Minimally Invasive Epilepsy Surgery Is it better Patrick

Minimally Invasive Epilepsy Surgery Is it better? Patrick Landazuri, M. D. Epilepsy Division August 5, 2016

Disclosures § None

Overview § § What is refractory epilepsy? Why should we do epilepsy surgery? Barriers to epilepsy surgery Minimally invasive techniques

Refractory epilepsy § Failure of two tolerated, appropriately chosen, and adequately dosed anti-epileptic medications § There can be limited 1 -2 year periods of seizure remittance in refractory epilepsy Kwan P, Schachter SC, Brodie MJ. “Drug-Resistant Epilepsy”. NEJM. 2011 Callaghan B, et al. “Remission and relapse in a drug-resistant epilepsy population followed prospectively”. Epilepsia. 2011

AED effectiveness Stein MA and Kanner AM. “Management of Newly Diagnosed Epilepsy”. Drugs 2009

Isn’t there just another medicine? Wang SP, et al. “Seizure recurrence and remission after switching AEDs”. Epilepsia 2013

First RCT for temporal lobe epilepsy (2001) Wiebe S, et al. “A Randomized, Controlled Trial of Surgery for Temporal-Lobe Epilepsy”. NEJM 2001

Guidelines Engel Jr. J, et al. “Practice parameter: Temporal lobe and localized neocortical resections for epilepsy”. Neurology 2003

ERSET (2012) Engel Jr. J, et al. “Early Surgical Therapy for Drug-Resistant Temporal Lobe Epilepsy”. JAMA 2012

Mortality benefits Sperling MR, Barshow S, Nei M, Asadi-Pooya AA. “A reappraisal of mortality after epilepsy surgery”. Neurology. 2016

Employment benefits Edelvik A, Flink R, Malmgren K. “Prospective and longitudinal long-term employment outcomes after resective epilepsy surgery”.

IQ benefits Boshuisen K, et al. “Intelligence Quotient Improves after Antiepileptic Drug Withdrawal following Pediatric Epilepsy Surgery”. Ann

Healthcare savings Langfitt JT, et al. “Health care costs decliene after successful epilepsy surgery”. Neurology. 2007

Benefits of successful epilepsy surgery § Seizure freedom § Increased quality of life § Able to decrease or titrate off AEDs § IQ increase secondary to AED withdrawal § Increased likelihood to return to work § Decreased healthcare costs (in the long run)

Continued referral difficulty Burneo JG, et al. “Disparities in surgery among patients with intractable epilepsy in a universal health system”. Neurology

Barriers § Physician § Educational § Patient

Canadian neurologist survey part 1 § 56% did not believe lack of seizure freedom was reason § § for referral 48% did not realize that failing 2 AEDs constituted drug resistant epilepsy 45% are not aware of the AAN clinical practice guidelines for epilepsy surgery 46% believe patients must be refractory for >1 year to warrant epilepsy surgery referral 20% have never referred a patient for surgical evaluation Roberts JI, et al. “Neurologists’ knowledge of and attitudes towards epilepsy surgery”. Neurology. 2015

Canadian neurologist survey part 2 § Neurologist concerns with referring patients § 34% report long wait times § 14% limited resources and access issues § 7% report distance concerns for their patients Roberts JI, et al. “Neurologists’ knowledge of and attitudes towards epilepsy surgery”. Neurology. 2015

Educational barriers § Suboptimal clinical exposure for neurology (and neurosurgery) residents § Relatively few didactics focused on non-AED treatment of refractory epilepsy § Better outreach to non-neurologists?

What do patients think of epilepsy surgery § Considered dangerous with 56% saying it’s very dangerous § Concern for adverse events § 47% say paralysis is possible § 61% say brain damage is possible § 45% say concern for loss of independence § Almost 30% of patients had pre-existing negative attitudes § Over half of that 30% were completely opposed § 73% think surgery should be the last resort § 56% would not undergo surgery unless a 100% success rate Erba G, et al. “Acceptance of epilepsy surgery among adults with epilepsy – What do patients think? ”. Epilepsy Behav. 2012

Patient characteristics and response to epilepsy surgery conversations § In favor of surgery § Adequately informed of risks and benefits (OR 2) § Higher level of education (OR 5) § High degree of trust with neurologist (OR 4) § Against surgery § The opposite of the above statements as well § Existing disability (OR 3) § Thus, educating patients does help § Did not sway many that were completely opposed though Erba G, et al. “Acceptance of epilepsy surgery among adults with epilepsy – What do patients think? ”. Epilepsy Behav. 2012

Standard anterior temporal lobe resection Wiebe S, et al. “A Randomized, Controlled Trial of Surgery for Temporal-Lobe Epilepsy”. NEJM 2001

Actual pictures from Google search “anterior temporal lobectomy” Untitled image. Retrieved July 30, 2016 from http: //www. augusta. edu/mcg/neurosurgery/clinicalprograms/esphoto_gallery. php “Scar over left temporal lobe after surgery”. Retrieved July 30, 2016 from

