By David King-Stephens, M.D.
Epilepsy, the neurological disorder characterized by recurrent, unprovoked seizures, is the third most common neurological disorder reported around the world. The sudden and unpredictable nature of seizures is one of the most disabling aspects of the disease. It may be associated with other neurological symptoms, such as mood or cognitive deficits, and results in severe psychosocial limitations.
Epilepsy is a heterogeneous disorder with diverse syndromes and etiologies that include structural abnormalities (e.g., stroke, tumors, malformations of cortical development, etc.), functional abnormalities (involving ion channels, as in autosomal dominant frontal lobe epilepsy due to an acetylcholine channelopathy) or a combination of both (familial temporal lobe epilepsy with audiogenic seizures). The behavioral characteristics of a seizure depend upon the location of the origin of the electrical abnormality and subsequent involvement of other structures. The different seizure types are classified according to whether they originate focally or in a generalized manner (Ref 1). Focal seizures may or may not involve alteration of consciousness or have secondary generalization. Generalized-onset seizures include primary generalized tonic–clonic, myoclonic, atonic, and absence.
In approximately 80% of the patients with newly diagnosed epilepsy, the cause of the epilepsy is identified by a neuroimaging study (secondary of symptomatic epilepsies) or EEG studies (primary generalized or genetic types of epilepsy). Most symptomatic epilepsies present with partial (or focal) onset seizures, while primary generalized epilepsies present with generalized onset seizures, such as myoclonus or absence seizures. The main type of treatment, aimed at preventing seizure recurrence, is with antiepileptic drugs (AED). Given the multiple causes of epilepsy, with different mechanisms of epileptogenesis, medications with different mechanisms of action are required to treat the different epileptic syndromes (Ref 2)
Classification of AEDs
Seventeen AEDs are currently approved in the U.S. These medications can be classified into different groups, as well as categorized into two groups depending on their spectrum of action: narrow spectrum, those that help to prevent the onset of partial-onset seizures, and broad-spectrum AEDs, which can help prevent both partial and generalized onset seizures. This classification is important in terms of the implications for treatment as narrow-spectrum anticonvulsant medications, such as phenytoin or carbamazepine, can exacerbate generalized-onset seizures, while certain pharmaco-resistant syndromes (that usually, but not exclusively, involve focal-onset seizures) may be amenable to surgical resection or therapy with neurostimulation (see Dr. Peter Weber’s article).
AEDs can also be classified according to the date when they were approved by the Food and Drug Administration to be marketed: The first generation of AEDs (four compounds) were approved before 1976 and the second generation (13 compounds) after 1990. Most broad-spectrum AEDs belong to the later generation.
A third way of classifying AEDs is by their mechanism(s) of action. Most compounds modulate voltage-gated ion channels, such as the sodium channel (thereby reducing excitatory synaptic function), or enhance the action of GABA (thereby increasing inhibitory synaptic function).
Differences Between the Different Classes of AEDs
In terms of efficacy, there are no convincing data showing significant differences in efficacy, when matching the appropriate AED for the appropriate seizure type3. But in terms of safety and tolerability, some of the second-generation AEDs do show significant benefits (Ref 4). Specifically, the pharmacokinetic properties (such as fewer drug-drug interactions) tend to be more desirable and there are lower probabilities of inducing end-organ toxicity (such as bone demineralization (Ref 5)) with some of the newer AEDs. In terms of tolerability, some of the newer compounds have lower rates of dizziness, diplopia, or other central nervous system side effects, including cognitive and behavioral problems (Ref 6).
Matching the AED to the Patient
When considering which AED to prescribe when managing a newly diagnosed patient with epilepsy, several considerations enter the equation. Foremost is the seizure or seizures type. As mentioned previously, narrow-spectrum AEDs might exacerbate generalized onset seizures. Secondly, gender, age, the presence of comorbidities, presence of polytherapy, and history of adverse effects are factors that need to be considered when initiating treatment with an AED.
In the case of women of childbearing potential, who will continue taking the AED during pregnancy, medications such as lamotrigine or carbamazepine do not increase the risk of fetal malformations when compared to pregnant women without epilepsy, while valproate or phenobarbital have a very high potential for inducing major malformations and neurodevelopmental delay (Ref 7, 8).
With respect to age, elderly patients tend to use polytherapy for treatment of comorbidities and therefore AEDs with few or no drug-drug interactions, such as levetiracetam or pregabalin, are desirable compared to AEDs with strong hepatic enzyme induction or inhibition, such as carbamazepine or valproate, respectively. In the case of comorbidities, such as cognitive problems or developmental delay, some AEDs tend to be associated with fewer cognitive side effects, such as levetiracetam or lacosamide, than medications such as phenobarbital, phenytoin, or pregabalin. In the case of psychiatric comorbidities (such as mood and anxiety disorders, which are present in up to 70% of patients with epilepsy), certain AEDs tend to be associated with negative effects, such as phenobarbital, topiramate, or levetiracetam, while lamotrigine and carbamazepine can have beneficial effects.
In patients with migraine, which is estimated to be increased fourfold in epilepsy patients when compared to the general population, topiramate and gabapentin might be the preferred AEDs due to their beneficial effects on headache. And in the case of patients with osteoporosis, medications such as phenytoin, carbamazepine, and valproate have shown to accelerate bone loss, while medications such as levetiracetam or lacosamide have not shown this toxicity. Finally, if a patient has a history of skin idiosyncratic reactions, AEDs such as lamotrigine, carbamazepine, and phenytoin might not be considered as the first choice for initiating treatment, given their high association with rash, and rather levetiracetam, pregabalin, or lacosamide might be a better choice.
Branded vs. Generic Formulations
Finally, given the potential differences in bioavailability between branded and generic formulations, which can range between 80% and 125% of the reference compound (with respect to the 90 confidence interval of the rations of the AUC, Cmax and Tmax) as per FDA guidelines (Ref 9, 10) , the American Academy of Neurology (Ref 11) and American Epilepsy Society recommend avoiding substituting between the different formulations.
It is now possible to better customize the treatment of epilepsy given the multiple AEDs available. For most newly diagnosed patients, the newer generation of AEDs seem to be the better choice given their safety, tolerability, and improved pharmacokinetic properties when compared to the older AEDs. Important factors to consider when deciding which AED to prescribe include seizure type, age, gender, presence of comorbidities, and type of formulation.
- Commission on Classification and Terminology of the International League Against Epilepsy (1989) Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 30: 389-99.
- King-Stephens, D. “Epilepsy: Anatomy, Physiology, Pathophysiology and Disorders.” Neuromodulation. Krames ES, Peckham PH, Rezai AR, Eds. Elsevier, London, England 2009: 619-624.
- Kwan P, et al. New England Journal of Medicine. 2000;342:314-9.
- Cloyd JC, et al. Pharmacotherapy. 2000;20:139S-151S.
- Pack A, et al. Neurology. 2003;60:A432.
- Brodie MJ, et al. Lancet. 2000;356:323-9.
- Meador K, et al, Neurology. 2006;67:407-12.
- Meador K, International Review on Neurobiology.
- Meyer MC. J Clin Psychiatry. 2001;62(Suppl 5):4-9.
- www.fda.gov/cder.orange/obannual, 2007.
- Neurology. 1990;40:1647-1651.
California Pacific Medical Center
- Neuroscience Institute Epilepsy Program -
Diagnosis, Medical Management, Epilepsy Surgery
San Francisco | Marin | San Mateo | San Francisco Bay Area