Seizures - cmetracker.net

10TH INTERNATIONAL EPILEPSY COLLOQUIUM CONTINUING MEDICAL EDUCATION

INTRACTABLE FOCAL EPILEPSY STATE OF THE ART: SURGICAL AND MEDICAL MANAGEMENT June 15 – 17, 2017 The Ritz-Carlton, South Beach Miami Beach, Florida, USA www.epilepsycolloquium.com

PRESENTED BY:

SPONSORED BY:

Welcome to

10th International Epilepsy Colloquium Intractable Focal Epilepsy State of the Art: Surgical and Medical Management June 15-17, 2017

The conference syllabus, evaluation and CME credit certificate are available online. Wifi: The wifi password for the meeting room is miami2017. Syllabus: The presentations can be downloaded from https://goo.gl/n9YtqH Evaluation and Credit Certificate: After the Colloquium has concluded:  Please go to https://www.surveymonkey.com/r/Colloquium2017 the link to the evaluation and certificate. You will also be emailed this link following the conference. 

At the end of the evaluation you will be automatically forwarded to the credit claim screen. If you have already registered with the Case Western Reserve University CME website, please log in using your email address and password. If you have never logged into the Case Western Reserve University CME website before, enter your email address, select the “I am a new user” radio button and follow the prompts.

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Enter CME Code 173527.

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You will be asked to enter the credits commensurate with your participation in the activity. Once you’ve entered those credits a certificate will come up that you can print for your records.

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Certificates of participation will be available on-site at the conclusion of the Colloquium.

For Further Information Contact the CME Program 10524 Euclid Avenue Cleveland, OH 44106-6026 Tel: (216) 983-1239 Fax: (216) 844-8133 Email: [email protected] http://case.edu/medicine/cme/

Program Agenda Thursday, June 15, 2017 8:00am

Registration and continental breakfast / Visit exhibits

8:30

Welcome Address Samden Lhatoo, MD

8:45

Distinguished Epileptologist Lecture: Intractable Focal Epilepsy in the 21st Century – How far have we really come? Samuel Wiebe, MD

EPIDEMIOLOGY, NATURAL HISTORY AND OUTCOME Chairs: Ley Sander, MD, PhD & Samden Lhatoo, MD 9:30

Intractability: The scale of the problem – Has it changed? Ley Sander, MD, PhD

10:00

Intractability – Have new AEDs made an impact? Frank Gilliam, MD

10:30

Mortality in the intractable population – Has anything changed? Michael Sperling, MD

11:00

Case discussion: Latency to surgery – Fact or fiction? Felix Rosenow, MD

11:30

Break / Visit exhibits & posters

11:45

Plenary Lecture: Epilepsy Surgery – Has the post-resection era begun? Philippe Ryvlin, MD, PhD

12:30pm

Lunch break / Visit exhibits & posters

CLASSIFICATION AND EPILEPSY INFORMATICS Chairs: Samuel Wiebe, MD & Michael Sperling, MD 1:30

Seizure tracking – Personalized care of intractability William Theodore, MD, PhD

2:00

What big data can do for intractability Brian Litt, MD, PhD

2:30

Epilepsy and seizure classification – A pragmatic look Hans Lüders, MD, PhD

3:00

Case discussion: Classification conundrums Hajo Hamer, MD

3:30


THE NEUROIMAGING OF INTRACTABILITY Chairs: John Duncan, MD & Philippe Ryvlin, MD, PhD 3:45

7T MRI in presurgical assessments – What are we chasing? Renzo Guerrini, MD

4:10

Functional imaging – Where do we stand now? Susanne Knake, MD, PhD

4:35

O2 enhanced and other MRI techniques in focal epilepsy Giridhar Kalamangalam, MD

5:00

Multi-modality imaging – How it helps John Duncan, MD

5:30

Case discussion: How imaging helps/does not help me Andreas Schulze-Bonhage, MD

6:00

Adjourn for the day

6:30

Welcome Reception

Friday, June 16 THE NEUROPHYSIOLOGY OF INTRACTABILITY Chairs: Hans Lüders, MD, PhD & Jean Gotman, PhD 7:30am

