Adjunctive Therapies for Drug-Resistant Focal-Onset Epilepsy

Madeline C. Fields, MD
Icahn School of Medicine at Mount Sinai, New York
Lara V. Marcuse, MD
Icahn School of Medicine at Mount Sinai, New York

Key Takeaways

  • Approximately 30% of patients with epilepsy continue to have seizures despite trials of 2 appropriate antiseizure medications, alone or combined.
  • Side effects may be compounded with the combined use of antiseizure medications with similar mechanisms of action.
  • Antiseizure medications may have paradoxical effects in children vs adults.
  • Patients with drug-resistant focal-onset seizures should be referred for evaluation at a level 3 or level 4 epilepsy center accredited by the National Association of Epilepsy Centers.
  • Given the occurrence of breakthrough seizures in patients with drug-resistant focal-onset seizures, every patient should have an individualized emergency seizure plan.
  • The range of approved antiseizure medications indicated as adjunctive treatment for the management of refractory focal-onset seizures has expanded significantly and aims to improve safety and tolerability while improving seizure control.

Madeline C. Fields, MD, and Lara V. Marcuse, MD, are co-directors of the Mount Sinai Epilepsy Program at the Icahn School of Medicine at Mount Sinai in New York, New York. Along with her primary clinical focus on the medical and surgical management of epilepsy, Dr Fields is interested in epilepsy in the context of conditions such as autism, dementia, and psychiatric disorders. Dr Marcuse’s areas of specialization include medication-resistant epilepsy, epilepsy procedures, pregnancy and epilepsy, post-traumatic epilepsy, the ketogenic diet, and the cognitive effects of epilepsy.

A post-hoc analysis involving adults with focal-onset seizures found that specific antiseizure medication combinations could increase the frequency of adverse events. Results also found that eslicarbazepine had fewer interactions with lamotrigine compared with carbamazepine.1 Can you comment on your experience with antiseizure medication combinations and controlling focal-onset seizures?

Dr Fields: After a patient has been diagnosed with focal-onset seizures, the first medication prescribed typically controls seizures approximately 50% of the time.2 If the patient continues to have seizures despite being on a therapeutic dose of 1 antiseizure medication, adding a second medication has been shown to control seizures nearly 70% of the time. Any patient who continues to have seizures despite trying 2 well-chosen antiseizure medications at appropriate doses, either alone or in combination, is considered to have drug-resistant epilepsy. Approximately 30% of people with epilepsy fall into this category.3
 
We have no fool-proof formula for what medication is going to be best for our patients with drug-resistant epilepsy. Taking a systematic and patient-focused approach is best. Also, before a medication is abandoned, we want to be sure it was given a fair trial at an appropriate dose so we will not have to return to it in the future.
 
Dr Marcuse: When adding a second antiseizure medication, we try to follow the theory of rational polytherapy by choosing adjunctive medications with different mechanisms of action. We do this with the hope that they will be more effective and lead to fewer side effects than being on 2 antiseizure medications with similar mechanisms of action. However, the evidence for rational polytherapy is quite thin!
 
We do know that we risk compounding side effects when medications with similar mechanisms of action are taken concomitantly. The study mentioned above examined 3 antiseizure medications — voltage-gated sodium channel inhibitors — with similar mechanisms of action. The mechanisms of action of eslicarbazepine and carbamazepine are so similarthat we were not surprised that patients on this combination risked having increased dizziness.

A long-term open-label extension trial found that patients experienced a 43.1% median reduction in focal seizure frequency from baseline and 43.6% of patients aged 16 years and older receiving brivaracetam as adjunctive therapy for focal-onset seizures experienced a response rate of at least a 50%.4 Additionally, an indirect treatment comparison study showed that both perampanel and brivaracetam are effective for the adjunctive treatment of focal-onset seizures in patients aged 12 years and older and had similar adverse event profiles.5 How do these findings align with results observed in your practice of treating those with treatment-resistant focal-onset seizures?

Dr Fields: Both of these medications, perampanel and brivaracetam, have been great additions to our armamentarium of medications. Brivaracetam seems to have less mood-destabilizing properties than some of our other medications and has a relatively quick titration period. Perampanel has a novel mechanism of action and can be used as a treatment for focal-onset seizures as well as for generalized epilepsy.
 
Our experience with these medications has been similar to the comparison study in that patients who do well on levetiracetam seem to do well on brivaracetam — albeit without as many mood side effects — but those on levetiracetam who are not well controlled similarly do not have much improvement when treated with brivaracetam. As this study points out, the similar mechanisms of action of brivaracetam and levetiracetam likely account for this. Despite perampanel’s black box warning of homicidal ideation, we have found that slowly increasing the dose tends to result in fewer side effects.

