Treatment of Refractory Epilepsy: Pre-surgical Evaluation, Surgical Options, and Neurostimulation

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2 Treatment of Refractory Epilepsy: Pre-surgical Evaluation, Surgical Options, and Neurostimulation Michael C. Smith, MD Director, Rush Epilepsy Center Professor and Senior Attending Neurologist Rush University Medical Center Chicago, IL

3 Surgical Treatment of Epilepsy Patient selection Diagnostic evaluation for surgical treatment Types of surgical treatment Outcomes of therapy: risk/benefit Seizure freedom/cognitive function

4 Partial Epilepsy: Goals of Therapy Render patient seizure-free Avoid neurological morbidity Improve quality of life Participating and productive member of society

5 Focal Epilepsy Treatment Old drugs (CBZ, PB, PHT, VPA) New drugs (FBM, GBP, LAC, LEV, LTG, OXC, PGB, TGB, TPM, VGB, ZNS, CLO, PER, PRP, EZO, ECZ, ESL, BRV) Electrical stimulation (VNS, RNS, DBS) Diet: Ketogenic, Atkins, Low Glycemic Index Epilepsy surgery: Ablative/resective/ disconnection

6 Response to AED (% patients) Response to AED Therapy: 5-Year Follow-Up 525 newly diagnosed patients 470 AED-naïve 55 AED-experienced 63% seizure-free for 1 year AED-naïve: 64% 60% after first or second monotherapy trial AED-experienced: 56% Most withdrawals or change of treatment were due to intolerable side effects AED-Naïve Patients 47% 13% 1% 3% First Second Third 2 drugs Monotherapy Trial Kwan P, et al. N Engl J Med

7 Epilepsy Efficacy of Treatment 63% were seizure-free the last year Only 11% who failed the 1st AED became seizure-free About 30-40% will have a difficult-to-control seizure disorder 0% seizure-free on >3 AEDs Brodie MJ, et al. Neurology

8 Definition of Intractable Epilepsy Some variability in published definitions but 3 main components: - Absence of response to 2 AEDs tolerated at reasonable doses - Minimal frequency (1 sz/m) or lack of seizure remission of 6-12 months - Duration of epilepsy of 1-10 years of uncontrolled seizures Berg AT, et al. Epilepsia. 2006; Berg AT. Neurol Clin. 2009; Kwan P, et al. Epilepsia

9 Medically Intractable Surgical Evaluation: My Criteria Failed two or more drugs to maximally tolerated dose (VPA, DPH, CBZ, LTG, LEV, TOP, ZNG) Different MOA Failure due to lack of efficacy not intolerance Add adjunctive AED or combination (LEV-LTG, VPA- LTG) with synergistic MOAs Unable to achieve complete seizure control within two years

10 Evaluation of the Medically Intractable Patient: Questions Does the patient have epilepsy? Need to record with EEG the events in question Nonepileptic event Psychiatric or medical etiology Have the AEDs used been appropriate for the seizure type? Have adequate blood levels been tolerated and documented to prove that seizures are medically intractable due to lack of efficacy, not tolerability?

11 Focal resections Surgical Decision Making First choice in appropriate candidates Importance of early intervention Palliative surgery (successful outcome does not always mean cure ) Vagus nerve stimulation (VNS) Corpus callosum division (CCD) Multiple subpial transection (MST)

12 NEJM August 2, 2001 Epilepsy Surgery: Comparative Study Randomized controlled study 80 pts with TLE London, Ontario, Canada Surgery effective (P<.001) QOL favors surgery (P<.001) Wiebe S, et al. N Engl J Med

13 NEJM Editorial Few accepted therapeutic interventions are as underutilized as surgical treatment of epilepsy Two million patients suffer with epilepsy in US 400,000 to 600,000 not controlled with AEDs 1990 survey: 1500 therapeutic surgical interventions Seizure-free rate: 70-90% with surgical therapy Quality of life for patients with epilepsy treated surgically is related to the reoccurrence of seizures QoL higher employment/school attendance in surgical group Engel J. N Engl J Med

14 Practice Parameters: TLE Surgery Epilepsy: chronic neurologic disorder affects 0.5-1% of world s population In the US and other industrial nations with many AEDs available, 30-40% of patients not adequately controlled WHO survey: disability from epilepsy accounts for ~1% of global burden of disease as measured by disabilityadjusted life years (DALYs) This ranks third behind affective disorder and alcohol dependence among neurologic disorders. Comparable to worldwide burden due to lung and breast cancer Engel J, et al. Epilepsia

