Abstract
Objective
To investigate the role of low-frequency repetitive transcranial magnetic stimulation (rTMS) along with conventional physiotherapy in the functional recovery of patients with subacute ischemic stroke.
Design
Double-blind, parallel group, randomized controlled trial.
Setting
The outpatient department of a tertiary hospital participants: first ever ischemic stroke patients (N=96) in the previous 15 days were recruited and were randomized after a run-in period of 75±7 days into real rTMS (n=47) and sham rTMS (n=49) groups.
Intervention
Conventional physical therapy was given to both the groups for 90±7 days postrecruitment. Total 10 sessions of low-frequency rTMS on contralesional premotor cortex was administered to real rTMS group (n=47) over a period of 2 weeks followed by physiotherapy regime for 45-50 minutes.
Main Outcome Measures
The primary efficacy outcomes were change in modified Barthel Index (mBI) score (pre- to postscore) and proportion of participants with mBI score more than 90, measured at 90±7 days postrecruitment. The secondary outcomes were change in Fugl-Meyer Assessment–upper extremity, Fugl-Meyer Assessment–lower extremity, Hamilton Depression Scale, modified Rankin Scale, and National Institute of Health and Stroke Scale (pre- to post-rTMS) scores at 90±7 days post recruitment.
Results
Modified intention to treat analysis showed a significant increase in the mBI score from pre- to post-rTMS in real rTMS group (4.96±4.06) versus sham rTMS group (2.65±3.25). There was no significant difference in proportion of patients with mBI>90 (55% vs 59%; P=.86) at 3 months between the groups.
Conclusion
In patients with subacute ischemic stroke, 1-Hz low-frequency rTMS on contralesional premotor cortex along with conventional physical therapy resulted in significant change in mBI score.
Stroke is the leading etiology for severe adult disability in the world.1 The stroke recovery may not be always complete. Though the acute stroke interventions have improved dramatically in last few decades with mechanical thrombectomy and thrombolytic therapy, very few studies are conducted in newer treatment modalities for stroke recovery. Repetitive transcranial magnetic stimulation (rTMS), a noninvasive approach, enhances cortical excitability which helps in the motor and functional outcomes of stroke. In stroke patients, the inhibitory activity from the unaffected hemisphere also contributes to the disruption in the affected hemisphere. Hence, 2 potential targets for transcranial magnetic stimulation (TMS) are either by suppressing the inhibitory activity of unaffected (contralesional) motor cortex via low-frequency rTMS (≤1 Hz) or by enhancing the excitability of affected cortex (ipsilesional) by high-frequency rTMS (≥1 Hz). But the therapeutic potential of rTMS is nonconclusive. A Cochrane systematic review and meta-analysis concluded that further evidence is required regarding efficacy of rTMS in stroke.2 Another meta-analysis claimed that rTMS had a positive effect on stroke motor recovery, and low-frequency rTMS may be better than high-frequency rTMS.3 There were severe methodological limitations in included studies especially not studying a clinically meaningful primary outcome such as activity of daily living score. Since there was a clinical equipoise, we conducted a randomized double-blind sham-controlled trial to test the hypothesis whether in patients with subacute ischemic stroke (<3 mo), the use of low-frequency rTMS along with standard physiotherapy will lead to better functional outcome compared to those receiving standard physiotherapy alone.
Methods
Participants, setting, and study design
Ours is as a single center, randomized, parallel group, double-blind, sham-controlled trial. We included patients aged 18-75 years, with first ever acute ischemic stroke, within last 15 days documented by computed tomography or magnetic resonance imaging scan of the head and National Institutes of Health Stroke Scale (NIHSS) of 4-20. We excluded participants who were medically unstable, pregnant, had coexistent brain lesions (tumor, infection), comatose, mechanical ventilation, history of epilepsy, or having any surgical implant or pacemaker. The study was registered under clinical trials with CTRI number CTRI/2016/02/006620 at www.clinicaltrials.gov.
