agents and their indications are given in Table 19.1 of Chapter 19.

TIPS AND TRICKS

There are two key steps to choosing an AED to initiate:

1. Assembling a list of agents with the highest probability of efficacy for the patient’s epilepsy syndrome

2. Choosing the safest agent on this list with the lowest chance of adverse effects concerning for the patient’s situation and medical comorbidity

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Table 11.1. The author’s suggested lists of preferred AEDs for focal and generalized epilepsy, current in 2014.

^aFDA approved specifically for monotherapy in at least some situations.

^bFDA approved for at least some seizure types in generalized epilepsy.

Identifying potentially effective agents

The list of possibly effective AEDs is determined by the epilepsy syndrome. It is important to determine whether the patient has a focal epilepsy, with focal seizures and secondarily generalized convulsions, or a generalized epilepsy, with seizures that are bilateral (generalized) at their onset, such as absence, myoclonic, and some generalized convulsions. This distinction is important primarily because certain AEDs are known to exacerbate some generalized seizure types, especially myoclonic or absence seizures, and so are typically avoided in generalized epilepsy. This phenomenon is best documented for carbamazepine, oxcarbazepine, gabapentin, pregabalin, tiagabine, and, in occasional cases, lamotrigine and phenytoin. There is inadequate information on use in generalized epilepsy of the most recently released agents – lacosamide, ezogabine, and perampanel. On the other hand, there is evidence from a randomized study that valproate may be less effective than carbamazepine for complex partial seizures. These points, taken together with safety and adverse effect considerations, lead to preferred (but not exhaustive) lists of AEDs for focal and generalized epilepsy available at the time of publication of this book (Table 11.1). The most recently approved agents, ezogabine and perampanel, are not included, as their role in clinical practice is still being determined. It should be noted that the US FDA has not specifically approved the generalized epilepsy indication for many AEDs. Also, many agents commonly used in monotherapy are not specifically FDA approved for this purpose, although older agents may be “grandfathered in.”

Treatment differs in special pediatric syndromes and situations. The most common initial agent for neonatal seizures is phenobarbital (Chapter 20), while infantile spasms in West syndrome are often treated with ACTH, high-dose corticosteroids, or vigabatrin (Chapter 21). Lennox–Gastaut syndrome is most commonly treated with valproate, lamotrigine, topiramate, rufinamide, clobazam, or felbamate (Chapter 21).

Comparing efficacy

Table 11.1 is based on clinical experience and opinion, but is there objective evidence that individual agents from the lists in Table 11.1 are more effective? Because of the difficulty and expense of designing and carrying out meaningful blinded randomized controlled trials comparing efficacy, level 1 evidence is sparse. Two VA cooperative studies found carbamazepine and phenytoin more effective than pyrimidine and phenobarbital, likely due to tolerance issues, and carbamazepine more effective than valproate for controlling complex partial seizures. The combined results of several randomized trials comparing carbamazepine and lamotrigine suggest that lamotrigine is better tolerated but similar in efficacy. A recent prospective trial comparing valproate, lamotrigine, and ethosuximide for new-onset childhood absence epilepsy demonstrated that lamotrigine is less efficacious than the other two but that ethosuximide is better tolerated than valproate. Therefore, in most situations, the choice among medications on the lists in Table 11.1 will not be based on comparative efficacy, but on other issues.

Safety and adverse effect concerns determine the final choice

Safety (Chapter 12) trumps all other concerns. Since felbamate is associated with risk of aplastic anemia or liver failure and vigabatrin with irreversible retinopathy, these agents are at the bottom of the medication choice list. Recently, an association between chronic ezogabine exposure and blue discoloration of lips, nail beds, and skin, as well as retinal pigmentary changes, has also been reported. The most common safety issue with AEDs is allergy (Table 11.2). Lamotrigine, carbamazepine, phenytoin, and phenobarbital are agents associated with higher risk of allergy, and a history of allergy to one of these increases the risk of a reaction to the others. Patients with a history of sulfa allergy may be at higher risk of allergy to zonisamide. Rapid introduction of lamotrigine and phenytoin has been demonstrated to increase the risk of allergic reaction. Possible allergic reactions to AEDs include maculopapular eruption and hypersensitivity syndrome, defined as a rash accompanied by multiorgan involvement, such as hepatitis and nephritis, fever, and arthralgias. The most serious reactions are Stevens–Johnson syndrome and toxic epidermal necrolysis, which are characterized by a blistering exanthema with mucosal involvement and skin detachment and have potential mortality.

Table 11.2. Choice of AEDs as a function of comorbidity and circumstances.

^aFDA approved for treatment of listed comorbidity.

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Ketogenic Diet and Alternative Therapies Accidents in Epilepsy Mortality in Epilepsy Epilepsy: When to Perform a Genetic Analysis Benign and Malignant Childhood Epilepsies Seizures in the Neonate

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