Seizures and Surgery: From Prophylaxis to Quality of Life

If epilepsy surgery fails to reduce a patient’s seizure frequency or AED use, can it still be considered a success? Maybe, argues a new analysis.

Treatment with neurostimulation does not adversely affect Quality of Life or mood and may be associated with improvements in QOL in patients, according to a new study in Epilepsy & Behavior. At two years in the study, 44 percent of patients had meaningful improvements in QOL, while 16 percent reported declines.

Writing that “counting seizures does not adequately reflect other important treatment effects on a patient’s life experience,” the authors argued the effectiveness of treatment in epilepsy includes QOL and emotional health.

They pulled data from a multicenter randomized controlled double-blinded trial of responsive neurostimulation in 191 patients with medically resistant focal epilepsy. During a four-month post-implant blinded period, patients were randomized to receive responsive stimulation or sham stimulation. All patients later received responsive neurostimulation in open label to complete two years. 

Compared with baseline—where treatment and sham groups did not differ—QOL improved in both groups at the end of the blinded period and also at one year and two years, when all patients were treated. At two years, 44 percent of patients reported meaningful improvements in QOL, and 16 percent reported declines.

Researchers saw no overall adverse changes in mood or in suicidality across the study and findings were not related to changes in seizures and AEDs; patients with mesial temporal seizure onsets and those with neocortical seizure onsets both experienced improvements in QOL.

It is important to note that QOL and mood were not the primary outcomes; the study was designed to assess overall efficacy and safety of responsive neurostimulation, said study author Kimford J. Meador, MD, at the Stanford Comprehensive Epilepsy Center, adding that the findings need to be replicated in a study designed directly to assess QOL and mood.

But Dr. Meador said he was somewhat surprised that though there we no changes seen related to seizures and AED use, patients with mesial temporal seizure onsets and those with neocortical seizure onsets both experienced improvements in QOL.

“But there may be apparent reasons,” he said in an interview with Practical Neurology™. “There was actually an improvement in QOL with reduced seizure frequency at the end of the first year but not at the end of the second year. Perception of QOL changes due to seizure changes may habituate with time so that other factors such as mood and other ongoing factors in life influence this perception.” He added that there was no consistent change or control of the change in AEDs. “Some AEDs can affect QOL, but others may not. So it is not surprising that QOL was not related to AED changes.”

More research on the topic is needed, but the literature does offer a theory on why QOL can improve if AED use or seizure frequency does not. “Response shift,” according to Schwartz and Sprangers,¹ is a change in a person’s self-evaluation as a result of a change in their internal standards, values or priorities, and conceptualization of quality of life. “Simplistically, one may view [these] measures differently, depending on their current health, treatment, social situations (such as support, ability to drive, ability to work), and priorities that may have changed (e.g., family may be more important if one’s health has changed), writes Alison Pack, MD in an unrelated article on QOL and epilepsy surgery.²

“Social scientists have defined three forms of response shift: The first is a reconceptualization or redefinition of the target construct over time. The second is a recalibration or change in an individual’s internal standards of specific measures, which often results in an underestimation of the change in studied measures. The third form is a reprioritization or change in an individual’s values, which may affect the importance of a specific measure, particularly in relation to other measures.”

Though response shift has been studied in multiple chronic health conditions, epilepsy has not been one of them.

“Although VNS has been available in the US since 1997, we are at the very beginning of the era of neurostimulation for epilepsy,” Dr. Kimford said. “This area will likely evolve as we explore stimulation parameters, new techniques and new locations to enhance therapeutic effects.”

Prophylactic AEDs Before Epilepsy Surgery Still Flummox Neurologists

The incidence of seizures following supratentorial craniotomy for non-traumatic pathology falls between 15 and 20 percent, according to the literature. Because postoperative seizures can precipitate the development of epilepsy, physicians sometimes prescribe AEDs pre- or post-operatively to prevent seizures following cranial surgery. This occurs despite uncertain evidence on the practice.

In a study published in Cochrane Database of Systematic Reviews, researchers tried to get a clearer understanding of the issue, but came back with a frustrating conclusion: “We don’t know whether prophylactic use of AEDs is effective or not in preventing seizures in patients undergoing craniotomy,” said study author Janette Greenhalgh, PhD, Senior Research Fellow at the University of Liverpool, in an interview with Practical Neurology™.

Selection and Analysis. The researchers reviewed eight randomized control trials (RCTs) and evaluated phenytoin against placebo, carbamazepine and phenytoin against no treatment, phenytoin versus valproate; zonisamide versus phenobarbital, and levetiracetam versus phenytoin. Of the five trials where an AED was compared with control, only one demonstrated a significant effect between AED treatment and controls for early seizure occurrence.

They included RCTs of people with no history of epilepsy who were undergoing craniotomy for either therapeutic or diagnostic reasons. Trials with adequate randomization methods and concealment were included, be they blinded or unblinded parallel trials. They did not stipulate a minimum treatment period, and trials using active drugs or placebo as a control group were included.

The researchers investigated outcomes including the number of patients experiencing seizures (early-occurring within first week following craniotomy, and late-occurring after first week following craniotomy), the number of deaths and the number of people experiencing disability and adverse effects. Due to the heterogeneous nature of the trials, they did not combine data from the included trials in a meta-analysis.

Dr. Greenhalgh said the small number of trials (eight) totaling roughly 1,600 patients was a limitation, as was the differences in trial protocols: “some gave treatment pre and post-op, others post-op only,” she said. It was also “Very difficult to draw any conclusions from the data on adverse events due to poor reporting of data.”

Findings. Of the head-to-head trials, none reported statistically significant differences between treatments for either early or late seizures. Additionally, one head-to-head trial showed an increase in the number of deaths following one AED treatment compared to another AED treatment. 

Given the results of the analysis, how should doctors approach this patient population? “We know that a proportion of patients undergoing craniotomy will have seizures at some point after the craniotomy,” Dr. Greenhalgh said. “There is no evidence to support prophylactic use of AEDs, and there is the risk that AEDs might do harm. If a seizure does occur the clinician should consider starting AED treatment to prevent further seizures.”

Going forward, she said the researchers need properly randomized RCT with sufficient numbers of patients to detect treatment differences. Comparing AED with placebo, standardized AE reporting and well-defined cut-off dates for data reporting (early/late seizures) are some of the areas that would improve the quality of studies.

“We also need to consider the types of treatments that should be considered,” Dr. Greenhalgh said. “AEDs are symptomatic treatments that are very unlikely to have any impact on the underlying biology of epileptogenesis. What we need is treatments that prevent the development of epilepsy, which might be trialed in patients with a brain insult. Such treatments are however still early in development.” n

1. Schwartz CE, Sprangers MAG. Methodological approaches for assessing response shift in longitudinal health-related quality-of-life research. Soc Sci Med. 1999;48:1531–1548.

2. Pack AM. Do Patients With Refractory Temporal Lobe Epilepsy Shift Their Quality of Life Priorities After Having Surgery? Epilepsy Curr. 2015 Jan-Feb; 15(1): 32–33.