What is the best treatment approach for patients with refractory epilepsy?

From the Guidelines

The best treatment approach for patients with refractory epilepsy involves treating seizures refractory to appropriately dosed benzodiazepines with a second-line agent, such as fosphenytoin, levetiracetam, or valproate, which have similar efficacy. This approach is based on the most recent and highest quality study available, which provides Level A recommendations for the management of adult patients presenting to the emergency department with seizures 1.

When considering treatment options for refractory epilepsy, it is essential to evaluate the patient's individual needs and circumstances. The treatment approach should be multifaceted, taking into account the patient's seizure type, epilepsy syndrome, comorbidities, and personal preferences.

Some key considerations in the treatment of refractory epilepsy include:

• Optimizing anti-seizure medications (ASMs) and considering trials of newer ASMs like brivaracetam, cenobamate, or perampanel
• Evaluating the patient for surgical options, such as resective surgery, which offers the best chance for seizure freedom in suitable candidates with focal epilepsy
• Considering neuromodulation therapies, such as vagus nerve stimulation (VNS), responsive neurostimulation (RNS), or deep brain stimulation (DBS), for patients who are not surgical candidates
• Dietary therapies, such as the ketogenic diet or modified Atkins diet, which can be effective in certain genetic epilepsies
• Addressing comorbidities, such as depression, anxiety, and sleep disorders, which can worsen seizure control

It is crucial to prioritize the patient's quality of life, morbidity, and mortality when making treatment decisions. Regular follow-up is necessary to assess the efficacy and side effects of interventions and make adjustments as needed. While older studies, such as those from 2014, provide valuable insights into the efficacy of various treatments, including valproate and levetiracetam 1, the most recent and highest quality study should guide treatment decisions.

From the FDA Drug Label

The effectiveness of zonisamide as adjunctive therapy (added to other antiepilepsy drugs) has been established in three multicenter, placebo-controlled, double blind, 3-month clinical trials (two domestic, one European) in 499 patients with refractory partial onset seizures with or without secondary generalization The effectiveness of levetiracetam as adjunctive therapy (added to other antiepileptic drugs) in adults was established in three multicenter, randomized, double-blind, placebo-controlled clinical studies in patients who had refractory partial onset seizures with or without secondary generalization

The best treatment approach for patients with refractory epilepsy is to use adjunctive therapy with medications such as zonisamide or levetiracetam, which have been shown to be effective in reducing seizure frequency in clinical trials 2, 3.

• Zonisamide has been established as an effective adjunctive therapy in three multicenter, placebo-controlled trials in patients with refractory partial onset seizures.
• Levetiracetam has also been shown to be effective as an adjunctive therapy in three multicenter, randomized, double-blind, placebo-controlled clinical studies in adults with refractory partial onset seizures. It is essential to carefully evaluate the patient's condition and medical history before initiating treatment, and to closely monitor them for potential side effects and interactions with other medications. Topiramate may also be considered, but its use requires careful monitoring of serum bicarbonate levels due to the risk of metabolic acidosis 4.

From the Research

Definition and Diagnosis of Refractory Epilepsy

• Refractory epilepsy is defined as epilepsy that is not controlled by medication, with 30 to 40% of people with epilepsy having seizures that are not controlled by medication 5.
• Patients are considered to have refractory epilepsy if disabling seizures continue despite appropriate trials of two antiseizure drugs, either alone or in combination 5.
• Apparent pharmacoresistance can result from a variety of situations, including noncompliance, seizures that are not epileptic, misdiagnosis of the seizure type or epilepsy syndrome, inappropriate use of medication, and lifestyle issues 5.

Treatment Approaches for Refractory Epilepsy

• Surgical treatment offers the best opportunity for complete freedom from seizures for patients who are pharmacoresistant 5.
• Surgically remediable epilepsy syndromes have been identified, but patients with more complicated epilepsy can also benefit from surgical treatment and require more specialized evaluation, including intracranial EEG monitoring 5.
• For patients who are not surgical candidates, or who are unwilling to consider surgery, a variety of other alternative treatments can be considered, including peripheral or central neurostimulation, ketogenic diet, and complementary and alternative approaches 5.
• Vagus nerve stimulation (VNS) is a neuromodulatory treatment that is used as an adjunctive therapy for treating people with medically refractory epilepsy, and appears to be an effective and well-tolerated treatment in adult and pediatric patients 6.

Management of Refractory Generalized Convulsive Status Epilepticus

• Status epilepticus that does not respond to first-line benzodiazepines or to second-line antiepileptic drugs is usually considered refractory and requires more aggressive treatment 7.
• The optimal treatment of refractory generalized convulsive status epilepticus (GCSE) has not been defined, but patients should be treated in an intensive care unit, as artificial ventilation and haemodynamic support are required 7.
• The drug treatment of refractory GCSE involves general anaesthesia with continuous intravenous anaesthetics given in doses that abolish all clinical and electrographic epileptic activity, often requiring sedation to the point of burst suppression on the EEG 7.

Predictors of Refractory Epilepsy

• About 20-40% of patients with epilepsy will be refractory to medical treatment with antiepileptic drugs, and it is unclear whether patients are already drug-resistant at the time of their initial presentation, or whether they become so over the course of their illness 8.
• Factors that may be used to predict whether or not a patient will respond favorably to AED therapy include the type of epilepsy, underlying syndrome, etiology, and the patient's history of seizure frequency, density, and clustering 9.
• Environmental factors, such as trauma and prior drug exposure, and genetic factors that predetermine the rate of absorption, metabolism, and uptake of a drug by target tissue may also uniquely impact an individual and influence their response to AED therapy 9.