Intractable Epilepsy: What Are the Options?

The last portion of the Annual Course on intractable epilepsy at this year’s American Epilepsy Society Annual Meeting was based on the case of a man who had failed multiple previous surgeries.

Dr. Elaine Wyllie, Professor of Neurology at the Cleveland Clinic Lerner School of Medicine, began by reviewing the risk factors for failure of epilepsy surgery:

• Long duration of epilepsy

• Non-lesional MRI

• Resection limitations due to “eloquent” cortex

• Bilateral abnormalities on MRI or PET

• Multifocal or poorly localized EEG abnormalities

She discussed choosing surgery, even when these risk factors were present, and emphasized that the traditional definition of surgical success-complete obliteration of seizures-may not always be the goal. Instead, surgical amelioration may be more appropriate in people with intractable epilepsy, with the objectives of reducing seizure burden, improving quality of life, and (in children) optimizing neurologic development.

Children may be particularly likely to benefit from epilepsy surgery, according to Dr. Wyllie. She discussed the results of a study of 18 children with bilateral epileptic foci who underwent surgery for palliation.¹ At a median follow-up of 1.4 years, 44% had no seizures (on medications) and 17% had more than 50% reduction in seizure frequency.

Dr. Dana Ekstein, Head of the Epilepsy Center at the Hadassah Medical Center in Israel, discussed the use of botanicals (herbs) in epilepsy. She indicated that complementary medicine in general and botanical use specifically is common in people with epilepsy, not only for seizure control but also for comorbidities and antiepileptic drug (AED) side effects, such as depression, anxiety, and memory impairment. Therefore, clinicians should inquire about botanicals, as patients are quite likely taking them.

Dr. Ekstein cited very recent studies suggesting that cannabidiol (CBD) is effective for seizures. A retrospective study involving children with intractable epilepsy reported that 52% experienced more than 50% reduction in seizure frequency with CBD-enriched cannabis.² Similarly, CBD was associated with a 39% rate of more than 50% reduction in seizure frequency in an open-label prospective trial of children and young adults with treatment-resistant epilepsy.³ Dr. Ekstein noted that this was similar to the 26%–43% response rates previously reported for 6 of the newer AEDs.

The effectiveness of botanicals has been demonstrated for certain comorbidities, according to Dr. Ekstein:

• St John’s wort: mild to moderate depression

• Kava: generalized anxiety

• Rosenroot: mild depression and fatigue; it also improves attention and mental performance

Side effects and drug interactions of botanicals must be kept in mind. Ephedra, St. John’s wort, ginkgo biloba, caffeine, creatine, star anise, star fruit, and evening primrose have been associated with seizures. A systematic review indicated that CBD is generally well-tolerated in adults. However, the two studies noted above reported substantial adverse event rates: 46% in children treated with CBD-enriched cannabis, including seizure aggravation,² and 79% in children and young adults receiving CBD.³ In the latter, the rate of serious adverse events was 30% and included 1 patient with sudden unexpected death in epilepsy.

The session ended with a debate regarding whether there is a time to eventually stop offering additional treatments to people with intractable epilepsy. Dr. Frank Gilliam, Professor of Neurology at the University of Kentucky, argued that “There is always hope! Keep trying!” After describing a child with double cortex syndrome who achieved dramatic improvement with responsive neurostimulation, Dr. Gilliam discussed a study of 139 patients with apparently drug-resistant epilepsy, 19% of whom eventually became seizure-free for at least 12 months after multiple drug trials.⁴ Of note, more than 15 different drugs were tried in these patients.

Dr. Gilliam emphasized the importance of AED side effects and comorbid depression in reducing the quality of life in people with pharmacoresistant epilepsy, suggesting that their amelioration may substantially improve subjective health. Use of the Adverse Event Profile tool helps clinicians identify AED-related side effects.⁵ It has been demonstrated to reduce AED adverse effects and improve quality of life, almost as much as the improvement seen after successful epilepsy surgery.

Dr. Lara Jehi, Director of Research at the Cleveland Clinic Epilepsy Center, argued the counterpoint, that “There are times to be hopeful, but also a time to stop.” She discussed two situations when stopping therapy is appropriate: when future treatment is medically futile and when treatment would violate the patient’s autonomy. Medically futile treatment is defined as “treatments that are unlikely to produce benefit for the patient;” physiologic improvement may occur but unless the patient perceives a benefit, the treatment would be considered futile. Likewise, when a person clearly desires no further treatment, it would be appropriate to stop.

Deciding to stop treatment tends to contradict caregivers’ natural view of hope as “doing everything.” But Dr. Jehi noted that hope should not be defined by the aggressiveness of interventions. There is a clear need to better delineate the risks and benefits of the large number of diagnostic and therapeutic options. This is particularly relevant in the setting of intractable epilepsy, as a strategy with a good success rate in a clinical trial involving patients with no previous treatment may have a very different likelihood of success in a person who has failed multiple other treatments.

Kossoff E, Chair, Annual Course, 2016, American Epilepsy Society Annual Meeting, www.aesnet.org.

References:

1. Ilyas M, et al. Seizure control following palliative resective surgery for intractable epilepsy-a pilot study. Pediatr Neurol. 2014;51(3):330-335.

2. Tzadok M, et al. CBD-enriched medical cannabis for intractable pediatric epilepsy: The current Israeli experience. Seizure. 2016;35:41-44.

3. Devinsky O, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016;15(3):270-278.

4. Neligan A, et al. Treatment changes in a cohort of people with apparently drug-resistant epilepsy: an extended follow-up. J Neurol Neurosurg Psychiatry. 2012;83(8):810-813.

5. Gilliam F, et al. Tolerability of antiseizure medications: implications for health outcomes. Neurology. 2004;63(10 Suppl 4):S9-S12.