15 Practice Parameters: TLE Surgery Surgical procedures for treatment of epilepsy 1985 ~500 year 1990 ~1500 year 2003 ~3000 year Estimated that there are 100, ,000 potential surgical candidates in US Early intervention may prevent or reverse the psychosocial sequelae of continued seizures in children Engel J, et al. Epilepsia

16 Practice Parameters: TLE Surgery Surgical efficacy compared to results from randomized clinical trials of AEDs Same patients with intractable partial epilepsy Responder rate (50% reduction of seizure frequency) of 50% is a good response Few patients rendered seizure-free Best results: VGB 6000 mg/d: 54% RR Most AEDs lower RR Vagal Nerve Stimulator: 30-50% RR at 1 year Engel J, et al. Epilepsia

17 Routine EEG Temporal Lobectomy: Presurgical Evaluation MRI head seizure protocol/volumetrics Long-term EEG monitoring to record sz Neuropsychological testing Sodium amobarbital study Other: MEG, fmri, SISCOM, PET, Intracranial EEG recording/stimulation

18 Wyllie E. The Treatment of Epilepsy: Principles and Practice. 4th ed

19 Wyllie E. The Treatment of Epilepsy: Principles and Practice. 4th ed

20 Imaging in Epilepsy: Surgically Remediable Syndromes Lesional epilepsy: tumor, vascular anomaly, malformation of cortical development Structural MRI Medial temporal lobe epilepsy: mesial temporal sclerosis Structural MRI, PET

21 CT vs MRI CT Neonate <2 years Acute insult MRI incompatible Acute hemorrhage Ca +2 MRI Focal seizure any age Focal fixed deficit Loss of prior control Resolution/details Axis variable T2 2D GRE for Ca +2 or hemosiderin Wieshmann UC. J Neurol Neurosurg Psychiatry

22 Standard MRI vs Epilepsy Protocol: Surgical Patients (N=90) Specificity % Sensitivity % Non-expert reader 22 _ Expert reader, standard MRI 40 _ Epilepsy protocol 89 >90 von Oertzen J, et al. J Neurol Neurosurg Psychiatry

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26 Multiple Normal 1.5T MRIs Prior to High Resolution 3T MRI Cortical malformation Left 3T MRI high resolution 3D structural scan Right 3T MRI high resolution Cubic FLAIR

27 Long Term Intracranial Monitoring Subdural Grid Implantation

28 Functional Brain Monitoring:

29 Surgery Epilepsies That May Benefit Mesial temporal lobe epilepsy Frontal lobe epilepsy Lesional focal epilepsy Focal encephalomalacia Tumor Vascular malformation Congenital developmental anomaly Neocortical cryptogenic epilepsy Available Interventions Resection of the seizure focus Multiple subpial transection when seizure focus is in eloquent cortex Destruction of seizure focus by gamma knife/rf/laser * Corpus callosotomy *Gamma knife is not FDA approved. Engel J, et al. Epilepsia. 2003; Wiebe S, et al. New Engl J Med. 2001; Zimmerman R, et al. Mayo Clin Proc. 2003; Treiman DM. Neuropsych Dis and Treat. 2010; Asadi-Pooya AA, et al. Epilepsy Behav

30 Randomized, Controlled Trial of Surgery for TLE 80 patients randomly assigned for surgery (40 pts) or AED therapy (40 pts) for 1 year Four of the 40 pts refused surgery. Six of the 36 patients required invasive pre-surgical investigation Results free of seizures that impair awareness: 58% randomized to surgery 8% randomized to AED therapy 64% actually had surgery P<.001 Wiebe S, et al. N Engl J Med

31 Temporal Lobectomy: Efficacy Long-term operative outcome (5 years) 62 of 89 pts (70%) seizure-free 18 of 89 pts (20%) significantly improved Sperling MR, et al. JAMA

32 Temporal Lobectomy: Operative Outcome Excellent outcome: 134 (77%) Seizure-free: 120 (69%) Operative complication: 2 (1%) Radhakrishnan K, et al. Neurology

