The Children's Adaptive Deep Brain Stimulation for Epilepsy Trial

All participants will complete a 4 week baseline assessment phase, then surgical implantation of the Picostim device and then a 4 week recovery phase. The participants will thereafter be randomised (1:1) and double-blinded to either an 'early stimulation' (DBS device switched on) or an 'delayed stimulation' (DBS device switched off) arm. Children allocated to receive early stimulation will complete 36 weeks of immediate active stimulation and children allocated to delayed stimulation will complete 12 weeks of inactive stimulation followed by 24 weeks of active stimulation.

The primary endpoint for all participants in the trial will be following 24 weeks of active stimulation. Secondary outcomes will be compared between the early and delayed stimulation arms following the first 12 weeks of the controlled phase.

The SMART-DBS study will recruit participants from the CADET Trial and the preceding CADET Pilot study. In both the CADET Trial and CADET Pilot studies, participants were fitted with the Picostim device and the device remains active. Participants who potentially meet the eligibility criteria will be provided with the PIS to consider participation in the adaptive DBS study.

• Deep Brain Stimulation (Device): Picostim DBS Device

Primary outcomes

• Seizure frequency reduction [24 weeks of active stimulation compared to baseline]: Seizure frequency reduction measured on carer-recorded seizure diaries

Secondary outcomes

• Seizure frequency [8-12 weeks following randomisation between the active and inactive stimulation arms]: Seizure frequency reduction measured on carer-recorded seizure diaries
• Seizure frequency [24 weeks of active stimulation compared to baseline]: Seizure frequency reduction measured on scalp EEG
• Seizure frequency [8-12 weeks following randomisation between the active and inactive stimulation arms]: Seizure frequency reduction measured on scalp EEG
• Seizure severity [24 weeks of active stimulation relative to baseline and comparison 12 weeks following randomisation between the active and inactive arms]: Seizure severity (according to the Hague Seizure Severity Scale). The HSSS scores range from 13 (least severe) and to 53 (most severe).
• Quality of life (PedsQL) [After 24-weeks of active stimulation, and 12 weeks following randomisation between the active and inactive stimulation arms]: The PedsQL (Pediatric Quality of Life Inventory) questionnaire provides a quantitative score ranging from 0 (worst possible QoL) to 100 (best possible QoL) (https://www.pedsql.org/).
• Quality of life (IPES) [After 24-weeks of active stimulation, and 12 weeks following randomisation between the active and inactive stimulation arms]: The Impact of Pediatric Epilepsy Scale (IPES) is a 12-item questionnaire that is answered by the carers of children with epilepsy that, as titled, aims to objectively measure the burden that epilepsy has on the child's life. The IPES scores range from 0 (lowest impact of epilepsy on the participant) to 33 (highest impact of epilepsy on the participant).

Sex: All, ages: 5 Years to 14 Years

Children enrolled in this study must:

* Be 5-14 years of age at consent.
* Have a diagnosis of LGS, as determined by:

  * Slow (<3.0Hz) spike-and-wave pattern and/or fast wave pattern (tonic seizures) detected on EEG at least six-months prior to the enrolment into the baseline period
  * History of drop seizures (tonic, atonic, or tonic-clonic) that precedes at least six-months prior to the enrolment into the baseline period
* Have experienced at least 10 seizures in the four weeks prior to enrolment.
* Have tried and not responded to two or more antiseizure medications prior to enrolment.
* Be taking one or more anti-seizure medication(s) at a stable dose for at least the four weeks prior to enrolment.
* Have a carer who is willing for their child's maintenance anti-seizure medications and ketogenic diet (if relevant) to be unaltered for the trial duration.
* Have a carer who is willing and able to comply with all the requirements of the study, including the completion of the seizure diary and periodic device charging.

Children enrolled in this study must not:

* Have received prior deep brain stimulation insertion.
* Have an active ('on') vagus nerve stimulator (or active within the six months prior to the baseline period).
* Have had a change in their anti-seizure medication prescription or stopped their ketogenic diet within the last 4 weeks
* Have started or made changes to the prescription of a ketogenic diet within the last 12-weeks
* Have abnormal thalamic anatomy detected on imaging that would render DBS either unsafe or unfeasible.
* Have a bleeding disorder(s).
* Have a medical condition(s)/factor(s) that would increase their anaesthetic risk to an unacceptable level.
* Have a nickel allergy.
* Be pregnant.