Minimally invasive techniques § § § Selective amygdalohippocampectomy Stereotactic radiosurgery Stereotactic radiofrequency ablation Laser thermal ablation Focused ultrasound ablation Neurostimulation

Selective amygdalohippocampectomy § § Multiple different surgical approaches Removes only the mesial structures Developed as a way to preserve lateral neocortex End goal to improve neuropsychological outcomes while maintaining seizure outcomes Josephson CB, et al. “Systematic review and meta-analysis of standard vs selective temporal lobe epilepsy surgery”. Neurology. 2013

Seizure and neuropsychology outcomes • Neuropsychology results varied • At worst, the results are no worse compared to ATL • Barrow Neurological Institute’s cohort showed: • 1/3 of LEFT surgeries have decrease in memory, verbal intellect, and naming Josephson CB, et al. “Systematic review and meta-analysis of standard vs selective temporal lobe epilepsy surgery”. Neurology. 2013 Gleissner U, Helmstaedter C, Schramm J, and Elger CE. “Memory Outcomes after Selective Amygdalohippocampectomy in Patients with Temporal Lobe Epilepsy: One-year Follow-up”. Epilepsia 2004 Hill SW, Gale SD, Pearson C, Smith K. “Neuropsychological outcome following minimal access subtemporal selective amygalohippocampectomy”. Seizure 2012

Stereotactic radiosurgery § Stereotactic delivery of ionized radiation § 200 separate sources are delivered at various vectors by linear accelerators to a focus point within the calculated center § Has been used for multiple lesion types as well as physiologically defined epilepsies § Tumors – high volume > low volume more likely to be seizure free § AVMs – make sure to get the AVM nidus § Cavernomas – perilesional tissue is epileptogenic too § Hypothalamic hamartoma – only 27% seizure free, but improved behaviors Quigg M and Harden C. “Minimally invasive techniques for epilepsy surgery: stereotactic radiosurgery and other technologies”.

Stereotactic radiosurgery MTLE § Prospective, randomized 20 vs 24 Gy § 30 patients (13 high dose) § The above study led to the ROSE trial § RCT for radiosurgery vs ATL § Closed early due to poor enrollment, but now awaiting results Barbaro NM, et al. “A Multicenter, Prospective Pilot Study of Gamma Knife Radiosurgery for Mesial Temporal Lobe Epilepsy: Seizure Response, Adverse Evetns, and Verbal Memory”. Ann Neurol. 2009

Radiographic progression of SRS Barbaro NM, et al. “A Multicenter, Prospective Pilot Study of Gamma Knife Radiosurgery for Mesial Temporal Lobe Epilepsy: Seizure Response, Adverse Evetns, and Verbal Memory”. Ann Neurol. 2009

SRS benefits/drawbacks § Biggest positive is this is truly non-invasive § Several drawbacks § Delayed development of radiosurgical lesion § Seizure reduction take between 9 -15 months to manifest § Seizure frequency can acutely worsen during acute swelling § Risk of radiation induced tumor is small (0. 64%) Quigg M and Harden C. “Minimally invasive techniques for epilepsy surgery: stereotactic radiosurgery and other technologies”.

Stereotactic radiofrequency ablation MTLE § Under MRI guidance, current at high frequency is applied to an electrode § Can be done during invasive monitoring if proper electrodes are used § Recently championed by one group in the Czech Rep § Report nearly 80% seizure freedom in 51 patient cohort § No MRI diagnoses or path reported § Good neuropsych outcomes Liscak R, et al. “Sterotactic radiofrequency amygdalohippocampectomy in the treatment of mesial temporal lobe epilepsy”. Acta Neurochir. 2010 Malikova H, Kramska L, Vojtech Z, Lukavsky J, Liscak R. “Stereotactic radiofrequency amygdalohippocampaectomy: two years of good

Stereotactic radiofrequency ablation Hypothalamic hamartoma § 100 patient cohort from § § Japan 71% total seizure freedom rate 86% gelastic seizure freedom Behavioral problems resolved if seizure free Behavioral improvement seen even with continued seizures Kameyama S, et al. “MRI-guided steretactic radiofrequency thermocoagulation for 1000 hypothalamic hamartomas? ”. J

Stereotactic radiofrequency ablation Palliative approaches § Due to the possibility of making small lesions, treatment consideration in eloquent locations § One small 7 patient series from Germany § Mostly palliative results § One with post operative aphasia that patient knew was a possibility § One case report from China of bilateral mesial radiofrequency ablations Wellmer J, et al. “Lesion guided stereotactic radiofrequency thermocoagulation for palliative, in selected cases curative epilepsy surgery”. Epilepsy Res. 2016

Laser thermal ablation § Delivery of energy with rapid and localized heating of tissue with sharp boundaries § Can monitor heat real time via MRI § Initially used for brain tumors § Rapidly being adopted for epilepsy Willie JT, et al. “Real-Time Magnetic Resonance-Guided Stereotactic Laser Amygadalohippocampotomy for Mesial Temporal Lobe Epilepsy”. Neurosurgery. 2014