33 Epilepsy Surgery: Extratemporal Non-lesional MRI is normal Limitations of ictal EEG Less favorable outcome Increased morbidity

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35 32 LP1 6 RP1 6 CORTICAL STIMULATION P6-P8 Left thumb tingling, twitch P16-P1 Left hand flexion P23-P1 head turn left P24-P1 Left hand clonic flexion P31-P1 head turn left P32-P1 left hand flexion P31-P32 all limbs extended (like a seizure) RP1-P1 left leg extension RP2-P1 all limbs extended RP1-RP2 all limbs extended RP3-RP4 head turn left LP1-LP2 Right foot inversion 8 LA1 4 RA Open circles: midline electrodes Filled circles: surface electrodes EEG Seizure onset Seizure onset Interictal discharge P16, P31, P32 SSEP Hand Foot

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37 Frontal Lobectomy: Operative Outcome 68 patients Excellent outcome: 59% Abnormal MRI: 72% Normal MRI: 41% Mosewich RK, et al. Epilepsia

38 % patients Long-term Seizure-free Rates Vary According to Surgery Type 70% 60% 66% 61% 59% Seizure free rates (defined by the authors; follow-up 5 years; results pooled if >2 studies) 50% 46% 46% 40% 35% 34% 30% 27% 20% 16% 10% N 3895 N 169 N 2334 N 82 N 35 N 99 N 169 N 486 N 74 0% TL HEMI TL+EXTRA PAR OCCI CALLO* EXTRA TL FRONT MST TL: temporal lobe; HEMI: hemispherectomy; TL+EXTRA: grouped temporal and extratemporal lobe; PAR: parietal lobe; OCCI: occipital lobe; CALLO: callosotomy freedom from drop attacks; EXTRA TL: grouped extratemporal lobe; FRONT: frontal lobe; MST: multiple subpial transections Téllez-Zenteno JF, et al. Brain

39 Longer Term Follow-up and AED Drug Withdrawal 50 consecutive patients with MTS Mean F/U=5.8 years 82% seizure free at 1 year 76% seizure free at 2 years 64% seizure free at 5 years No further recurrence beyond 5 years 29% of recurrence associated with withdrawal of meds Lowe AJ, et al. Epilepsia

40 Quality of Life Outcome Multicenter study: 396 cases Compared to pre-op baseline, at 3 months QOL, anxiety, depression improved (P<.0001) QOL was highly correlated with seizure outcome Spencer SS, et al. Neurology

41 Cost-Effectiveness 200 patients, intention-to-treat analysis projected over 35 years By year 8, surgery was more cost-effective in direct costs than medical treatment This does not take into account the effect on QOL and indirect costs Wiebe S, et al. J Epilepsy

42 Corpus Callosum Division Corpus callosum division is a palliative procedure to improve the seizure control of patients with medically intractable epilepsy who have no localizable, single surgically resectable lesion Developed by Van Waganen in Rochester, New York, in 1939, refined by Wilson at Dartmouth in the 1970s, and others to the present

43 Corpus Callosum Division: Patient Outcomes % of patients with drop seizures (as a primary indication) achieve a 50% or greater reduction in seizures 21-67% of those with tonic-clonic seizures (as a primary indication) have a >50% reduction Seizure-free rates range from 2-5% Fuiks KS, et al. J Neurosurg. 1991; Wilson DH, et al. Neurology

44 Indications for Multiple Subpial Transection (MST) MST may be used alone or more commonly with cortical resection MST is used when the epileptogenic zone originates in or overlaps eloquent cortex where a resection is precluded due to the expected functional loss Eloquent cortex includes primary sensorimotor cortex and speech cortex

45 Technique of MST

46 Efficacy of MST: Worldwide Significant Improvement No Worthwhile Improvement Neurologic Complications Author, Year No. of Patients Only MST MST & RES MST Only MST & RES No. of Patients Type (No. of Patients) Shimizu, et al Sawhney, et al Zonghui a - 18 a Wyler, et al Mild motor (1) Hufnagel, et al Pacia Mild speech deficits (2); mild motor deficits (3); overt speech deficits (2) Mild dysnomia (7); moderate dysphasia (1); loss of proprioception in hand (1) Rougier, et al Patil, et al Rush Epilepsy Center Permanent (7); transient (8); sensorimotor (13) TOTAL MST=multiple subpial transection; RES=resection a In this study, it was not clear whether MST alone versus MST-resection was performed.

