Transcript rTMS
Dec 7, 2012 Youichi Saitoh, M.D., Ph.D. Department of Neuromodulation and Neurosurgery Office for Univeristy-Industry Collaboration, Osaka University Electrical motor cortex stimulation; EMCS EMCS expand to the world from Japan Rasche et al., Pain, 2006 Saitoh et al. J Neurosurg 2000 Department of Neurosurgery, Osaka University Graduate School of Medicine Efficacy of EMCS on intractable neuropathic pain Approximately half of the patients satisfy No large double-blinded clinical trials Saitoh and Yoshimine, Acta Neurochir Suppl, 2007 Saitoh Y et al, Acta Neurochir, 2007 Repetitive transcranial magnetic stimulation (rTMS) Figure-8-coil is most popular Eddy current Cochrane review O’Connell NE et al, 2010 Non-invasive brain stimulation techniques for chronic pain Single doses of high-frequency rTMS of motor cortex may have short-term effects on chronic pain. Efficacies of cranial electrotherapy stimulation and transcranial direct current stimulation are uncertain. VS Multi-centered, Randomized, double-blind, sham-controlled, crossover study 2009 〜2011 This study was funded by the Japanese Ministry of Health, Labour and Welfare with a Health and Labour Sciences Research Grant. Randomized, double-blind, shamcontrolled, crossover study Real (5Hz) and sham stimulations are randomized. Double-blind Randomized Crossover Study Specialist of biological statistics randomized the patients to two groups. Validation of efficacy and safety of daily rTMS for 2 weeks. Previous studies were mostly single session Primary endpoint is VAS, secondary is SF-MPQ Realistic sham is applied. Synchronized cutaneous electrical stimulation is delivered. Hamada M et al, Mov Disord, 23:1524-31, 2008 70 patients Randomized, double-blind, shamcontrolled, crossover study Seven centers Rehabilitation, Hokaido Univ. Neurology, Fukushima Neurosurgery, Nihon Univ. Neurosurgery, Hamamatsu Univ. Neurosurgery, Osaka Univ. Neurology, Kinki Univ. Neurology, Univ. of Occulational Protocol of sham-controlled crossover study Observation day Examination rTMS Agreement Background MRI/EEG Subjective sign Objective sign Adverse effect VAS SF-MPQ BDI □ Intervention Observation 1 2 3 4 5 6～7 8 9 10 11 12 13～14 15 16～21 22 23～28 29 □ □ □ □ □ □ □ □ □ □ □ □ □ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ◆ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ PGIC ○ ○ ○ ○ VAS, Visual analogue scale; SF-MPQ, short form of McGill pain questionnaire; BDI, Beck depression inventry ○ ○ ○ ○ ○ ○ Trial profile Real first Sham first Results of short-term effect of VAS Primary endpoint Group A (Real) Group A (Sham) Group B (Real) Group B (Sham) 14 12 VAS reduction rate % (SEM) 10 8 6 4 2 0 -2 1 2 3 4 5 8 First week 9 10 11 Second week First period 12 1 2 3 4 5 8 First week 9 10 11 Second week Second period 12 Day Results of short-term effect of SF-MPQ Secondary endpoint Group A (Real) Group A (Sham) Group B (Real) Group B (Sham) 30 SF-MPQ reduction rate % (SEM) 25 20 15 10 5 0 1 2 3 4 5 8 First week 9 10 11 Second week First period 12 1 2 3 4 5 8 First week 9 10 11 Second week Second period 12 Day Patient global impression of change (PGIC) Intervention Beck depression inventory (BDI) Intervention Forest Plot of subgroup analyses Number of patients Number of responders Mean efficacy rate (%) Interaction p value [95% CI] Sex Male 39 9 23 Female 22 3 13.6 Age [ 10.6 - 31.8 ] [ - 34.9 ] - ] 46.7 ] 2.9 [ <60 24 6 25 [ 9.8 - ≥60 37 6 16.2 [ 6.2 - Underlying disease [ 32 - ] 50 10 20 [ 10 - 33.7 ] Non-cerebral lesion 11 2 18.2 [ 2.3 - 51.8 ] - ] [ Thalamus 28 3 10.7 [ 2.3 - 28.2 ] Lenticular nucleus 17 6 35.3 [ 14.2 - 61.7 ] Others 16 3 18.8 [ - 45.6 ] Face 6 1 16.7 Upper limb 32 8 Lower limb 23 3 Treated painful region 4 [ - ] 0.4 - 64.1 ] 25 [ 11.4 - 43.4 ] 13 [ - 33.6 ] - ] Pain laterality [ 2.7 [ Left 27 6 22.2 [ 8.6 - 42.2 ] Right 34 11 17.6 [ 6.8 - 34.5 ] - ] Previous treatment [ Medication alone 43 9 20.9 [ 10 - Block 12 2 16.7 [ 2.1 - 48.4 ] Others 6 1 16.7 [ 0 - 64.1 ] 0 20 40 60 36 0.513 ] Cerebral lesion Lesion site 0.509 ] 1 0.14 0.588 0.407 1 80 Efficacy rate (%) Figure 6: Forest plot of subgroup analyses Short-term efficacy rate (VAS reduction rate subtracting sham of ≥10%) of each subgroup was shown. 95% CIs were calculated by exact binominal method. Adverse effects Discussion This prospective study shows daily high-frequency rTMS is transiently effective for pain relief in intractable neuropathic pain patients (70 cases). There has been no serious adverse effects. The real rTMS, compared with the sham, showed significant short-term improvements in VAS and SF-MPQ scores without a carry-over effect. The result of PGIC suggested cumulative effect. More than once a day or continuous rTMS treatment may improve the effect. In this study, 81% of enrolled patients were post-stroke pain and 60.7 y.o. (mean) which is older than previous studies. Therefore, the effect was mild but significant. Cerebral mechanism of pain relief (EMCS, rTMS) rTMS M1 ACC PFC Modulate pain recognition S2 Ins Th PAG Elicit plastic changes Modulate a pain threshold Pain relief Thank you for attention!!