Early Surgery for Drug Resistant Epilepsy May Limit Cognitive Disabilities

MedicalResearch.com Interview with:
Dr. Manjari Tripathi Professor, Epileptology, Neurology
Dr. P Sarat Chandra, Chief epilepsy Neurosurgeon
AIIMS, New Delhi

MedicalResearch.com: What is the background for this study?:

  1. Surgery for drug resistant epilepsy (DRE) is an accepted procedure for children and there have been multiple surgical series and surgical techniques published in literature. However, till date there are no randomized controlled trials (RCT) available to objectively demonstrate the safety and efficacy of surgical therapy in children with DRE. There are till date only 2 randomized trials for adult patients with drug resistant epilepsy (both for mesial temporal sclerosis only, Wiebe S et al, New Eng J Med, 2001 & Engel J et al, JAMA, 2012).
  2. Children constitute a significant proportion of patients undergoing surgical therapy for DRE (close to 50% in tertiary centers). They have unique problems associated due to uncontrolled epilepsy and some of these include epileptic encephalopathy and status epilepticus. In addition, surgery is also associated with problems like hypothermia, issues related to blood loss etc. Thus the senior author (Manjari Tripathi) and her team felt that a RCT would be very important to objectively assess the role of surgery and hence designed this study.

MedicalResearch.com: What are the main findings?:

  1. The senior author and her team (Manjari Tripathi) work at the largest tertiary center in India (the All India Institute of Medical Sciences, New Delhi) and this forms the largest referral center for the country for epilepsy surgery. The center works up and treats a significant population of patients who suffer from DRE. Being the only center doing high-end epilepsy surgery in Northern India, the waiting period admission for surgery for DRE is around 1 year. This provided the team an opportunity to randomize the patients into 2 arms. One being in the medical arm (a group which continued medical therapy and received surgery at the usual wait list of around 1 year) and the other being the surgical arm (a group which received surgical therapy immediately).
  2. A total of 116 patients were randomized, of which 57 were assigned to the surgical arm and 59 were assigned to the medical arm. The baseline characteristics of both the arms were similar. The mean age of patients was 9-10 years of age, the mean onset of epilepsy in both groups was at 1.5-3 years of age. 68-84% of the children had >1 seizure/ day. Both the groups were significantly impaired in their cognitive, social & QoL functions (as assessed by Binet Kamat Intelligence Quotient, Social Quotient on Vineland Social Maturity Scale, Child Behaviour Checklist and Pediatric Quality of life).
  3. The surgical arm included various surgical procedures as felt appropriate to the underlying pathology. This was different from the earlier RCT’s which consisted of only temporal lobectomy performed for mesial temporal sclerosis.
  4. Following surgery a total of 77% were seizure free at 1 year of follow up as compared to only 7% being seizure free in the medical arm. Estimates of the probability of being seizure-free at 12 months on Kaplan–Meier analysis were 36.7% in the surgery group and zero in the medical-therapy group (hazard ratio for freedom from seizures in the surgery group, 6.2; 95% CI, 4.6 to 8.2; P<0.001)
  5. The secondary outcome scores were also better in the surgical group indicating that early surgery significantly reduces the incidence of cognitive disabilities associated due to uncontrolled epilepsy.
    1. Hague Seizure Severity scale at 1 year was significantly better in the surgery group than in the medical-therapy group (between group difference in the change from baseline, 19.4; 95% CI, 15.8 to 23.1; P<0.001).
    2. Binet–Kamat test for intelligence quotient was not significant in the surgery group (P = 0.29) and was significantly reduced in the medical therapy group (P<0.001). However, the between-group difference in change from baseline to 12 months was not significant (difference, 2.5; 95% CI, −0.1 to 5.1; P = 0.06).
  • Vineland Social Maturity Scale test did not show significant change from baseline in the mean social quotient in either group (surgery P = 0.07; and medical therapy P = 0.24), but the between-group difference in the change from baseline significantly favoured the surgery group (difference, 4.7; 95% CI, 0.4 to 9.1; P = 0.03).
  1. Child Behaviour Checklist was significantly better in the surgery group (P<0.001) but not in the medical-therapy group (P = 0.36). This also resulted in a significant between-group difference that favoured the surgery group (difference, 13.1; 95% CI, 10.7 to15.6; P<0.001).
  2. Paediatric Quality of Life Inventory was better significantly in the surgery group (P<0.001) but not in the medical therapy group (95% CI, 3.5 to 4.9; P = 0.74). This also resulted in a significant between-group difference in the change from baseline that favoured the surgery group (difference, 21.9; 95% CI, 16.4 to 27.6; P<0.001).
  3. Adverse events: Though there were no deaths in either group, surgery resulted in serious adverse events in 33% of cases (n=19). A majority of them (n =17) included monoparesis or hemiparesis (most of them again as a result of hemispherotomy where this is an expected adverse event). 15/17 of these patients improved at 1 year of follow up. Thus most of the adverse events improved significantly. 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.

MedicalResearch.com: What should readers take away from your report?

Response: This study has conclusively shown that surgical therapy for DRE in children is significantly effective as compared to the medical therapy (77% vs 7% respectively). In addition, early surgery also prevents cognitive disabilities associated with DRE. Most of the adverse events associated with surgery were expected neurological deficits due to surgery being performed in the area sustaining that function, and most of these deficits improve subsequently.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Response: This study not only proves the beneficial effect of surgery but also demonstrates the deleterious effects of seizures on the paediatric developing brain due to continued uncontrolled seizures. This study may encourage surgeon to perform early surgery in children with DRE. It may also provide impetus to intervene in these children early.

MedicalResearch.com: Is there anything else you would like to add? Any disclosures?

Response: We would like to thank the patients and their families who have participated in this study. The study was funded by Dept of Biotechnology (Ministry of Science and Technology) and Indian Council for Medical Research (ICMR).

Citation:

Surgery for Drug-Resistant Epilepsy in Children

Rekha Dwivedi, Ph.D., Bhargavi Ramanujam, M.D., D.M., P. Sarat Chandra, M.Ch., Savita Sapra, Ph.D., Sheffali Gulati, M.D., D.M., Mani Kalaivani, Ph.D., Ajay Garg, M.D., Chandra S. Bal, M.D., Madhavi Tripathi, M.D., Sada N. Dwivedi, Ph.D., Rajesh Sagar, M.D., Chitra Sarkar, M.D., and Manjari Tripathi, M.D., D.M.

N Engl J Med 2017; 377:1639-1647
October 26, 2017DOI: 10.1056/NEJMoa1615335

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