Transcranial Direct Current Stimulation, Treatment of Childhood Drug-Resistant Lennox-Gastaut Syndrome, A Pilot Study
Condition: Lennox-Gastaut Syndrome
MeSH terms: Lennox Gastaut Syndrome; Syndrome
Study type: Interventional
Phase: Phase 4

Summary: 
      Background: Lennox-Gastaut syndrome (LGS) is a severe childhood epileptic syndrome with high
      pharmacoresistance. The treatment outcomes are still unsatisfied. The investigator previous
      study of cathodal transcranial direct current stimulation (tDCS) in children with focal
      epilepsy showed significant reduction in epileptiform discharges. The investigator
      hypothesized that cathodal tDCS when applied over the primary motor cortex (M1) combined with
      pharmacologic treatment will be more effective for reducing seizure frequency in participants
      with LGS than pharmacologic treatment alone.

      Material and Method:

      Study participants were randomized to receive either:

        1. pharmacologic treatment with 5-consecutive days of 2 milliampere (mA) cathodal tDCS over
           M1 for 20 min or

        2. pharmacologic treatment plus sham tDCS. Measures of seizure frequency and epileptic
           discharges were performed before treatment and again immediately post-treatment and 1-,
           2-, 3-, and 4-week follow-up.
    

Detailed description: 
      Participant recruitment and informed consent Study participants were recruited via
      advertisement at the pediatric outpatient department, Srinagarind Hospital, Faculty of
      Medicine, Khon Kaen University, Thailand. The study procedures were described to any eligible
      participants who expressed an interest in participating in the study by a pediatric
      neurologist.

      Criteria for LGS were defined according to the triad of:

        1. polymorphic intractable seizures that are mainly tonic, atonic, and atypical absence
           seizures,

        2. cognitive and behavioral abnormalities,

        3. EEG with paroxysms of fast activity and slow (less than 2.5 Hz) generalized spike-wave
           discharges (GSWD).

      The diagnosis was confirmed by a pediatric neurologist using the thoroughly history taking,
      physical examination, EEG, and brain MRI.

      Study inclusion criteria included:

        1. diagnosis of LGS;

        2. failure of more than two first-line antiepilepsy drug (AEDs) to control seizures;

        3. average seizure frequency of more than one per month for 18 months and no more than
           three consecutive seizure-free months during that interval;

        4. age between 6 and 15 years.

      The exclusion criteria were

        1. drug addiction, pregnancy, skull defect, and other serious neurological diseases; and

        2. change in dosage of antiepileptic drugs or use of herbal remedies and other alternative
           therapies.

      All participants' guardians gave their written informed consent. The study conformed to the
      declaration of Helsinki and was approved by the Ethics Committee of Khon Kaen University
      (Identifier number: Human Ethic (HE) 521232.

      Experimental design

      The current study was a randomized double-blind controlled trial performed over a total of 6
      weeks consisting of:

        1. a 1-week period of observation to assess the baseline seizure frequency,

        2. a 5 consecutive days of 2 mA cathodal tDCS for 30 minutes, and

        3. 4 weeks of follow-up.

      Just before the treatment phase, study participants were randomized in a 2:1 ratio in blocks
      of four randomization to receive either (a) pharmacologic treatment plus active tDCS
      stimulation or (b) pharmacologic treatment plus sham tDCS stimulation for 5 days.
      Participants were asked to continue their routine anti-epileptic medication regimen
      throughout the duration of the 6-week trial.

      Pharmacologic treatment

      Since there is a considerable degree of heterogeneity with LGS, individualized approaches are
      necessary. The investigator firstly uses the antiepileptic drugs that currently approved by
      the Food and Drug Administration and available in our institute: lamotrigine, topiramate,
      clobazam, and clonazepam depended on seizure types. The investigator gave lamotrigine 1-20
      mg/kg/day with slowly titration for tonic, tonic-clonic, atypical absences, and atonic
      seizures. Clobazam 0.25-3.5 mg/kg/day was added in the cases that refractory to lamotrigine
      and in the participants with myoclonic seizures. The investigator used clonazepam 0.04-0.2
      mg/kg/day instead of clobazam in some cases when clobazam was not available. We used
      topiramate 1-10 mg/kg/day in the participants who refractory to lamotrigine and clobazam. In
      some cases, that refractory to the aforementioned antiepileptic drugs, the investigator gave
      zonisamide 1-20 mg/kg/day, levetiracetam 10-80 mg/kg/day, and nitrazepam 0.1-0.8 mg/kg/day
      [8].

      Randomization and Blinding Prior to the treatment phase, study participants were randomized
      in a 2 : 1 ratio in blocks of four randomizations (by OT) to receive either (1) active tDCS
      stimulation or (2) sham tDCS stimulation. Participants were asked to continue their routine
      medication regimen throughout the trial. The staff who generated the random allocation
      sequence, enrolled participants, and assigned participants to interventions were not involved
      in any assessments. After assignment to the intervention groups, the pediatric neurologist
      who carried out the seizure assessments (NA) was blind to treatment condition. Because the
      study participants were also blind to treatment condition, this is a double-blind study.