47 Neurostimulation for Epilepsy Responsive Neurostimulation (RNS) FDA approval (2014) Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy SANTE Trial Denied FDA approval Vagal Nerve Stimulation (VNS): FDA-approved for adjunctive treatment of epilepsy (recently approved for pts >4 years old)

48 Open-Loop Neurostimulation Stimulation delivered continuously or on a clock cycle Closed-Loop Neurostimulation Stimulation is delivered only in response to detected epileptiform activity stim stim stim Detection Stimulation stim stim stim stim stim Examples: VNS and DBS * Example: RNS *DBS is not approved for epilepsy

49 VNS Approved Indication In 1997, the US Food and Drug Administration (FDA) approved vagus nerve stimulation (VNS) as adjunctive therapy for reducing the frequency of seizures in patients >12 years of age with partial onset seizures refractory to antiepileptic medications. In 2017, the FDA expanded its use as adjunctive therapy for patients >4 years of age with partial onset seizures that are refractory to antiepileptic medications. FDA Product Information.

50 Left Cervical Vagus Nerve Approximately 80% afferent fibers Total fibers ~ 80, ,000 1 C-Fibers Non-myelinated (~ 80%) A&B-Fibers Myelinated (~20%) 80% <3 µm ( small ) 15%, 3-9 µm ( medium ) 5%, 10 µm ( large ) C-fiber activation not believed to be involved in VNS efficacy 2,3 1 Hoffman HH, Schnitzlein HN. Anat Rec. 1961; 2 Krahl SE, et al. Epilepsia 2001; 3 Koo B, et al. J Clin Neurophysiol

51 VNS Therapy Device Electrodes Bipolar Lead Implantable Pulse Generator

52 VNS Stimulation Bipolar, Biphasic charge balanced Constant current Intermittent stimulation Output current A 1 Sig. Freq. B Pulse Width

53 VNS Parameters Parameter Units Range Typical *Output Current Milliamps (ma) Signal Frequency Hertz (Hz) *Pulse Width Microseconds (µs) 130-1, *Signal On-time Seconds (sec) Signal Off-time Minutes (min) *Independent, On-demand magnet mode parameters also available

54 Duty Cycle Calculation OFF TIME (Minutes) ON TIME (Seconds) Note: ON times should not exceed OFF times

55 Vagus nerve Synapses bilaterally on the nucleus of the solitary tract (NTS) in the medulla oblongata NTS projects to brainstem nuclei (locus coeruleus and dorsal raphe magnus) that modulate serotonin and norepinephrine (NE) to the entire brain NTS has widespread projections to limbic, reticular, and autonomic cerebral structures VNS MOA Nemeroff CB, et al. Neuropsychopharmacology. 2006; Henry TR. Neurology

56 VNS Therapy Works via Several Pathways VNS Therapy Neurotransmitter Expression Cerebral Blood Flow Changes in EEG Norepinephrine 1,2,7 GABA 3,5,6 Serotonin 4,5 Aspartate 4,5 Thalamus 8,11 Cortex 8,11 Desynchronization EEG rhythms 9,10 Anti-convulsive effect 1 Roosevelt RW, et al. Brain Res. 2006; 2 Hassert DL, et al. Behav Neurosci. 2004; 3 Woodbury DM, Woodbury JW. Epilepsia. 1990; 4 Hammond BM, et al. Brain Res. 1992; 5 Ben-Menachem E, et al. Epilepsy Res. 1995; 6 Marrosu F, et al. Epilepsy Res. 2003; 7 Krahl SE, et al. Epilepsia. 1998; 8 Henry TR, et al. Epilepsia. 2004; 9 Wang H, Zylka MJ. J Neurosci. 2009; 10 Koo B, et al. J Clin Neurophysiol. 2001; 11 Vonck K, et al. Seizure

57 Percentage of all magnet swipes Missed Treatment Opportunities Occur During the Night When Magnet Usage Is Less Frequent >10 million magnet activations have been recorded since FDA approval in % 5% 4% 3% 2% 1% 0% Data on file, Cyberonics, Houston, TX.

