Epilepsy Surgery Works – So Why the Wait?

Commentary

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. 2017;37717:1639–1647.

BACKGROUND: Neurosurgical treatment may improve seizures in children and adolescents with drug-resistant epilepsy, but additional data are needed from randomized trials. METHODS: 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. RESULTS: 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%). CONCLUSIONS: 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.

There are very few randomized clinical trials in epilepsy surgery due to concerns that such a trial would be unethical and anticipation that most patients would not choose to participate in such a trial. This difficulty was noted in the Early Randomized Surgical Epilepsy Trial comparing temporal lobectomy within 2 years of establishing medical intractability (failure of 2 or more AEDs) against patients receiving medical treatment alone. The trial was halted on account of slow enrollment—only 38/76 subjects screened completed the trial, short of the 200 patient goal. However, none of the patients in the medical group became seizure free compared with 11/15 (73%) in the surgical group (p < 0.001) (1). In a study from Canada, Wiebe et al. (2) were able to show a significant difference in seizure freedom between patients offered temporal lobectomy within 4 weeks of completing their presurgical evaluation versus those placed on a waiting list prior to completing their evaluation (58% seizure free in the surgery group versus 8% in the medical group). These patients had agreed to the study prior to undergoing randomization.

In a recent study from India, Dwivedi and colleagues confirmed the superiority of epilepsy surgery over medical treatment in children with drug-resistant epilepsy; 77% in the surgery group were seizure free versus 7% in the medical therapy group (p < 0.001). The children in the surgical group ranged in age from 10 months to 17 years (median age 9 years). They underwent temporal as well as extratemporal resections, hemispherectomy, corpus callosotomy, or hypothalamic hamartoma surgery. Only 7/59 (7%) in the medical therapy group were seizure free at the end of 12 months. Improvements were also seen in quality of life, behavior, and social maturity in the surgery group; this was observed even in those children who developed sensorimotor or cognitive deficits postoperatively (3).

These three randomized trials have clearly shown the superiority of surgery over medical therapy in children and adults with focal epilepsy be it temporal, extratemporal, hemispheric, or due to hypothalamic hamartoma. Jenny et al. (4) noted seizure outcomes in children ≤3 years to be better than for children 4- to 17-years old. Improvement in quality of life measures has been shown in children and adults undergoing epilepsy surgery compared to those receiving only medical therapy (5–7). Moosa et al. (7) examined the long-term functional outcomes after hemispherectomy in children—the presence of MRI abnormalities in the contralateral hemisphere and pre-existing quadriparesis negatively affected functional outcomes. Younger age at surgery correlated with poor reading skills but not spoken language. Children with Rasmussen encephalitis were more likely to experience worsening of hemiparesis after surgery than children with other etiologies. However, etiology had no effect on ability to achieve independent walking status (7). The morbidity and mortality of epilepsy surgery in infants and children is quite low at tertiary epilepsy centers.

Time to epilepsy surgery is a critical factor influencing both seizure and developmental outcomes. Radhakrishnan et al. (8) reported higher seizure recurrence in those with positive family history, normal neuroimaging and histopathology, residual spikes on the postoperative EEGs, secondarily generalized seizures, and duration of epilepsy ≥5 years (8).

At tertiary epilepsy centers worldwide, children with medically refractory epilepsy are evaluated for epilepsy surgery. Notwithstanding their efforts there are other factors, which explain delays in receiving epilepsy surgery including:

1. Inability to recognize seizures in young children by parents or even physicians, resulting in delays before being diagnosed correctly.

2. A mistaken belief that children will “out-grow” their seizures even when they do not have benign childhood epilepsy. Remission is seen only after seizures come under control for a period of time, usually accompanied by disappearance of spikes in the EEG.

3. No apparent lesion on MRI. Focal dysplastic lesions seen at a younger age may become less visible between 6 and 24 months of age, only to be seen again once myelination is complete (9, 10). Use of an epilepsy protocol MRI and 3-Tesla imaging may identify focal dysplasia not otherwise seen (11).

4. EEG abnormalities in young children may be generalized, multifocal, nonlateralizing, or even falsely lateralizing (12). Over time, epileptiform discharges as well as slowing become more focal. Seizure semiology also evolves over time, as children are better able to describe their auras and lateralizing signs are more evident (13, 14). Patients initially regarded as unsuitable surgical candidates when younger, may turn out to be candidates for surgery later on.

5. Socioeconomic, cultural beliefs, and health insurance barriers also delay receiving epilepsy surgery. Sadly some physicians also view epilepsy surgery as a treatment of last resort.

Diagnostic video-EEG after failure of one seizure medication is reasonable to determine the seizure type(s) and select the next appropriate medication. After failure of a second drug (alone or in combination), presurgical evaluation should be considered. Close follow-up and periodic reassessment are essential in making sure that every child with epilepsy receives optimal care. Children who are not epilepsy surgery candidates can benefit from other treatment options, including newer seizure medications, ketogenic diet, or neurostimulation.

From the caregiver's perspective most parents wished their child had undergone surgery earlier; their children had waited longer for surgery compared with those who were satisfied with the timing of surgery. They were also willing to accept a lower likelihood of seizure freedom and more willing to accept a deficit other than cognitive decline following surgery (15).