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Home , Frontal lobe, Limbic system, Temporal lobe, Temporal lobe epilepsy

NEUROMODULATION IN

Colin Van Hook, M.D., M.P.H. Ochsner Medical Center Department of International Center for Epilepsy WHAT IS ???

• “The alteration of nerve activity through targeted delivery of a , such as electrical stimulation or chemical agents, to specific neurological sites in the body.” INS definition • Chronic pain • Movement disorders • Psychiatric disorders • / injury • Cardiovascular disease • Gastrointestinal disease • Genitourinary or colorectal disorders • Epilepsy NEUROMODULATION IN EPILEPSY: WHEN TO CONSIDER IT

• Medically Refractory: In an analysis of 1,098 patients with newly diagnosed epilepsy at a one center between 1982 and 2006 (Brodie 2012) • 49% became free on the first medication tried • 13% became seizure free on the second medication tried • 3.7% became seizure free on the third medication tried • 1/3 of patients remain medically refractory NEUROMODULATION IN EPILEPSY: WHEN TO CONSIDER IT

• Non-Surgical candidates • Primary • Multiple seizure foci NEUROMODULATION IN EPILEPSY

• VAGAL NERVE STIMULATOR (VNS) • RESPONSIVE NEUROSTIMULATOR (RNS/NEUROPACE) • (DBS) VAGUS NERVE ANATOMY

• CN X (VAGUS NERVE) • Exits jugular foramen with CN IX and CN XI then travels in the carotid sheath with the common carotid and the internal jugular • AFFERENT FIBERS = 80% • Solitary Nucleus and Spinal Trigeminal Nucleus • EFFERENT FIBERS = 20% • Originate in Dorsal Motor Nucleus and Nucleus Ambiguus • Parasympathetic fibers to the viscera • Right CNX provides significantly more innervation to heart compared to left (this is why VNS placed usually on left CN X) VAGUS NERVE ANATOMY

• Projects to Nucleus Tractus Solitarius BILATERALLY (Henry, Neurology 2002) VAGUS NERVE PROJECTIONS

• Vagus nerve works through Nucleus Tractus Solitarus(NTS) and Pontine Parabrahcial Nucleus (PBN) • Limbic • : implicated in temporal epilepsy • Insula: connections to • Autonomic • Connections to and periaqueductal gray (PAG) • Reticular structures •

Henry 2002. VAGUS NERVE AND

• 1938 (Bailey and Bremer) • Stimulation of vagus nerve produced EEG changes in cats

• 1952 (Zanchetti) • Intermittent vagal nerve stimulation decreased or eliminated chemically induced focal epileptiform discharges

• 1960s • Repetitive stimulation of vagus nerve led to synchronize or desynchronize cortical electrical activity • Seizures caused by hypersynchronized cortical activity thus VNS could desynchronize

• 1985 (Zabara) • Hypothesized that VNS antagonizes hypersynchronous states using animal studies VAGUS NERVE AND THE CORTEX

• 3HZ spike-wave initiated in thalamus and propagated via pathways to the cortex • Hypothalamic hamartomas with gelastic seizures • Intracranial recordings of cerebellar dysplastic lesions show discharges originating in that structure • In several cases of epilepsy, seizures continued following cortical resection with subsequent seizure freedom following resection of deep structures with electrographic discharges originating in the . VNS: CLINICAL EVIDENCE

Design # patients Seizure type Results radomized E01/2 (1988-1992) Single-blinded 14 Partial 28% reduction in seizure frequency E03 (1990-1992) Randomized 114 Partial Mean 24.5% reduction in frequency double-blind with 31% having >50% reduction active control E04 (1991-1995) Open label, 116 Partial or Mean 21.5% reduction in frequency non-blinded generalized with 29.3% having >50% reduction E05 (1995-1996) Randomized 199 Partial Mean 27.9% reduction in frequency double-blind with 23.4% having >50% reduction active control VNS CLINICAL EVIDENCE

• Reduction of seizure frequency > 50% (Morris and Mueller, Neurology 1999) • 1 year = 36.8% patients • 2 years = 43.2% patients • 3 years = 42.7% patients • Well tolerated • 75% patients continued

• There is a persistent VNS‐induced effect and indicate that its efficacy is dependent on the cumulative stimulus duration (Takaya, Epilepsia 1996). VNS APPROVAL

• In 1997, the FDA approved the VNS Therapy System for use as an adjunctive therapy in reducing the frequency of seizures in adults and adolescents over 12 years of age with partial onset seizures refractory to antiepileptic medications

• In 2017, device was FDA approved for children as young as 4 due after data from Japan Post‐Approval Study (PAS) in which followed patients implanted between 2010 and 2012.

