Neurology's Silent Killer: Drug-Resistant Epilepsy

Commentary

Disparities in Surgery Among Patients with Intractable Epilepsy in a Universal Health System.

Burneo JG, Shariff SZ, Liu K, Leonard S, Saposnik G, Garg AX. Neurology 2016;86:72–78.

OBJECTIVE: To assess the use of epilepsy surgery in patients with medically intractable epilepsy in a publicly funded universal health care system. METHODS: We performed a population-based retrospective cohort study using linked health care databases for Ontario, Canada, between 2001 and 2010. We identified all patients with medically intractable epilepsy, defined as those with seizures that did not respond to at least 2 adequate trials of seizure medications. We assessed the proportion of patients who had epilepsy surgery within the following 2 years. We further identified the characteristics associated with epilepsy surgery. RESULTS: A total of 10,661 patients were identified with medically intractable epilepsy (mean age 47 years, 51% male); most (74%) did not have other comorbidities. Within 2 years of being defined as medically intractable, only 124 patients (1.2%) underwent epilepsy surgery. Death occurred in 12% of those with medically intractable epilepsy. Those who underwent the procedure were younger and had fewer comorbidities compared to those who did not. CONCLUSION: In our setting of publicly funded universal health care, more than 10% of patients died within 2 years of developing medically intractable epilepsy. Epilepsy surgery may be an effective treatment for some patients; however, fewer than 2% of patients who may have benefited from epilepsy surgery received it.

A patient once told me, “Dr. Jehi, I wish I had cancer: people would then feel bad for me and try to help: I could at least talk about my problem. Instead, I have epilepsy and I should hide it because it somehow counts against me: once people know, they flee me as if they don't know what to do with me anymore.” Today, 50 million people around the world have epilepsy. At least one-third of them, like my patient, have drug-resistant epilepsy (DRE). The article by Burneo et al., chosen for this commentary, squarely tells us that collectively, as a society, we “don't know what to do with them anymore.”

The facts are these: Once a patient with epilepsy continues to have seizures despite adequately trying two antiepileptic drugs, their diagnosis becomes DRE (1). From the moment this DRE diagnosis is made, we know that 1% will die from sudden death in epilepsy every year, and 12% will die (all-cause mortality) over the subsequent 2 years. Endless literature has been written on the negative effects of DRE on quality of life (3), psychosocial comorbidities (4), and its huge financial societal burden (5). In this commentary though, let's just focus on this one hard outcome: 12% will die within 2 years of determining that their seizures are drug resistant, unless we stop their seizures.

Let's consider what our next step could be after realizing that a patient has DRE. We can choose to react by adjusting seizure medications and doing nothing else: with that, the odds of making our patients seizure-free are approximately 3% per year (6). We can choose to pursue a neuromodulation-based therapy: with that, the expected outcome is palliative, as approximately 50% of patients achieve a 50% reduction in seizure frequency (7, 8). One report mentions a 13% chance of a 12-month remission with responsive neurostimulation: an encouraging number, but of questionable long-term significance considering that 33% of patients with DRE achieve a similar 12-month remission with medical therapy alone, but most of these “honeymoon” periods (71% to be exact) are not sustained and devolve into the patient's original pattern of uncontrolled epilepsy (6). Last, we could choose to follow the guidelines of the American Academy of Neurology (9) and perform an evaluation for possible epilepsy surgery: with that, should the patient be a candidate for resective surgery, the chances of becoming seizure-free are approximately 60% after a temporal lobe surgery and 30% to 40% after an extratemporal resection (10, 11). Considering these numbers, even in the “worst case scenarios,” the superiority of resective surgery in achieving sustained seizure-freedom is unquestionable. So, what are we actually choosing to do? What is happening to our patients once the diagnosis of DRE is made?

Study after study shows that, as a community, we by far favor the nonsurgical treatment options. In the Canadian example at hand by Burneo et al., only 124 patients of 10,661 (1.2%) with DRE underwent epilepsy surgery within 2 years of being defined as medically intractable. Only about 2% had received a video-EEG evaluation within the same time frame. Data from the United States show similar trends (12). These numbers do not illustrate a very emphatic vote of support for offering surgery soon after a patient is identified as having DRE. The obvious question becomes: since we know that surgery is the most effective treatment option, why aren't we recommending it sooner to our patients? Many excuses emerge. Nobody can promise a patient 100% seizure-freedom after surgery, and there is a long way to go for all of us to better understand and improve upon our surgical outcomes. Also, surgery comes at a price: neurosurgical complications can happen, and the procedure is costly. So, one may think that there is nothing wrong with deferring a surgical evaluation or intervention until other less-invasive options have been exhausted. After all, surgery may be more effective, but it is more risky than all the other options, so “let's try everything else first, and we can always refer for surgery if nothing works.” The logic seems reasonable, but is it valid? To answer that, let's consider the price of waiting, the price of deferring surgery.

We recently published (10) that while more than 60% of patients with drug-resistant frontal lobe epilepsy become seizure-free after epilepsy surgery if operated on within 5 years of epilepsy onset, only about 30% become seizure-free with later surgery. In the group with a normal brain MRI (traditionally considered the worse epilepsy surgery candidates), the split in the chances of seizure-freedom between early and late surgery were even more dramatic, with more than 80% rendered seizure-free by early surgery as opposed to 10% with later surgery. To be clear, “early” versus “late” surgery in this context was defined as less versus more than 5 years. So, as we defer surgery, the patient may be losing a chance at a better surgical result. Extensive pediatric literature details the significant cognitive losses that inflict children with epilepsy as the duration of their disease is prolonged, highlighting the developmental price of delaying a surgical cure (13). Added to the risks of deferring surgery, we now have more evidence for a significant mortality risk associated with DRE, a risk that was already shown in multiple prior studies (14–16). Therefore, deferring surgery buys us time, but may cost the patient chances of seizure-freedom, cognitive benefits, and years of life expectancy.

So, the next time we see in our clinic a patient with DRE, and we ponder about the risks of our next step to “try” before their next follow-up visit in 6 months or a year, let's remember that their epilepsy, like cancer, is a fatal disease. It is a slower killer though: it only kills 12% over 2 years.