Registration and continental breakfast

8:00

Early ictal spread – What it means for surgery Fabrice Bartolomei, MD, PhD

8:30

High frequency oscillations – What we know now Jean Gotman, PhD

9:00

Ictal and inter-ictal infraslow – How to look and what it means Shasha Wu, MD, PhD

9:30

Case Discussion: Utility of HFOs and Infraslow in surgical practice Julia Jacobs, MD, PhD

10:00


10:15

Plenary Lecture The Epileptogenic Zone – Current Concepts Jerome Engel, MD, PhD

EPILEPSY SURGERY – GLOBAL ASPECTS Chairs: Philippe Kahane, MD, PhD & Edouard Hirsch, MD 11:00

Epilepsy surgery in the USA – Under or over-utilized? Stephan Schuele, MD

11:20

Is non-invasive evaluation sufficient in most cases: Jayanti Mani, MD

11:40

Is ECoG sufficient enough in difficult cases? Michael Duchowny, MD

12:00

Epilepsy surgery in children: What is different from adults? Prasanna Jayakar, MD, PhD

12:20pm

Building epilepsy surgery programs: The Iranian experience Shahram Amina, MD

12:40

Epilepsy surgery in Korea Seung Bong-Hong, MD

1:00

Lunch break / Visit exhibits Poster viewing and competition

LESION NEGATIVE INTRACTABLE EPILEPSY: PRACTICAL CONSIDERATIONS Chairs: Jerome Engel, MD, PhD & Susanne Knake, MD, PhD Part 1: Temporal lobe epilepsy 2:00

Mesio-Temporal lobe epilepsy – Case discussion Edouard Hirsch, MD

2:25

Neocortical temporal lobe epilepsy – Case discussion Soheyl Noachtar, MD

2:50

Temporal plus epilepsy – Case discussion Philippe Ryvlin, MD

3:15

Minimalist surgery in TLE – Hippocampal transection Shahram Amina, MD

3:40


LESION NEGATIVE INTRACTABLE EPILEPSY: PRACTICAL CONSIDERATIONS Chairs: Hajo Hamer, MD & Stefano Francione, MD, PhD Part 2: Frontal lobe epilepsy – Case based discussions 4:00

Orbito-frontal epilepsy Philippe Kahane, MD, PhD

4:25

Anterior cingulate epilepsy Nuria Lacuey, MD

4:50

SSMA epilepsy Hans Holthausen, MD

5:15

Dorsolateral frontal lobe epilepsy Franҫois Dubeau, MD, PhD

5:40

Surgical outcomes of frontal lobe resections Jonathan Miller, MD

6:10

Adjourn for the day

Saturday, June 17 7:30am

Registration and continental breakfast

8:00

Plenary Lecture The neuropathology of lesion negative focal epilepsy Maria Thom, MD, PhD

NEW CHALLENGES IN INSULO-OPERCULAR AND POSTERIOR CORTEX EPILEPSIES Chairs: Soheyl Noachtar, MD; Felix Rosenow, MD; Sylvain Rheims, MD, PhD 8:45

Recognizing insulo-opercular epilepsy – Case discussion Dang Nguyen, MD

9:15

Recognizing posterior cingulate epilepsy – Case discussion Philippe Kahane, MD, PhD

9:45

Surgery of the insulo-opercular complex: Yes we can Stéphan Chabardes, MD, PhD

10:15

Surgery of the posterior cortex: Does it work and is it safe? Stefano Francione, MD

10:45


EPILEPSY SURGERY IN SPECIFIC SITUATIONS Chairs: Franҫois Dubeau, MD, PhD and Andreas Schulze-Bonhage, MD 11:00

Presurgical evaluation of polymicrogyria – Should we? Louis Maillard, MD

11:30

Invasive evaluation of hemispheric malformations – Can we? Sylvain Rheims, MD, PhD