• As of 2017, >100,000 patients treated with VNS VNS IN GENERALIZED EPILEPSY

• Labar (Neurology 1999) showed >50% reduction in 11 of 24 patients with medically resistant IGE • Ng and Devinsky (Seizure 2004) compared seizure frequency reduced by > 50% in partial vs. symptomatic generalized vs. idiopathic generalized • Partial (PE)= 47.1% patients (N=138) • Symptomatic generalized (SGE)= 46.1% patients (N=13) • Idiopathic generalized (IGE) = 57.1% patients (N=14) • Furthermore, higher proportion of patients with IGEable to achieve 50% or greater reduction in seizure frequency and reduced antiepileptic drug • Partial = 9.4% • Symptomatic generalized = 7.7% • Idiopathic generalized = 35.7 VNS AND DEPRESSION

• Reduction in depression scores was noted in E03/5 and two subsequent studies (Harden 2000 and Elger 2000) showed trend to depression reduction was INDEPENDENT of seizure reduction

• One year trial of VNS for patients with depression (n=185) or bipolar I/II (n=20) refractory to at least 2 medications showed a significant reduction in symptoms on the 24 item Hamilton Rating Scale for Depression. (Rush 2005)

• Five year open-label, non-randomized trial of patients with treatment resistant depression showed reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) in patients with VNS (n=494) versus treatment as usual (n=301). (Aaronson 2017)

• In 2005 FDA approved VNS for adjunct treatment in depression but coverage denied by US Committee on Medicare and Medicaid Services VNS AND QUALITY OF LIFE

• PuLsE (Open Prospective Randomized Long-term Effectiveness) trial showed significant improvement in Quality of Life in Epilepsy Inventory-89 total score (QOLIE-89) in 61 patients with VNS versus 61 patient with medical therapy only (Ryvlin 2017)

• VNS patients with autism showed improved alertness, verbal communication, , and school performance (Levy 2010) VNS OPERATIONS

• Battery powered device • Leads placed in carotid sheath around left vagus nerve and connected to subcutaneous programmable pacemaker • Typical battery life is 5-10 years based on settings VNS OPERATIONS

Pulse width

Signal frequency

Output current Amount of electrical current delivered in a single pulse of stimulation Signal frequency Number of pulses per second (measured in Hz) Pulse width Duration of a single pulse within a stimulation period VNS OPERATIONS

Parameter Units Range Typical Output current milliamps 0–3.5 1.25 Signal frequency hertz 1–30 20-30 Pulse width microseconds 130–1000 250-500 ON time seconds 7–60 30 OFF time minutes 0.2–180 5 Magnet Settings Output current milliamps 0–3.5 1.50 Pulse width microseconds 130–1000 500 ON time seconds 7–60 60 VNS OPERATIONS: CYCLING AND DUTY CYCLE

• Initial settings typically: • Several small studies do not support increased efficacy for “Rapid Cycling” typically Output current 0.25mA • connotating 7 seconds “on” and 30 seconds • Signal frequency 30Hz “off” • Pulse Width 250-500 microseconds • Not recommended as this will wear down • “On” 30 seconds battery faster • “Off” 5 minutes • Duty cycle should be <50%

ON time + 4 seconds

ON time + OFF time VNS MAGNET

• Patient or other swipes magnet on generator for 1 second which gives additional current/stimulation to stop or shorten seizure • Morris. Epilepsy and Behavior 2003. • Patients in E03 trial with active magnets were more likely to report improved seizure control than patients with inactive magnets • In the E04 trial, 22% of patients using the magnet reported seizure termination and 31% reported seizure diminution • Magnet output current should always be higher (usually 0.25mA higher) than parameter output VNS SAFETY