We have no fool-proof formula for what medication is going to be best for our patients with drug-resistant epilepsy. Taking a systematic and patient-focused approach is best.
Madeline C. Fields, MD

In a review, researchers concluded that levetiracetam may be a superior add-on treatment option in children with focal-onset seizures due to its favorable efficacy and low toxicity.6  However, a phase 3, randomized, double-blind, placebo-controlled study failed to demonstrate superiority of eslicarbazepine vs placebo as adjunctive therapy in children with refractory focal-onset seizures.7 What are some patient characteristics or risk factors that a clinician should consider prior to choosing an appropriate adjunctive therapy for children with focal-onset seizures?

Dr Fields: The first thing to consider is age. Some medications cannot be given to children younger than a certain age because of adverse effects. For example, valproic acid has a high risk of causing liver failure in children younger than 2 years of age and is contraindicated in this age group. There are so many causes of epilepsy in infants and children, and this can make it difficult to determine the best medication. Some epileptic conditions that affect children, such as Dravet syndrome, should not be treated with certain antiseizure medications like eslicarbazepine acetate.8
 
Dr Marcuse: In the pediatric population, sometimes there can be paradoxical effects with antiseizure medications. For example, phenobarbital can be sedating in adults but it can cause hyperactivity in children. In the first study mentioned above, levetiracetam did well when used as an adjunctive therapy for children with focal-onset seizures. Levetiracetam can cause mood irritability and instability so we sometimes avoid it in children who are already suffering from mood difficulty.
 
Regarding eslicarbazepine as adjunctive therapy, the second study noted above failed to show a statistically significant improvement in children older than 6 years of age using the primary endpoints. However, a post-hoc analysis did show improvement in standardized seizure frequency at the higher dose of 30 mg/kg per day.7 We believe that eslicarbazepine has a place in the treatment toolbox for this age group.

In an open-label, nonrandomized, 24-week study of adult patients with treatment-resistant focal-onset seizures receiving eslicarbazepine as a later adjunctive therapy, results demonstrated a 22.8% median reduction in standardized seizure frequency, at least 50% responder rate of 38.5%, and seizure freedom rate of 9.6%.9 Have you noted similar outcomes in your patients receiving eslicarbazepine as a later adjunctive therapy?

Dr Marcuse: Yes, we have experienced similar results. Eslicarbazepine can be given once a day which is very nice for patients who have a hard time taking medications twice a day.


Eslicarbazepine acetate adverse effects
Flip
Adverse effects commonly reported are dizziness, somnolence, nausea, headache, diplopia, vomiting, fatigue, vertigo, ataxia, blurred vision, and tremor.

How does timing of adjunctive antiseizure medication therapy (early initiation vs later initiation) influence antiseizure medication choice?

Dr Marcuse: The timing of the second antiseizure medication is not determined so much by us as physicians but by the patient’s epilepsy. Some patients have frequent seizures days to months apart and others have more sporadic seizures, months to years apart. Taking each patient’s care on a case-by-case basis and staying in close communication with the patient help determine the timing of adjunctive therapy.
 
Dr Fields: We typically try 1 antiseizure medication first, then check blood levels when possible to make sure it is therapeutic before adding additional medication. If a patient continues to have seizures despite therapeutic drug levels and compliance, then we may either replace the first medication or try a combination of 2 antiseizure medications. When trying 2 antiseizure medications, we try to follow the rational polytherapy concept mentioned above.

Can you briefly elaborate on some monitoring parameters and counseling points that health care providers should touch on following initiation of adjunctive therapy for patients with treatment-resistant focal-onset seizures?

Dr Marcuse: Health care providers should follow the individual guidelines for blood monitoring for each antiseizure medication. Some antiseizure medications such as levetiracetam have virtually no interactions with other medications and do not damage organs, so blood monitoring is not necessary. Other medications such as felbamate require frequent monitoring due to the risk of aplastic anemia. Frequent or “routine” antiseizure medication level checks are not required and may waste health care resources. At the same time, awareness of antiseizure medication levels are very useful in certain moments, like when a patient is in the emergency room with a breakthrough seizure and it is not clear if the seizure was caused by medication noncompliance or drug resistance. 
 
As health care providers, we have to anticipate life changes before they happen and this is particularly true with women of child-bearing age. In this group, it is important to prescribe folic acid and get patients on medications that are known to be safer in pregnancy — keeping in mind that many pregnancies are not planned.
 
For each antiseizure medication, the health care provider must educate their patients on common as well as rare but serious adverse events. We must counsel our patients on driving and seizure first aid and do frequent mood assessments, as our patients are at risk for anxiety and depression. This is also a population that has breakthrough seizures, so every patient should have an individualized emergency seizure plan.