      Active and Sham Transcranial Direct Current Stimulation.

      tDCS was applied via water-soaked pair of surface sponge electrodes (35 cm2) and delivered
      through battery-driven power supply. The constant current stimulator had a maximum output of
      10 mA (Soterixmedical, Model 1224-B, New York, USA). The stimulation site over the left M1,
      located based on the international electroencephalography (EEG) 10/20 electrode placement
      system. The reference electrode was placed over the right shoulder area. The tDCS device was
      designed to allow sham stimulation by placing the control switch in front of the instrument
      which was easily covered by an opaque adhesive during stimulation. Therefore the participants
      or their gradients could not know whether active or sham stimulation. The power lit up
      indicator was also on the front of the machine during the time of intervention both in active
      and sham stimulations. However, in sham stimulation, the current was discontinued after 30
      seconds while the power indicator remained on [18].

      Measures Number of seizures Since Lennox-Gastaut Syndrome compose of many seizure types. All
      seizures were classified according to the International League Against Epilepsy Revised
      Classification of Seizures [29]. The participants were monitored by video-EEG in order to
      classify the types and frequencies of seizures, and all of the caregivers were taught how to
      count and classify seizures on the basis of observations and video recordings. The caregivers
      were also taught the rules for diary recording prior to the baseline period. All of the
      caregivers were blinded to both treatment and sham group. In case of the participant who had
      more than 1 caregiver. The investigator suggested them to refer the daily diary to the person
      who cared the participant in time.

      Number of seizure was the primary outcome variable, and was assessed by using a daily diary.
      For the baseline (pre-treatment) assessment, the caregivers were asked to record the number
      of seizures every day for 7 days during the baseline period on a daily diary. These 7 days
      numbers of seizures were averaged into a single rate per day of baseline average seizure
      frequency. During the 5 consecutive day of treatment, the caregivers were asked to record the
      daily children seizure frequency. Finally, daily 24-hour recording were administered for four
      weeks following treatment. 1-, 2-, 3-, and 4-week composite number of seizures were computed
      as an average of the daily number of seizures for each epoch (i.e., the 1-week follow-up
      average number of seizures = average of 7 daily number of seizures the first week after
      treatment).

      Epileptic discharges

      Epileptic discharges, the secondary outcome variable of this study, were recorded by a
      trained staff. EEG was acquired from all participants using a 32-channel, international 10-20
      system of electrode placement (Neuvo, Compumedics, Australia with PerFusion EEG software).
      EEG was collected for 30 minutes in the awake state only. EEG was recorded as a single
      session at baseline, immediately, 1-, 2-, 3- and 4- weeks follow-ups. EEG data were analyzed
      by visual inspection. The numbers of epileptic discharges in the 30-minute recording were
      assessed by a practicing pediatric neurologist and clinical neurophysiologist (N.A.), who was
      blinded to the treatment condition. The EEGs that included as abnormal EEGs in LGS are slow
      spike-wave complexes at <3 Hz that occur during wakefulness. The complexes consist of a spike
      (duration < 70 msec) or a sharp wave (70-200 msec), followed first by a positive deep trough,
      and then a negative wave (350-400 msec). Paroxysmal fast rhythms (10-20 Hz) occur mainly
      during non-rapid eye movement sleep [30]. One slow spike-wave complex or one episode of
      paroxysmal fast rhythms were counted as one epileptic discharge.

      Vital signs and oxygen saturation monitoring

      All participants were closely observed by physicians during and post-treatment. Oxygen
      saturation and vital signs were monitored for 30 minutes before, during, and 30 minutes after
      the treatment. Pulse rate was measured by automatic sphygmomanometer (Ua-767 Plus, UK) in the
      supine position. Blood pressure (mm Hg) was measured by automatic sphygmomanometer (Ua-767
      Plus, UK) in the supine position with a pediatric-size cuff wrapped around the right upper
      arm. Body temperature was measured by an axillary electronic thermometer. Respiratory rate
      was measured by counting chest rising for 60 seconds. Pulse oximeter was placed on the left
      index finger to monitor oxygen saturation throughout the procedure.

      Adverse events

      Adverse events as well as other signs and symptoms were reported by participants' guardians
      every day after treatment. Theses self-recordings terminated at 4 weeks after stimulation.

      Statistical analysis

      The investigator first computed means and standard deviations (SD) of the demographic and
      outcome variables for descriptive purposes. Next, the investigator compared the two treatment
      conditions (active tDCS versus sham tDCS) on all baseline outcome measures to ensure baseline
      equivalence using t-tests. Results are presented as means and SD. Both the primary (seizure
      frequency) and exploratory (epileptic discharges) hypotheses were tested using repeated
      measures analysis of variance (ANOVA) followed by Least Significant Difference to help
      understand any significant effects found. To describe the clinically meaningfulness of any
      changes, the investigator computed the percent reduction of number of seizures and epileptic
      discharges in each condition from pre- to post-treatment and from pre-treatment to 4-week
      follow-up. For all analyses, p values of < 0.05 were considered statistically significant.
      Analyses were completed using STATA software, version 10.0 (StataCorp, College Station, TX).
    

Intervention name(s): tDCS
Intervention type(s): Device
Intervention description(s): brain stimulation by cathodal electrode at motor cortex
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Transcranial direct current stimulation; Cathodal stimulation; Childhood Pharmacoresistant epilepsy; Lennox-Gastaut syndrome