• Side Effects • Data from E0S trials • Voice alteration/hoarseness 66.3 % • Cough 45.3% • Pharyngitis 34.7% • Dyspnea 24.2% • Most resolved after 1-2 years of continued treatment • Mild increase in hypopnea and apnea in patients with OSA, may unmask latent OSA (Marzed, Edwards, Sagher. Epilepsia 2003) VNS: MANAGING SIDE EFFECTS

• Reduce pulse width from 500 to 250 • Reduce frequency from 30 to 20 • TAPE MAGNET OVER DEVICE TO AVOID VOICE CHANGE VNS AND MRI

• Safe for brain, lumbar spine, and extremities! • NOT SAFE for cervical and thoracic spine • PRIOR to MRI reprogram • Output current = 0.0 • Magnet current = 0.0 • Autostimulation = 0.0 • AFTER imaging • Reset to previous parameters • Perform diagnostic, should show IMPEDENCE = OK TRANSCUTANEOUS VNS (T-VNS)

• Stimulation applied to auricular branch of CNX at the tragus • 5 of 7 patients showed a reduction in seizure frequency at 9 months (Stefan 2012) • Randomized, double-blind controlled trial (cMPsE02) showed no statistical difference in change in seizure frequency between high and low stimulation groups at 20 weeks (Bauer 2016). • NEMOS system is approved in Europe • LOW THRESHOLD FOR APPROVAL – EFFICACY NOT NEEDED VNS: WHO TO CONSIDER?

PRO CON • Option for anyone who is not a candidate for resection • required • No cognitive side effects • Battery replacement 5-10 years • Compliance is not an issue • Still need AEDs • Improved quality of life • Rarely seizure-freedom (5%) • More alertness • What are best settings? • Less daytime sleepiness • Improved memory • Improved mood • Provides patient/family with of control • Safe in pregnancy RESPONSIVE NEUROSTIMULTION: AN ALTERNATE APPROACH

OPEN LOOP STIMULATION: CLOSED LOOP NEUROSTIMULATION: VNS OR DBS RNS CORTICAL STIMULATION

• In the 1950’s Penfield and Jasper noted that cortical stimulation could disrupt epileptiform activity and lead to suppression of both normal and epileptiform activity at distant sites. • Cooper (1978) noted that closed loop stimulation of the could reduce seizures • Kinoshita et al (2004, 2005) noted reduction in interictal spikes in high versus low open-loop stimulation in patients undergoing intracranial monitoring and functional mapping. RESPONSIVE NEUROSTIMULATION (RNS/NEUROPACE) RESPONSIVE NEUROSTIMULATION (RNS/NEUROPACE)

• Allows for significant amounts of electorcortography (ECoG) recording based on several triggers • Scheduled storage (up to 4) • Magnet swipes by the patient • Long episode: specified duration of time meeting detection parameters • Saturation: when ECoG amplitude exceeds a designated threshold RESPONSIVE NEUROSTIMULATION (RNS/NEUROPACE)

• Multi-center, double-blind, randomized controlled trial (Morrell 2011)

• 191 patients with partial onset seizures with ≥3 seizures per month despite ≥2 medications trials were implanted with RNS after 12 week baseline period between 2005 and 2008

• Patients were randomized 1:1 for stimulation versus sham with blinded gathering outcome data and medications held the same during 12 week evaluation period RESPONSIVE NEUROSTIMULATION (RNS/NEUROPACE)

• Mean seizure frequency remained reduced in stimulation(41.3%) versus sham (9.4%) at three months (p=0.012) • 29% of treatment group showed ≥50% reduction in frequency at the end of the blinded period with increase to 46% at two years post implant • 7% were seizure free for the most recent three months at the end of the 2 year evaluation period. • Serious adverse events occurred at 12%, less than 15% noted in patients with intracranial electrode placement for • In 2013, the FDA approved RNS for the treatment of medically-refractory partial onset epilepsy RESPONSIVE NEUROSTIMULATION (RNS/NEUROPACE)

• In an open-label follow, 191 patients were followed for an average of 5.4 years and showed a sustained response rate (≥50% reduction) of >60% at six years post-implant

• Serious adverse events were rare following immediate implantation period.

