Y P O Potential clinical applications of TMS in pediatrics C T O N O D E S Aaron Boes, MD, PhD A Sidney R. Baer Clinical Neuroscience Fellow, BIDMC E Pediatric Neurologist, MGH L P
Y P O C T O N Disclosure: Off-label uses of TMS will be discussed O D E S A E L P
Y P O Topics C T Highlight of a few areas in which TMS may find clinical O applications in the pediatric population in the near future. N - Depression O - Rehabilitation D - Epilepsy - Autism E - ADHD S A - Tourrettes E L P
Y P O C T O Please interrupt, ask questions. N O D E S A E L P
Y P O Challenges and opportunities in pediatrics C T Neurodevelopmental disorders are common. 1 in 6 (Boyle, O 2011) N O D Neuropsychiatric disease = #1 worldwide cause of disability E age 10-24 and overall (Lancet, 2011 & 2013) S Current therapies are inadequate A E L P
Y P O Current knowledge gap in clinical neurology and psychiatry… C T Brain disorders currently conceptualized of in terms of O dysfunctional networks (Bianchi, 2012) N Diagnoses are based on behavior \ subjective symptoms, O not network dysfunction. D Therapy does not target dysfunctional networks. E S A E L P
Y P O Bridging the gap – Diagnosis and therapy targeting C dysfunctional networks T O N O D E S A E L P
Y P O Why Pediatrics – Why now? C T O All neurodevelopmental disorders and almost 2/3 of neuropsychiatric disorders manifest in the pediatric population N (Kessler, 2005) O Prevention or early diagnosis \ intervention leads to better outcomes. D E S Research on adults may not apply to pediatric patients A E L P
Y P O Interventions in younger people = better return on investment C T O N O D E S A E L P Heckman, Science , 2006 .
Y P O C T O Depression N O > D E S A E L P
Y P O • Clinical problem: C T - Pediatric depression is common, 11% (nimh.nih.gov) O - 30% of adolescents have complete remission with therapy N March, 2007; March, 2004, Brent 2008, Walkup 2010 O > D E S A E L P
Y P O • Clinical problem: C T - Pediatric depression is common, 11% (nimh.nih.gov) O - 30% of adolescents have complete remission with therapy N March, 2007; March, 2004, Brent 2008, Walkup 2010 O > D ________________________________ E - rTMS works for adult depression S - Younger age may be a predictor of treatment response A (Gershon, 2003; Janicak, 2002, Avery, 2008) E L P
Y P O Use of TMS in treating pediatric depression C T O N O Cristopher Wall Paul Croakin D E S A E L P
Y P O TMS in depressed adolescents C T O Prospective, open multicenter trial of rTMS N in adolescents that have not responded to O two prior antidepressant agents. Age14 – > D 17. E S A E L P
Y P O TMS in depressed adolescents C T O Results: N 7 of 8 tolerated procedure. O > 1 dropped out after first 5 minutes, scalp D discomfort. E S A E L P
Y P O C T O N O D E S A E L P
Y P Larger trial ongoing O C T O N O D Randomized, double-blinded, sham-controlled trial. E S N = 50, projected completion 12/2016 A Age range 12-21 E L Sites: Rochester MN, Charleston, South Carolina P
Y P O C T O N Rehabilitation O > D E S A E L P
Y P O • Clinical problem: C T - Pediatric stroke and cerebral palsy are relatively common O and rehabilitation often does not restore function N O > D E S A E L Bernadette Gillick, Warren Lo, Adam Kirton, Calgary U. Of Minnesota P Ohio State
Y P O C T O 2008, Lancet Neurology N N = 10, 9-13 yo, 1 Hz contralesional, 100% MT, 1200 pulses, 20 minutes x8 days O D E S A E L P
Y P O Spastic cerebral palsy N = 17, All with CP C T Randomized, sham O controlled N O 6 sham, 6 1 Hz, 5 5 Hz > D 5 sessions; 90% MT E Increased range of S motion for 5 Hz A E L P
Y P O • More to read…. C T O N O > D E S A E L P
Y P O C T O N Epilepsy O > D E S A E L P
Y P O Sample case: C 15 year old boy was getting dressed this T morning when his father heard a loud thud. O A few minutes later the father checked on N him and he was sleepy, confused and had O bit his tongue. The confusion improved over D 20 minutes. He has one similar episode, but E nobody observed either. S A E L P
Y P O Differential diagnosis… C T O - Seizure N -Syncope (fainting) O -School avoidance (geometry exam) D E S A E L P
