General study design
STARTS is a single-centre, two-arm, randomised controlled, parallel-group clinical trial. The study will enrol patients with refractory mTLE, who will be followed up for 1 year after treatment. Primary outcome measures will include intelligence quotient. Secondary outcome measures will include seizure outcome, visual filed, quality of life, average hospitalisation expenses, and adverse events.
Participants selection
The study aims to enrol male or female participants ranging in age from 14 to 65 years who have had drug-resistant seizures for at least 2 years and who have been determined via detailed evaluation to be candidates for surgery prior to randomisation. Patients will be evaluated based on seizure history and mTLE semiology from outpatient and multidisciplinary team (MDT). Presurgical examinations will be carried out before enrolment. The following eligibility criteria have been adopted:
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Normalized treatment with at least one or more first-line antiepileptic drugs (AEDs) for more than 2 years with still seizure attack. Appropriate doses must have been administered, and treatment must have failed due to inefficacy rather than intolerance.
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Persistence of disabling seizures (at least three times per 3 months or greater) and at least one or more seizures in the preceding month.
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Age ≥ 14 years at enrolment.
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Simple and complex partial seizures, with or without secondary generalised seizures beginning in childhood or later, with or without prior febrile convulsions.
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Auras occurring in isolation that are not primary sensory in nature (other than olfactory or gustatory).
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Intelligence quotient (I.Q.) greater than 70.
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Hippocampal atrophy on T1-weighted magnetic resonance imaging (MRI) with increased ipsilateral mesial signal on T2-weighted and Flair MRI.
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Inter-ictal EEG showing focal or lateralised spikes over the temporal, frontal, or sphenoid electrode.
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Ictal EEG onset that is focal or lateralised on the ipsilateral side.
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Ipsilateral temporal focal hypometabolism on positron emission tomography (PET).
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Consensus of ipsilateral mesial temporal origin based on a multidisciplinary discussion.
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Ability to understand and speak Mandarin.
Exclusion criteria are as follows:
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A history of serious cerebral insult after the age of 5.
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Progressive neurological disorders or mental retardation (I.Q. <70).
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Psychogenic seizures.
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Focal neurological deficits other than memory disturbances.
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Any unexplained focal or lateralised neurological deficits other than memory dysfunction.
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Temporal neocortical or extratemporal lesions on MRI.
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Psychosis, current or recent substance abuse, suicidality, or anorexia.
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Severe systemic disease.
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Unequivocal focal extratemporal EEG slowing or interictal spikes.
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Lesions outside of the mesial temporal area on MRI.
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Diffuse unilateral or bilateral hypometabolism on PET.
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Contralateral or extratemporal ictal onset.
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Persistent extratemporal/predominant contralateral focal interictal spikes or slowing; generalized interictal spikes.
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Inclusion in any clinical trial.
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Pregnancy.
Interventions
All participants will be randomised into two groups: an ATL group (arm 1) and an SEEG-guided RF-TC group (arm 2). The full technological flow of this RCT is shown in Fig. 1.
Patients enrolled in arm 1 will undergo open ATL following pre-surgical evaluation, which will be conducted as established by Wiebe et al. in their RCT for mesial temporal lobe epilepsy.4 Two experienced neurosurgeons will perform ATL for mTLE and resection will be 5.5 cm on the non-dominant hemisphere or 4.5 cm on the dominant hemisphere, as referenced in Wiebe et al4. The mesial part of the resection will include the ipsilateral amygdala, hippocampus, and uncinate gyrus. The full procedure will be recorded by the neurosurgeons performing the resection. Patients will continue taking the same AEDs that they had been taking prior to surgery under the supervision of a neurologist. Patients will not stop AED treatment until the 1-year follow-up even if they do not experience seizures.
Patients enrolled in arm 2 will undergo SEEG implantation and RF-TC for mTLE. SEEG implantation will be performed following pre-surgical evaluation. The target points of the SEEG electrodes will cover the mesial part of the ipsilateral temporal region. Both long-axis and parallel vertical depth electrodes generating a 3-Dimensional space will be designed to guide RF-TC in cases of small ablation volume (Fig. 2). For each patient, bipolar coagulation will be performed on each of two contiguous contacts of the longitudinal and vertical electrodes using the same parameters. Contacts between electrodes will be further coagulated at intervals of < 5 mm to ensure freedom from vascular injury. This modified approach provides extended volume including the amygdala, hippocampus, subiculum, and part of the entorhinal cortex (Fig. 2). Similarly, patients will not stop taking AEDs until the 1-year follow-up.
Outcomes
The primary outcome measure is cognitive function after treatment, which will be assessed using the Chinese version of the full-scale Wechsler Adult Intelligence Scale-IV (WAIS-IV-C) for adults (> 16 years old) or the Chinese version of the Wechsler Children’s Intelligence Scale-IV (WCIS-IV-C) for children. Assessments will be performed before and 1 year after surgery. Higher values are considered indicative of better outcomes.
Secondary outcomes are as follows:
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Post-surgical seizure outcomes after 1 year based on Engel classification. Engel 1A and 1B will be considered to reflect seizure freedom, while Engel 1C-4 will be considered to reflect seizure recurrence. Seizure outcomes will be assessed at 3, 6, and 12 months via telephone interviews or outpatient visits with the patient and direct relatives. Seizures occurring within the first 2 weeks after surgery will not be considered to reflect seizure recurrence.
