Y P O C T O Neurological Applications of N Transcranial Magnetic Stimulation O D Mouhsin Shafi, MD/PhD E Berenson-Allen Center for Noninvasive S Brain Stimulation A BIDMC, Harvard Medical School E L P
Y P Overview of Talk O C • FDA-Approved Indications T – Presurgical Motor & Language Mapping O – Migraine N • Diagnosis / Prognosis O D – Motor outcome after stroke, Epilepsy, Vegetative state E • Therapeutics S A – Review of results across neurologic indications E L P
Y P Overview of Talk O C • FDA-Approved Indications T – Presurgical Motor & Language Mapping O – Migraine N • Diagnosis / Prognosis O D – Motor outcome after stroke, Epilepsy, Vegetative state E • Therapeutics S A – Review of results across neurologic indications E L P
Y P Motor / Language Mapping O C T O • FDA approval of Nexstim N NBS device for: – Mapping of the primary O motor cortex D – Localization of cortical areas E that do NOT contain S essential speech function A – For pre-procedural planning E L P Picht 2011 Neurosurgery
Y Motor mapping P O • Comparing nTMS to Direct C Cortical Stimulation (DCS): – Mean distance between nTMS T & DCS hotspots was 7.83 +/- O 1.18 mm for APB (95% CI 5.36 to 10.36 cm) N – nTMS and DCS hotspots were in same gyrus for all patients O D E S A E L P Picht 2011 Neurosurgery
Y P nTMS vs fMRI O C • Several studies have evaluated accuracy of motor mapping with nTMS vs fMRI (with DCS as gold standard) T O – Forster 2011, Neurosurgery : 10 pts, mean distance to DCS hotspot 10.5 +/- 5. 7 mm for nTMS vs 15.0 +/- 7.6 mm for fMRI N – Mangraviti 2013, Neurol Sci : 7 patients, mean distance to DCS O hotspot 8.5 +/- 4.6 mm for nTMS vs 12.9 +/- 5.7 mm for fMRI D Coburger 2013, Neurosurg Rev : 30 E patients; all 30 completed nTMS, S whereas only 23 completed fMRI. A Authors binned results into 4 E levels, where 1 is most accurate, 4 L is least accurate P
Y P Motor mapping w/ nTMS improves outcome? O C • Krieg 2014 Neurosurgery : Compared outcomes in 100 consecutive patients bw 2010-2013 vs 100 historical T controls without nTMS from immediately prior period O – All patients underwent intraoperative MEP monitoring as well N – Craniotomy size significantly smaller in nTMS group O – 12 pts in nTMS group improved, vs only 1 in control group D – Residual tumor in 22% of nTMS group vs 42% of controls E S A E L P
Y P Motor mapping w/ nTMS improves outcome? O C • Frey 2014 Neurosurgery : Compared outcomes in 250 consecutive pts from 2007 – 2012 with 115 controls T from 2005-2007 O – 165 cases with intraoperative stimulation mapping, nTMS N location of primary motor cortex confirmed in all cases. O – In 82 cases with navigated intraop stim, mean distance bw D nTMS and DCS hotspot was 6.2 mm (range 0.4 – 14.8 mm) – Gross total resection achieved in 59% of nTMS group vs only E 42% of historical control, with no change in post-op deficits S A Progression-free survival E significantly higher in nTMS group than in control group L P (15.5 vs 12.4 months), although no change in overall survival
Y P Language mapping O C • Picht 2013, Neurosurgery : Evaluated nTMS and DCS responses during language mapping in 20 patients with T O tumors close to left-sided language areas N O D E S A E L P
Y P Language mapping … O C T O • A subsequent study (Tarapore 2013, N NeuroImage ) also O demonstrated high D negative predictive value, with E improved specificity S A E L P
Y Compared with fMRI and DCS P O C Ille 2015a, b: T Compared language O mapping results from N rTMS (C) and fMRI (D) O with those from DCS D (B) E S A E L P
Y P And may have beneficial effects O C T O N O D E S A E L P Early language deficits decreased Craniotomy size smaller w/ TMS Sollman 2015
Y P Abortive therapy migraine O C • FDA approval for the SpringTMS single-pulse T portable TMS system obtained for abortive therapy O of migraine with aura N – 2 pulses of TMS administered approximately 30s apart to occipital region O D E S A E L P Image from www.medgadget.com
Y P Efficacy in acute migraine O C • Randomized 201 patients with migraine with aura, 1-8 episodes per month, aura for at least 30% of episodes T O – 201 randomized, 164 had migraines and treated N • Higher pain-free response rates after 2 hours (39% in verum vs 22% in sham), sustained at 24 and 48 hours O D HOWEVER, a number of secondary endpoints (patients E who achieved no or mild pain 2h S after treatment, use of rescue A drugs, consistency of pain relief, E global assessment of relief) L showed no significant differences P Lipton, Lancet Neurology 2010
