VNS Therapy for Epilepsy

Identifying patients with refractory epilepsy

Determining the point at which epilepsy is considered refractory can be challenging. With the many AEDs now available, the question is how many AEDs—alone or in combination—to try before turning to nonpharmacologic options. Typically, patients with refractory epilepsy have shown limited success with any single AED or combination of AEDs. Brodie and Kwan suggested a staged approach to epilepsy therapy that includes considering nonpharmacologic options after 2 to 3 well-tolerated AEDs fail to produce adequate seizure control.1 Furthermore, evidence from clinical studies indicates that there are clinical and diagnostic predictors that identify patients at risk for refractory epilepsy. By recognizing these markers, you may help patients with refractory epilepsy get early and appropriate treatment and encourage improved health outcomes.

Prognosticators of Refractory Epilepsy

  1. Limited success with any single AED or combination of AEDs2
    Typically, patients with refractory epilepsy have not had an adequate response to 2 to 3 appropriate AED regimens.
  2. Response to first AED trial2
    In Kwan and Brodie’s study, only 11% of patients whose first AED failed because of inadequate seizure control ever achieve seizure freedom, even with subsequent AED trials. If the first AED failure was due to intolerable side effects, only 41% ever became seizure free with AEDs.
  3. Predictors related to intolerable side effects
    Several factors that may specifically indicate an increased risk for pharmacoresistance due to intolerable side effects include age (the very young and very old), baseline neurologic compromise, drug titration rate, polytherapy, and a history of drug intolerability.
  4. Seizure frequency before initial therapy2
    Patients who had more than 20 seizures before initial therapy were more likely to have persistent seizures than those with fewer seizures before the first AED trial. (51% vs 29%, P<0.001). A large number of seizures prior to therapy may be a result of an underlying pathophysiology that later manifests as refractory epilepsy.
  5. Early age at onset3
    In a study by Ko and Holmes, early age of epilepsy onset independently predicted a greater risk of refractory epilepsy.
  6. Cause or origin of seizures2
    The prevalence of persistent seizures appears to be higher in patients with symptomatic (structural abnormality) or cryptogenic epilepsy (unknown cause) compared with idiopathic epilepsy (genetic basis for disease). (40% vs 26%, P=0.004).
  7. Electroencephalographic (EEG) factors3
    There is a strong association between intractable seizures and several EEG factors: abnormal EEG background, including diffuse slowing, asymmetry, abnormal amplitude, high frequency of spikes or sharp waves, and focal spike and wave activity. Diffuse slowing and focal spike and wave activity independently predicted intractability.
  8. Imaging with positron emission tomography (PET)4
    PET imaging may predict refractory epilepsy in patients who undergo epilepsy surgery. In 30 patients with mesial temporal lobe epilepsy (MTLE), the interictal metabolic pattern in a specific network of connected regions (the temporal pole, the medial temporal region, the anterior part of the lateral temporal neocortex, and the basofrontal region) achieves better prediction of seizure prognosis 2 years after surgery than the hypometabolism in a single temporal lobe.

1 Brodie MJ, Kwan P. Neurology. 2002;58(suppl 5):S2-S8.

2 Kwan P, Brodie MJ. N Engl J Med. 2000;342:314-319.

3 Ko TS, Holmes GL. Clin Neurophysiol. 1999;110:1245-1251.

4 Dupont S, et al. Arch Neurol. 2000;57:1331-1336.

Refractory Epilepsy