58 Heart-Brain Connection: Mechanisms and Prevalence of Cardiac Changes in Epilepsy 82% of patients with epilepsy experience rapid heart rate increase associated with a seizure 1 Carter R, et al. The Human Brain Book. 2009; 1 Eggleston KS, et al. Seizure

59 What is the AspireSR? The first and only VNS Therapy that provides responsive stimulation to heart rate increases that may be associated with seizures. Seizure cessation, reduced seizure severity, and improved postictal recovery were observed in AspireSR clinical studies. AspireSR may be appropriate for patients with drugresistant epilepsy who are candidates for VNS Therapy. Data on File, Cyberonics, Inc. Houston TX.

60 Seizure Cessation During Automatic Stimulation was Observed in AspireSR Clinical Trials >60% of seizures treated (N=46) ended during automatic stimulation For seizures that ended during stimulation (N=28), the closer stimulation was to seizure onset, the shorter the seizure duration Data on File, Cyberonics, Inc. Houston TX.

61 VNS in Epilepsy: Updated AAN Guidelines Recommendation VNS may be considered as adjunctive treatment for children with partial or generalized epilepsy VNS may be considered in patients with Lennox Gastaut (LGS) In adult patients receiving VNS for epilepsy, improvement in mood may be an additional benefit VNS may be considered progressively effective in patients over multiple years of exposure Optimal VNS settings are still unknown, and evidence is insufficient to support the recommendation for the use of standard stimulation vs. rapid stimulation to reduce seizure occurrence Level C C C C U Other: Extra vigilance in monitoring for site infection should be undertaken in children. C=Possibly effective, ineffective or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population U=Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven. Morris GL, et al. Neurology

62 Clinical Use: VNS Maximize current load? Fast cycle/regular Stimulation intensity (2-3 ma) On time (30 sec) Off time (1.8 min) Delay in maximal benefit months Decrease SE by decreasing stimulation frequency from 30 Hz to 20 Hz

63 Clinical Impact: VNS Rush Series over 350 patients At 6 months ~ 35% responder rate At 1 year ~ 46% responder rate Postictal state decreased in the majority Severity of seizures improved in the majority Mood improved in the majority

64 RNS System

65 CT Scan Showing the Implanted Stimulator and Intracerebral Electrodes

66 Right-sided Seizure with No Stimulation

67 Left-sided seizure detected by subdural electrodes Comparison of the ictal EEG response to increased therapeutic stimulation from 2.5 to 4.5 ma Response to 2.5 ma Electrographic seizure that progressed to clinical CPS then GTC Response to 4.5 ma Electrographic and clinical response to therapeutic stimulation

68 Responsive Neurostimulation: Efficacy Morrell MJ. Neurology

69 RNS System Clinical Trial Efficacy Results: 29% responder rate for Treatment Group (N=95) at 4 months (27% in sham group) Responder rates for total seizures increased during the open label period from: - 29% at 4 months (N=95), - to 44% at 12 months (N=181), - to 55% at 24 months (N=174) 14.5% had at least one 6-month seizure free period Improves Quality of life Morrell MJ, et al. Epilepsia, 2008; Morrell MJ, et al. Neurology. 2011; Heck CM, et al. Epilepsia. 2014; Bergey GK. Neurology

70 RNS System Temporal Lobe Epilepsy Clinical Trial Efficacy Results: N=93 with MTLE, 68 bilateral, 17 left, 8 right 37% mean reduction in seizures vs. 21% in control group (P=.01) Both groups showed decrease in seizures after implantation Salanova V, et al. Neurology. 2010; Morrell MJ, et al. Neurology

71 Multi-center Prospective Randomized Double-blind Parallel design SANTE Study Design

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73 Median % Seizure Reduction SANTE Trial: Results Effectiveness dependent on region of seizure onset: Temporal lobe onset P= P=.038 P= Control Stimulation End Implant Double Blind Open Label Long Term (N=110) (N=108) (N=99) (N=81) Fisher R, et al. Epilepsia

74 SANTE Trial Conclusions 110 patients implanted The primary objective was met: Stimulation reduced seizures Improvement over time: 68% reduction by 3 years No stimulation related deaths No symptomatic hemorrhages (some seen on imaging) Results submitted for publication and for FDA approval Approved by the Advisory Committee, but denied by the full FDA Committee due to questions about length of study and statistical outliers. Fisher R, et al. Epilepsia