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Visual field examination results: We will compare the number of patients with visual field defects between arm 1 and arm 2 before and 1 year after surgery.
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The number of participants with procedure-related complications 1 year after surgery, including postoperative stroke with or without symptoms (via MRI); postoperative intracranial bleeding with or without symptoms (via MRI); postoperative intracranial infection; postoperative wound infection; and postoperative subcutaneous dropsy.
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Quality of life after treatment. Values will be assessed using the Quality of Life in Epilepsy-89 scale (QOLIE-89) for adults (age: 17–60) and the Quality of Life in Epilepsy-48 scale (QOLIE-48) for children (age: 14–16) 1 year after surgery.
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Average hospitalisation expenses 1 month after surgery.
All clinical and outcome-related data will be collected by two experienced clinicians (one neurologist and one neurosurgeon). Detailed data collection and follow-up time line are shown in Table 1. For each patient, a Case Report Form (CRF) including comprehensive patient information, clinical data, scale results, and outcomes will be completed.
Table 1
Assessment
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Baseline
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Follow up
7 ± 2 days
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Follow up
90 ± 7 days
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Follow up
180 ± 7 days
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Follow up
360 ± 14 days
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Informed consent
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Demographics
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History of epilepsy
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Physical examination
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EEG
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*□
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AEDs
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□
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Visual field assessment
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□
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WAIS-IV-C/WCIS-IV-C
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□
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□
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QOLIE-89/QOLIE-48
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□
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Engel classification
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□
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□
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PET
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□
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MRI
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□
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*□
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Adverse events
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□
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Concomitant medication
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□: required; *□: optional; EEG: electroencephalogram; AEDs: antiepileptic drugs; WAIS-IV-C: Chinese version of the Wechsler Adult Intelligence Scale-IV;
WCIS-IV-C: Chinese version of the Wechsler Children’s Intelligence Scale-IV; QOLIE-89: Quality of Life in Epilepsy-89; QOLIE-48: Quality of Life in Epilepsy-48; PET: positron emission tomography; MRI: magnetic resonance imaging.
Sample size
The sample size was calculated based on our previous experience (cognitive performance decrease of 25% after ATL), similar to findings reported in earlier studies.18 Approximately 5% of patients exhibited decreased cognitive performance after SEEG-guided RF-TC in our previous series, while most previous studies have reported improvements or a lack of impairment.20–22 We expect to enrol 20 patients in each arm using a one-sided 95% confidence interval, a non-inferiority limit of 10%, and an expected withdraw rate of 20%. Thus, we aim to include a total of 40 patients in this trial. Patients will be recruited from outpatient and MDT with strict inclusion criteria.
Participants will be replaced if they withdraw at any time prior to the final follow-up supervised by Dr Yong-Zhi Shan and Guo-guang Zhao. Those who withdraw from the study during treatment because of specific medical or technical events will also be monitored and replaced. The trial conduct will be audited by the investigators with the whole MDT monthly.
Randomisation and blinding
All patients and their direct relatives will be informed regarding the intentions and technological procedures involved in the study at the time of hospitalisation. Written informed consent will be obtained following patient agreement. The sealed-envelope system will be used for randomisation of the patients into two groups. The envelope will be supported by a recognised third-party organisation. Neither the investigator nor the participants will be aware of each envelope’s contents.
Clinicians will know the exact allocation of each patient, and blinding will not be performed. In addition, patients will not be blinded due to the differences between the treatment strategies. Patients will also provide written informed consent the day prior to surgery.
Statistical analysis
In the present study, we aim to compare treatment outcomes between two different surgical strategies for mTLE. Kaplan-Meier estimator will be conducted to compare the seizure outcome between two groups at 3, 6,12 months’ interval. Cognitive function, visual field defects and Engel class I outcomes will be compared between the groups using χ2 tests or t tests. Subgroup analysis will be made if the results are positive. Average complication rate and hospitalisation expenses will be qualitatively compared between the two groups. For each separate group, a Logistic analysis will be made to further explore the factors which may affect the outcomes (p < 0.05). Statistical analysis will be performed using SPSS version 21 (SPSS Inc., Chicago, IL, USA) and/or MATLAB_R2018a (MathWorks Inc., Natick, MA, USA).
Patient and public involvement
We are here to state that the patients or public were not involved in the design of our research. The protocol and the design of this study were discussed and developed by MDT including neurologists, neurosurgeons, neuroimaging physicians and neuropsychology physicians.
Ethical considerations and results dissemination
Written informed consent will be obtained from all participants and their representatives. The STARTS protocol has been approved by the ethics committee at Xuanwu Hospital and will be conducted in accordance with the Declaration of Helsinki. The data monitoring committee will consist of one neurosurgeon and two neurologists independent from this study. STARTS is also registered at the US National Institutes of Health (ClinicalTrials.gov: NCT03941613, registered on May 8, 2019). The schedule and the results of this study the will be open on ClinicalTrials.gov website and will also be open to peer-reviewed journals. If possible, the results will be shown on the national conference and will be further discussed accompany with specialists on the same research field. All the participants’ personal information will be confidential to the public and journal.