Laser thermal ablation for MTLE § Emory cohort (2013) § 13 patients (9 with HS) § 6/9 seizure free in HS group § 1/4 seizure free in non-HS group § Thomas Jefferson cohort (2015) § 12/20 seizure free (almost all had HS) § 3/4 non-responders seizure free after ATL Willie JT, et al. “Real-Time Magnetic Resonance-Guided Stereotactic Laser Amygadalohippocampotomy for Mesial Temporal Lobe Epilepsy”. Neurosurgery. 2014 Kang JY, et al. “Laser interstitial thermal therapy for medically intractable mesial temporal lobe epilepsy”. Epilepsia 2015

Laser thermal ablation of other etiologies § Miami Children’s cohort § 7/17 seizure free in total (heterogenous pathology) § 8/17 had previous resection § 4/8 showed improvement § Focal cortical dysplasia - 2/7 seizure free § Cavernomas § Periventricular nodular heterotopia § 2 patients – both seizure free after subsequent clinical care § Completion of corpus callosotomy § 50% seizure reduction in palliative procedure § 4/5 Engel class I (5 th seizure free with resection) Lewis EC, et al. “MR-guided laser interstitial thermal therapy for pediatric drug-resistant lesinoal epilepsy. ” Epilepsia. 2015 Mc. Cracken DJ, et al. “Magnetic Resonance Thermometry-Guided Stereotactic Laser Ablation of Cavernous Malformations in Drug-Resistant Epilepsy: Imaging and Clinical Results”. Neurosurgery. 2015 Ho AL, et al. “Stereotactic laser ablation of the splenium for intractable epilepsy”. Epilepsy Behav Case Rep 2016

patient selection with laser thermal ablation Willie JT, et al. “Real-Time Magnetic Resonance-Guided Stereotactic Laser Amygadalohippocampotomy for Mesial Temporal Lobe Epilepsy”. Neurosurgery. 2014 Kang JY, et al. “Laser interstitial thermal therapy for medically intractable mesial temporal lobe epilepsy”. Epilepsia 2015

Focused ultrasound ablation Monteith S, et al. “Transcranial magnetic resonance-guided focused ultrasound for temporal lobe epilepsy: a laboratory feasibility study”. J Neurosurg. 2016

Neurostimulation § Vagus nerve stimulation § Responsive neurostimulation § Deep brain stimulatoin

Vagus nerve stimulation (VNS) § 51% reduction in seizures after one year Englot DJ, Chang EF, Auguste KI. “Drug-Resistant Epilepsy”. J Neurosurg. 2011

Reponsive neurostimulation (Neuropace) § Implantable depth or strip electrodes that record real time electrocorticography § Deliver an electrical stimulus when it sees the Ecog seizure pattern § Ideal candidates § Multifocal epilepsy § Epileptogenic zone in eloquent cortex § Efficacy § 44% seizure reduction at year one § 53% seizure reduction at year two § “ 12. 9% had at least 1 seizurefree period of 1 year or longer” § Implant site infections (9%) § 5. 5% had device removal Bergey G, et al. “Long-term treatment with responsive brain stimulation in adults with refractory partial seizures”. Neurology

Deep brain stimulation § 5 patient case series from Colombia in HH § 3 patient case series from China in BTLE § 91%, 92%, and 95% seizure reduction Fisher R, et al. “Electrical stimulation of the anteriori nucleus of thalamus for treatment of refractory epilepsy”. Epilepsia. 2010 Benedetti-Isaac JC, et al. “Seizure frequency reduction after posteriomedial hypothalamus deep brain stimulation in drug-resistant epilepsy associated with intractable aggressive behavior”. Epilepsia. 2015 Jin H, et al. “Hippocampal deep brain stimulation in nonlesional refractory mesial temporal lobe epilepsy”. Seizure 2016

Where are minimally invasive techniques useful? § Small lesions § Radiographic § Electrophysiological § § Multifocal Deep structures High medical risk patients? Patient preference

How does this fit in at KU? § From Jan 2012 – May 2016 § 23 surgeries, with 14 being seizure free § 8/11 ATL seizure free § 3/5 neocortical seizure free § 3/7 ablations seizure free § 3/5 MTS seizure free § 2 palliative cases (one seizure free after ATL) § Stereoencephalography techniques § RNS implantation site § Selected as a site for prospective trial for laser ablation of mesial temporal lobe epilepsy § In consideration for a neocortical epilepsy RCT Munyon C, Sweet J, Luders H, Lhatoo S, Miller J. “The 3 -Dimensional Grid: A Novel Approach to Stereoelectroencephalography”. J Neurosurg. 2015

Take home § Resection remains the gold standard § Data remains limited for all minimally invasive modalities § Use of minimally invasive techniques completely hinges on adequate localization of the epileptogenic zone § No significant neuropsychological benefit has been demonstrated yet § Minimally invasive treatment options may open up avenues for some patients who would otherwise be resistant to epilepsy surgery

Thank you