Procedure
Prerandomization run-in period
The baseline clinical assessment of the recruited participants was done by first author who is certified in NIHSS. Baseline data including demographics, risk factor profile, biochemical parameters, imaging parameters, stroke subtype, NIHSS, modified Rankin Scale (mRS), modified Barthel Index (mBI), Hamilton Depression Scale (HAMD), and Fugl-Meyer Assessment of upper and lower extremity were carried out at the time of recruitment. A trained licensed physiotherapist gave standard physical therapy to all the recruited participants till study completion (90±7d).
All participants received standard of care that includes passive, active, and active assisted exercises. Participants were encouraged to continue standard therapy at home after discharge, and the total number of hours of an individual exercise was not monitored.
Randomization
Participants were randomly assigned in a 1:1 ratio to receive either real rTMS or sham rTMS. Randomization was done using a computer-generated randomization sequence. Allocations were concealed using sealed, opaque, numbered envelops and were opened only during the time of randomization phase. The investigator, physiotherapist, and participants were masked to the treatment allocation. Laboratory technician who was not part of the study was responsible for the random allocation of participants to sham or real rTMS group. The outcome assessor was also blinded to allocation.
Interventions
Low frequency rTMS was performed using Magstim Rapid2 stimulatora equipped with air cooled figure of 8 coil (70 mm), ie, biphasic pulse was used for rTMS. The resting motor evoked potential (MEP) was ascertained using an electromyogram, recording from the abductor pollicis brevis in keeping with the International Federation of Clinical Neurophysiology recommendations.4 The coil was placed tangentially to the scalp over the hand area of the primary motor cortex to calculate hot spot. Hot spot was defined as the location on the scalp where stimulation of a slightly supra threshold intensity elicited the largest MEP in the abductor pollicis brevis muscle. After the hot spot was identified, resting motor threshold was determined using the lowest stimulus intensity to produce MEP of >50μV peak to peak amplitude in 5 of 10 subsequent trails. If no MEP was obtained at the time of hot spot calculation in the affected ipsilesion M1, then the hotspot was defined as the symmetric location to the contralesion M1. The stimulation parameters were chosen in accordance with the safety guidelines for rTMS.4 Total 750 pulses, 75 trains using low frequency (1 Hz) with inter train interval of 45 seconds at calculated intensity of 110% resting motor threshold (Fc3/Fc4), was administered to the randomized patient by a qualified technician in the Institute TMS Laboratory. Localization was done using 10-20 electroencephalogram (EEG) method. Sham rTMS pulses were administered using the same stimulation parameters.
Over the contralesion premotor cortex area with the figure of 8 coil angled at 90 degrees from the scalp. Patient was awake throughout the rTMS administration. The rTMS sessions on each day was followed by 45-minute conventional physical therapy regime given by a trained physiotherapist.
Monitoring for complications
All the participants were monitored for any adverse events. A checklist of previously reported side effects was used to report any possible adverse events.
Outcomes
The coprimary efficacy outcomes were changes in mBI score (pre- to post-rTMS) and functional independence score (mBI) >90, measured at 3 months of stroke onset. The secondary efficacy outcomes were changes in Fugl-Meyer Assessment of upper extremity, Fugl-Meyer Assessment of lower extremity, mRS, and NIHSS scores (pre- to post-rTMS) at 3 months.
Sample size
Sample size was calculated for primary clinical efficacy outcome, mBI with a superiority hypothesis assumption. Calculation was based on the study done by Khedr et al,5 who reported 34.6% and 7.7% of good or excellent outcome under rTMS and sham rTMS, respectively, which yielded a sample size of 45 in each arm (90% power and a 2-sided α level of 5%). Adjusting for 10% attrition we estimated a sample size of 100 (50 in each arm).
Statistical analysis
Statistical analysis was performed using Stata version 14.1b and was based on modified intention to treat principle. Normal distribution was tested using Kolmogorov-Smirnov statistic. Study data were not after normal distribution; hence, nonparametric tests were applied. For categorical data, 2 × 2 table was generated. Chi-square test or Fisher exact test was applied to compare the properties in the 2 groups. Between-group comparisons were carried out using Wilcoxon rank-sum test. Wilcoxon signed-rank test was used to assess changes in the scores within the same group. McNemar test was applied for the categorical variable.[…]