Y P Overview of Talk O C • FDA-Approved Indications T – Presurgical Motor & Language Mapping O – Migraine N • Diagnosis / Prognosis O D – Motor outcome after stroke, Epilepsy, Vegetative state E • Therapeutics S A – Review of results across neurologic indications E L P
Y MEPs predict functional recovery after P acute stroke O C T O N O D E S A E L P Stinear 2012, Brain
Y Paired-pulse measures identify cortical P O hyperexcitability in Epilepsy C T O N O D E S A Paired-pulse measures suggest altered excitation E / inhibition balance in patients with newly- L diagnosed epilepsy compared to healthy controls P Badawy 2007 Ann Neurol
Y P And predict response to medications O C TMS-EMG paired-pulse measures normalize in T patients who respond to O meds; no such changes seen N those with ongoing seizures O D E S A E L P Epilepsy patients, before meds Badawy 2010, Ann Neurol Epilepsy patients, after meds Normal controls
Y P Diagnosis of Persistent Vegetative vs O Minimally Conscious State Casali 2013, Science Trans Med C T O N O D E S A E L Decreased complexity of evoked response in subjects with loss of P consciousness due to any etiology, and in patients with vegetative versus minimally conscious versus locked-in states M /F
Y P Overview of Talk O C • FDA-Approved Indications T – Presurgical Motor & Language Mapping O – Migraine N • Diagnosis / Prognosis O D – Motor outcome after stroke, Epilepsy, Vegetative state E • Therapeutics S A – Review of results across neurologic indications E L P
Y P Theraputic effects? O C • rTMS has been studied as a therapeutic modality in different neurologic conditions including T – Epilepsy O – Migraine prevention N – Motor rehabilitation after stroke O – Cognitive rehabilitation in post-stroke aphasia, post- stroke neglect and Alzheimer’s Disease D – Movement Disorders (primarily Parkinson’s) E – Chronic Pain S – Tinnitus A • However, FDA indication has not been yet obtained E for any of these (multi-center trials currently L underway in several disease conditions) P
Y P Key References O C • Handbook of Clinical Neurology T – Volume 116, Pages 2-763, 2013; Edited by Andres O Lozano and Mark Hallett N – Overview of Deep Brain Stimulation and Noninvasive O Brain Stimulation across spectrum of neurologic D diseases • Lefaucheur et al, Clinical Neurophysiology 2014 E S – Recent evidence-based review/guidelines on A therapeutic use of rTMS in neurologic and psychiatric E diseases L P
Y P Quality of studies varies O C • Studies classified into class I, II, III or IV based on quality of evidence T O N O D E S A E L P Brainin 2004 Eur J Neurol
Y P Classification of biases O C T O N O D E S A E L P Cochrane Handbook for Systematic Reviews of Interventions, 2008
Y P Assessing studies O C T O N O D E S A E L P Cochrane Handbook for Systematic Reviews of Interventions, 2011
Y P Blinding in TMS studies is difficult O C • TMS produces – An auditory clicking sound w/ bone conduction T O – A tapping sensation (trigeminal afferents) N – Contraction of the temporalis and frontalis muscles O • Particularly problematic in trials in which “real” D stimulation is used to determine motor threshold for titration of stimulation intensity crossover trials E compromised, parallel-group studies are needed! S A • Recently, placebo coils that can be preprogrammed E and that use electrical stimulation to produce scalp L sensations have become commercially available P
Y P An overview of the current evidence O C T O N O D E S A E L P Shafi et al, in preparation
Y P Epilepsy O C • Trials have assessed the utility of rTMS in T medication-refractory epilepsy (~1/3 of patients) O – Typically apply low-frequency rTMS to the epileptic N focus or have applied to the vertex (regardless of O location of epileptic focus) D E S A E L P Lefaucheur 2014 Clin Neurophys
Y P Parallel-group studies O C T O N O D E S A E L P Shafi et al, in preparation
Y P Remarkable effects sometimes seen O C T O N O D E S Sun 2012 Epilepsia A • Decrease in seizure frequency greater than is typically E seen in pharmacologic trials L • But beneficial effects only seen when rTMS is targeted P specifically to the seizure focus on the neocortical surface • Multi-center trials needed to confirm findings!
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