75 Ablative Surgery Radio frequency ablation - Lesional ablation Gamma knife ablations - Lesional and MTLE ablation MRI guided laser ablation - Lesional and MTLE ablation

76 Radiosurgical Treatment Conformal radiation directed at temporal portion of the amygdala, the anterior 2 cm of the hippocampus and adjacent parahippocampal gyrus Total volume within 50% isodose line between 5.5 and 7.5 cc Treatment isocenters: 2-6

77 Typical Clinical Response Initial increase in auras with simultaneous decrease in focal seizures Headaches Radiological changes

78 One Year Post Radiosurgery

79 Two Years Post Radiosurgery

80 Gamma Knife Ablation for MTLE European Prospective Study 1 21 pts treated 24Gy (1 died MI) At 2 years: 65% Seizure free 9/20 (44%) visual field cut, no neuropsych deterioration US Prospective Study 2 30 pts randomized high dose 24Gy (13 pts) vs low dose 20Gy (17 pts) At 36 months, 77% high vs 59% low dose seizure free Visual field deficit: 61% high vs 41% low dose Verbal memory: Improves 12%, worsens 15% 1 Regis J, et al. Epilepsia. 2004; 2 Barbaro N, et al. Ann Neurol

81 Potential Risk of Radiosurgery for Epilepsy Risk of ongoing seizures while waiting for radiosurgical effect 2 to 3 years (including sudden death from epilepsy) Neuropsychological deficits Language/Memory Visual field defects Quadrantanopsia (relatively likely) Homonymous hemianopsia (in Europe with >8 cc volume)

82 Pre Image Target Minimally Invasive Neurosurgery For ablation of Amygdala-Hippocampal Complex Target Area Axial T2 FLAIR image Courtesy of Cascin, Marsh, Worrell, Gompel; Mayo Clinic, 2012.

83 Ablation Verification Ablation Pre Ablation Damage Model Post Ablation Axial images Courtesy of Cascin, Marsh, Worrell, Gompel; Mayo Clinic, 2012.

84 MRI Guided Laser Ablation Using Stereotactic Frame MRI, guided laser is placed in the amygdala and a series of MRI guided laser ablations in amygdala/hippocampus 13 patients (9 with MTS), 15 procedures: f/u 1-25 months 7/13 (54%) Sz free Engel class IA, B, or D 2/13 (15%) Class IVB; 3/13 (23%) Class IIIA, 1 recent Failures occurred early; 2 went on to resection Mean volume of ablation 60% - didn t correlate:outcome 1 small occipital subdural hemorrhage; one homonymous hemianopia Neuropsych: no worsening,improved naming/object 6m Small series, needs longer follow up? Late failures Willie JT, et al. Neurosurgery

85 MRI Guided Laser Ablation Using Stereotactic Frame, MRI guided laser is placed in the amygdala and a series of MRI guided laser ablations in amygdala/hippocampus 41 pts TLE, +/- MTS underwent SLAH 5/41 (12%) did not maintain seizure freedom Repeat ablation amygdala, entorhinal cortex, parahippocampal gyrus with 1-3 trajectories 5/5 seizure free, however mean follow-up only 6 mo? Long-term efficacy Willie JT, et al. Neurosurgery

86 MRI Guided Laser Ablation Using Stereotactic Frame, MRI guided laser is placed in the amygdala and a MRI guided laser ablation in amygdala/hippocampus 23 pts TLE, +/- MTS underwent laser ablation 65% Engel Class 1 (free of disabling seizures ) at 1 year FU Sparing of the medial head of hippocampus was correlated with persistent of disabling seizures( p=0.01) Laterally trajectory showed trend for poor outcome(p0.08)? Long-term efficacy Jermakowicz W, Kanner A. Epilepsia

87 Conclusions Surgical treatment of epilepsy is effective and cost-effective in the appropriate patient Evidence-based data suggests that surgery is more effective than best medical care for TLE Radiosurgery/Laser ablation appear effective in TLE, but are not FDA-approved. Thalamic stimulation for multifocal epilepsy is effective, but denied FDA-approval. Vagal nerve stimulation is FDA-approved as adjunct treatment and in Lennox-Gastaut and may be progressively more effective over time. Responsive neurostimulation is effective in multifocal epilepsy and was FDA-approved in 2014.