Thursday, November 2, 2017

Surgery for drug-resistant epilepsy in children

Dwivedi R, Ramanujam B, Chandra PS, Sapra S, Gulati S, Kalaivani M, Garg A, Bal CS, Tripathi M, Dwivedi SN, Sagar R, Sarkar C, Tripathi M. Surgery for Drug-Resistant Epilepsy in Children. N Engl J Med. 2017 Oct 26;377(17):1639-1647.

Neurosurgical treatment may improve seizures in children and adolescents with drug-resistant epilepsy, but additional data are needed from randomized trials.
In this single-center trial, we randomly assigned 116 patients who were 18 years of age or younger with drug-resistant epilepsy to undergo brain surgery appropriate to the underlying cause of epilepsy along with appropriate medical therapy (surgery group, 57 patients) or to receive medical therapy alone (medical-therapy group, 59 patients). The patients in the medical-therapy group were assigned to a waiting list for surgery. The primary outcome was freedom from seizures at 12 months. Secondary outcomes were the score on the Hague Seizure Severity scale, the Binet-Kamat intelligence quotient, the social quotient on the Vineland Social Maturity Scale, and scores on the Child Behavior Checklist and the Pediatric Quality of Life Inventory.
At 12 months, freedom from seizures occurred in 44 patients (77%) in the surgery group and in 4 (7%) in the medical-therapy group (P<0.001). Between-group differences in the change from baseline to 12 months significantly favored surgery with respect to the score on the Hague Seizure Severity scale (difference, 19.4; 95% confidence interval [CI], 15.8 to 23.1; P<0.001), on the Child Behavior Checklist (difference, 13.1; 95% CI, 10.7 to 15.6; P<0.001), on the Pediatric Quality of Life Inventory (difference, 21.9; 95% CI, 16.4 to 27.6; P<0.001), and on the Vineland Social Maturity Scale (difference, 4.7; 95% CI, 0.4 to 9.1; P=0.03), but not on the Binet-Kamat intelligence quotient (difference, 2.5; 95% CI, -0.1 to 5.1; P=0.06). Serious adverse events occurred in 19 patients (33%) in the surgery group, including hemiparesis in 15 (26%).
In this single-center trial, children and adolescents with drug-resistant epilepsy who had undergone epilepsy surgery had a significantly higher rate of freedom from seizures and better scores with respect to behavior and quality of life than did those who continued medical therapy alone at 12 months. Surgery resulted in anticipated neurologic deficits related to the region of brain resection.

From the manuscript:

In this single-center, randomized, controlled trial, seizure outcomes 1 year after epilepsy surgery were significantly better than after continued medical therapy alone. Of the 57 patients who underwent surgery, 44 (77%) became seizure-free and 13 (23%) had ongoing seizures of varying degrees (class 2 to class 5 on the International League Against Epilepsy scale) (Supplementary Appendix, Section 1, Tables S1 and S2). In comparison, 93% of those receiving medical therapy alone continued to have seizures. In the surgery group, 21 patients (37%) were completely seizure-free during the entire 12-month period, whereas during the first weeks after surgery, the other 23 patients continued to have seizures; these episodes subsequently decreased in frequency, a feature that has been observed in other series of epilepsy surgery.14 A substantial proportion of the children in the surgery group had anticipated major postoperative motor, sensory, or cognitive deficits that were related to the area of the brain that was resected or disconnected.

Complete freedom from seizures occurred in all the patients in our trial who had undergone temporal lobectomy, as compared with only 38% of those who had undergone the same surgery in another randomized trial of epilepsy surgery that included only adults with a longer duration of epilepsy than the children in our trial. The difference in ages and duration of epilepsy between the two trials may explain the difference in results.

The between-group difference in the change from baseline to 12 months in the mean intelligence quotient was not significant in our trial, and it is possible that the 12-month interval of observation was too brief to observe a change in this measure. The improvements that were observed in other cognitive, behavioral, and quality-of-life scores in the surgery group may have been due to a reduction in the frequency of seizures; conversely, the deterioration in these measures in the medical-therapy group may be attributed to a continuation of seizures, which has been associated with poor cognitive functioning in children.15-24 In two nonrandomized trials, overall quality-of-life scores were significantly better among children who had undergone epilepsy surgery than among those who had received only medical therapy after 2 years or more of follow-up.   An observational study comparing surgical versus medical treatment in children with epileptic encephalopathy in infancy and early childhood showed that surgery resulted in better seizure control and a better developmental quotient than did medical therapy.

Our trial has some limitations. First, we included patients undergoing many types of epilepsy surgeries that were directed at several underlying pathological causes of seizures. However, the patients who were included in the trial reflect the populations encountered at a referral center for pediatric epilepsy. Second, there was an overrepresentation of hypothalamic hamartomas in our trial as compared with some other series. And third, our statistical analysis plan called for an outdated approach of last observation carried forward for missing data of secondary outcomes, although the effect was relatively minor, since information was missing in only one patient.

Serious adverse events due to the surgery included major motor, sensory, and cognitive deficits that were related to the area of the brain that was resected or disconnected. Despite these deficits, quality-of-life measures were significantly better in the surgery group, possibly because of better seizure control.

In conclusion, surgery in children with drug-resistant epilepsy resulted in higher rates of cessation of seizures at 1 year and better scores on some measures of behavior and quality of life than continued medical therapy alone. Some patients in the surgery group had anticipated serious neurologic consequences, including hemiparesis, some of which improved over time.

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