• Improvement in QUOLIE scores was sustained through year 4 on follow up (p=0.001) IMPLICATIONS OF LONG TERM RECORDING IN RNS

• In initial RNS trial, 82 patients with bilateral mesial RNS electrode placement (King-Stephens 2015). • 71 were presumed to have seizure foci bilaterally based on EEG • 11 had suspicion of involvement of contralateral temporal lobe with other diagnostic modality (i.e. bilateral MTS) • 16% had only unilateral seizures after 4.6 years • 32% had first contralateral seizure after more than 4 weeks post-implant • Of 71 subjects presumed to have bilateral onset, 9 had only unilateral onset after 5 years. DEEP BRAIN STIMULATION

• Open loop stimulation (similar to VNS) • Cerebellum has been studied due to theory that stimulation of Purkinje cells could intensify inhibitory output to the thalamus • Hippocampal stimulation has shown promising results in small trials • Centramedian thalamic nucleus stimulation has shown some effect in generalized • Anterior Thalamic Nucleus with extensive connections through the has shown the most benefit

Lin, Epilepsia 2017 DBS FOR EPILEPSY: SANTE TRIAL

• Multicenter, randomized, double blind study of 110 patients with partial onset seizure (Fisher 2010)

• Patients were followed for a 3 month blinded period followed by a 2 year open label period DBS FOR EPILEPSY: SANTE TRIAL

• By the end of the blinded period, there was a seizure reduction rate of 14.5% in the control group versus 40.4% in the stimulation group (p=0.0017)

• No statistically significant change in 50% responder rates or QUOLIE during blinded phase DBS FOR EPILEPSY: SANTE TRIAL

• In patients followed long term, median reduction in seizure frequency was • 41% at 13 months (n=99), • 56% at 25 months (n=81), • 67% at 37 months (n=42). • 50% responder rate was 54% at 2 years • QUOLIE score improved significantly at 13 and 25 months (p<0.001) • No clinical hemorrhages associated with with device DBS FOR EPILEPSY: SANTE TRIAL

• Salanova (2015): at five years • Median reduction in seizure frequency increased to 69% • 50% responder rate increased to 68% • 16% (17 of 109 patients) reported seizure freedom of at least the prior 6 months • Improvements in QUOLIE remained statistically significant • Half of patients required battery replacement at 35 months DBS FOR EPILEPSY

• In 2010, CE (Conformité Européenne) Mark approved DBS of the anterior thalamic nucleus for treatment of medically refractory partial onset seizures in Europe. • In April 2018 the FDA approved DBS of the anterior thalamic nucleus for treatment of medically refractory partial onset seizures in the United States EXTERNAL TRIGEMINAL NERVE STIMULATION (E-TNS)

• In 50 patients randomized to control or stimulation, there was a significant drop in seizure frequency in the stimulation group during a 3 month blinded period (p=0.01) but no difference between groups p=0.078). • Follow-up open label period of 35 patients showed sustained reduction in seizure frequency (Soss 2015) • NeuroSigma eTNS began multicenter, Phase 3 trial for partial seizures beginning in 2014 • Approved in Europe ,Canada, Australia for epilepsy, depression, ADHD REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION (R-TMS)

• FDA approved for depression 2008, headache 2013, OCD in 2018 • Magnetic field stimulates a small area of cortex causing depolarization of nearby • Each pulse arrives during late inhibitory phase of last causing decreased cortical excitability (Reithler 2011) • 60 patients with partial onset seizures randomized to either 90% or 20% of resting motor threshold (rMT) daily for 2 weeks (Sun 2012) • High stimulation group showed an 80% reduction in seizure frequency (p<0.01) in comparison to baseline versus 2.3% in low stimulation group which was maintained over 10 weeks • There was significant reduction in the number of epileptiform discharges on EEG before and after treatment in the high stimulation group only TRANSCRANIAL DIRECT CURRENT STIMULATION (T-DCS)

• tDCS hypothesized to change resting membrane potential by influencing ion concentrations, transmembrane proteins, and synaptic function to altering cortical excitability • 28 patients with mesial randomized to placebo stimulation or to 2mA tDCS for either 3 days, or 5 days with TCD 1ch Stimulator (San-Juan 2017) • There was a significant reduction in mean in seizure frequency between both treatment groups and placebo stimulation at 2 months post-treatment (p=0.0001) • 5 min showed 54.6% reduction • 3 min showed 43.4% reduction • Placebo showed 62.5% reduction THE END!!!