Dr Fields: Health care providers should refer these patients to a level 3 or level 4 National Association of Epilepsy Centers (NAEC)-accredited epilepsy center for evaluation.10 Video-electroencephalogram (EEG) monitoring is an important diagnostic tool to characterize seizures and confirm that new event types are seizures and not psychogenic nonepileptic events.
 
Having more medication choices is wonderful, but patients who have drug-resistant focal-onset seizures should be considered for other interventions such as deep brain stimulation, responsive neuro-stimulation, resective surgery, and laser ablation. There is a barrier of stigma and fear regarding epilepsy — and particularly regarding epilepsy surgery. Evaluation at a level 4 NAEC-accredited center allows patients with epilepsy and their loved ones to be educated about all the appropriate options for them.

We must counsel our patients on driving and seizure first aid and do frequent mood assessments, as our patients are at risk for anxiety and depression. This is also a population that has breakthrough seizures, so every patient should have an individualized emergency seizure plan.
Lara V. Marcuse, MD

What questions would you like to see researchers investigate in future studies regarding later adjunctive therapies in this patient population?

Dr Marcuse: As experienced epileptologists, we want to do more than make educated guesses when picking the next antiseizure medication. We have all had patients for whom we finally get on a magic combination of medications, yet when we try that combination with another patient — even a patient with a similar type of epilepsy — the outcome does not replicate. We are hoping for an era of precision medicine in which the patient’s genetics, biochemistry, and/or epilepsy type can be used to select the next antiseizure medication.

The Q&A was edited for clarity and length.

Disclosure

Lara V. Marcuse, MD, reported an affiliation with NeuroPace, Inc.

References

1. Abou-Khalil B, Klein P, Shah A, et al. Tolerability of adjunctive eslicarbazepine acetate according to concomitant lamotrigine or carbamazepine use: a subgroup analysis of three phase III trials in adults with focal (partial-onset) seizures. Epilepsy Res. 2018;147:80-86. doi:10.1016/j.eplepsyres.2018.08.011
 
2. Goldenberg MM. Overview of drugs used for epilepsy and seizures: etiology, diagnosis, and treatment. P T. 2010;35(7):392-415.
 
3. Verrotti A, Tambucci R, Di Francesco L, et al. The role of polytherapy in the management of epilepsy: suggestions for rational antiepileptic drug selection. Expert Rev Neurother. 2020;20(2):167-173. doi:10.1080/14737175.2020.1707668
 
4. Ben-Menachem E, Baulac M, Hong SB, et al. Safety, tolerability, and efficacy of brivaracetam as adjunctive therapy in patients with focal seizures, generalized onset seizures, or Unverricht-Lundborg disease: an open-label, long-term follow-up trial. Epilepsy Res. 2021;170:106526. doi:10.1016/j.eplepsyres.2020.106526
 
5. Trinka E, Tsong W, Toupin S, et al. A systematic review and indirect treatment comparison of perampanel versus brivaracetam as adjunctive therapy in patients with focal-onset seizures with or without secondary generalization. Epilepsy Res. 2020;166:106403. doi:10.1016/j.eplepsyres.2020.106403
 
6. Cao Y, He X, Zhao L, et al. Efficacy and safety of Levetiracetam as adjunctive treatment in children with focal onset seizures: a systematic review and meta-analysis. Epilepsy Res. 2019;153:40-48. doi:10.1016/j.eplepsyres.2019.04.001
 
7. Kirkham F, Auvin S, Moreira J, et al. Efficacy and safety of eslicarbazepine acetate as adjunctive therapy for refractory focal-onset seizures in children: a double-blind, randomized, placebo-controlled, parallel-group, multicenter, phase-III clinical trial. Epilepsy Behav. 2020;105:106962. doi:10.1016/j.yebeh.2020.106962
 
8. Strzelczyk A, Schubert-Bast S. A practical guide to the treatment of Dravet syndrome with anti-seizure medication. CNS Drugs. 2022;36(3):217-237. doi:10.1007/s40263-022-00898-1
 
9. Hixson J, Gidal B, Pikalov A, et al; on behalf of the Study 701 Investigators. Efficacy and safety of eslicarbazepine acetate as a first or later adjunctive therapy in patients with focal seizures. Epilepsy Res. 2021;171:106561. doi:10.1016/j.eplepsyres.2021.106561
 
10. Ostendorf AP, Ahrens SM, Lado FA, et al. United States epilepsy center characteristics: a data analysis from the National Association of Epilepsy Centers. Neurology. 2022;98(5):e449-e458. doi:10.1212/WNL.0000000000013130

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Reviewed September 2022