Y P O EEG: C T O N O D A single routine EEG is only ~66% sensitive. E S A Sleep deprivation, hyperventilation and E strobe light slightly improve sensitivity. L P Image http://www.seattlechildrens.org/kids-health/image/ial/images/884/884_image.gif
Y P O Could TMS increase the sensitivity of EEG, C moving from a passive test to actively T O probing for abnormalities? N O D E S A E L P
Y P O C T O N O D E S A E L P
Y P O Study Design: C T O - Comparing standard EEG to EEG + TMS (single pulse directed at N each electrode site, looking for abnormal discharges). O - 15 controls and 15 patients with focal-onset epilepsy D E S A E L P http://www.neuroconn.de/diagnose_en/
Y P O Study Results: C T O - TMS+EEG had no false positive results in N controls. O - Sensitivity of standard EEG: 80% D - Sensitivity of standard EEG + EEG\TMS: E 100% S A E L P
Y P O Sample case: C 15 year old boy with possible seizure. T O N - EEG: Abnormal O - Which medicine to start? D E S A E L P
Y P O Could motor cortex neurophysiology, as C assessed with TMS, guide medication T O selection? N O D E S A E L P
Y P O TMS neurophysiology measures relate to neurotransmitter C systems (e.g. SICI:GABA A LICI – GABA B ICF – glutamate) T O Seizure medicines work differentially on neurotransmitter N systems O D We’re beginning to understand how specific medicines impact TMS-measured neurophysiology (e.g. Lang, 2013) E ________________ S It is possible we could select medicines to correct specific A abnormalities in an individual patient. E L P
Y P O Sample case: C T O - EEG: Abnormal N - Which medicine to start? O - Now on keppra D E S A E L P
Y P O C After starting our patient on 1 gram of keppra twice T a day the mother asks “how do we know that the O medicine is working?” N O > D E S A E L P
Y P O C After starting our patient on 1 gram of keppra twice T a day the mother asks “how do we know that the O medicine is working?” N O Could TMS measures of motor cortex > D neurophysiology give us a clue as to whether the medication is effective? E S A E L P
Y P O C T O N O D E S A E L P
Y P O Design C T • 99 drug naïve patients about to start a seizure O medicine had TMS-based neurophysiological N testing. O • They had repeat testing 4-16 weeks later. > D • They were followed up one year later. E S A E L P
Y P O Results C T • At one year 69 of 99 were seizure free. O N O > D E S A E L P
Y P Effective treatment associated with rise in motor threshold O C T O N O D E S A E L P
Y P O Conclusion C T Increased motor threshold and increased O intracortical inhibition after starting a seizure N medicine may predict its effectiveness. O > D E S A E L P
Y P O Sample case: C Now, fast forward 2 years. Our patient has T tried multiple medications and seizures O persist. An MRI has revealed a focal cortical N dysplasia that is the source of the seizures. O D E S A E L P
Y P O C T O N O D E S A E L P
Y P O Sample case: C fMRI and TMS mapping reveal the dysplasia T is immediately adjacent to motor cortex O hand and face area. Surgery would risk N causing hemiparesis. O D E S A E L P
Y P O TMS for the treatment of epilepsy C T Focal epilepsy often does not respond to O medication and surgery often is not a viable option N O Low frequency TMS is able to decrease excitability > D of underlying cortex. E S Can 1 Hz rTMS to the seizure focus be used to A treat the epilepsy? E L P
Y P O C T O N O D E S A E L P
Y P O Design C T • 64 patients with medically refractory focal O epilepsy N • Group randomly split into treatment and sham O groups, defined by strength of TMS pulse (90% > D vs. 20% motor threshold) E • Daily TMS x14 days. S • Outcome measures: Seizure frequency + A epileptiform discharges on EEG E L P
Y P O C T O N O D E S A E L P
Y P O Results C T • Significant seizure reduction and improved O interictal EEG pattern in treatment group. N • Only 2 patients in treatment group at medial O temporal lobe epilepsy and they did not respond > D E S A E L P
Y P O What about therapeutic rTMS with deep C seizure foci? T O N O > D E S A E L P
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