12:00

Combining SEEG and grids – Can we do this? Nitin Tandon, MD

12:30pm

Case discussions Susan Arnold, MD

1:00

Lunch break / Visit exhibits & posters

EPILEPSY SURGERY: NON-SURGICAL ASPECTS Chairs: Andres Kanner, MD and Cormac O’Donovan, MD 2:00

Impact of genetic findings in epilepsy surgery Karl Klein, MD

2:30

The neuropsychiatric aspects of intractability Andres Kanner, MD

3:00

Neuropsychological assessment – What’s changed? Philip Fastenau, PhD

3:30

Case discussions Naiara Garcia, MD

4:00

Break

4:15

Case Discussions – BRING YOUR OWN CASES Panel: Prasanna Jayakar, MD, PhD; Felix Rosenow, MD; Nitin Tandon, MD; Louis Maillard, MD, PhD; Philippe Kahane, MD, PhD

6:00

Colloquium adjourns

Faculty Shahram Amina, MD Case Western Reserve University University Hospitals Cleveland Medical Center USA Dr. Amina reported no financial relationship with a commercial interest relevant to this activity.

Susan Arnold, MD University of Texas Southwestern Medical Center at Dallas USA Dr. Arnold reported no financial relationship with a commercial interest relevant to this activity.

Fabrice Bartolomei, MD, PhD Aix-Marseille University Centre Saint-Paul Hôpital Henri Gastaut France Dr. Bartolomei receives salary from Eisai for Board Memership, and the CME Program has determined there is no conflict of interest.

Stéphan Chabardes, MD, PhD University Hospital, Grenoble Grenoble Institute of Neurosciences France Dr. Chabardes has received honoraria from Medtronic, Boston Scientific, and Med Tech, and the CME Program has determined there is no conflict of interest.

François Dubeau, MD, PhD Montreal Neurological Institute and Hospital McGill University Canada Dr. Dubeau reported no financial relationship with a commercial interest relevant to this activity.

Michael Duchowny, MD Nicklaus Children’s Hospital USA Dr. Duchowny reported no financial relationship with a commercial interest relevant to this activity.

John Duncan, MD University College London National Hospital for Neurology and Neurosurgery UK Dr. Duncan reported no financial relationship with a commercial interest relevant to this activity.

Jerome Engel, MD, PhD UCLA Health USA Dr. Engel reported no financial relationship with a commercial interest relevant to this activity.

Philip Fastenau, PhD Case Western Reserve University University Hospitals Cleveland Medical Center USA Dr. Fastenau receives salary from Eli Lilly, and the CME Program has determined there is no conflict of interest.

Stefano Francione, MD, PhD Claudio Munari Epilepsy Surgery Centre Italy Dr. Francione reported no financial relationship with a commercial interest relevant to this activity.

Naiara Garcia, MD University of Miami USA Dr. Garcia reported no financial relationship with a commercial interest relevant to this activity.

Frank Gilliam, MD University of Kentucky USA Dr. Gilliam reported no financial relationship with a commercial interest relevant to this activity. Presentation will include discussion of unlabeled/investigational uses of a commercial product.

Jean Gotman, PhD Montreal Neurological Institute and Hospital McGill University Canada Dr. Gotman reported no financial relationship with a commercial interest relevant to this activity.

Renzo Guerrini, MD University of Pisa and IRCCS Fondazione Stella Maris Italy Dr. Guerrini reported no financial relationship with a commercial interest relevant to this activity.

Hajo Hamer, MD University Hospital Erlangen Germany Dr. Hamer has received honoraria from UCB, Desitin, Eisai, Novarits and Bial, and the CME Program has determined there is no conflict of interest.

Edouard Hirsch, MD University Hospital Strasburg Institute for Children and Adolescents with Epilepsy France Dr. Hirsch reported no financial relationship with a commercial interest relevant to this activity.

Hans Holthausen, MD Epilepsy Center for Children and Adolescents, Schoen-Klinic Germany Dr. Holthausen reported no financial relationship with a commercial interest relevant to this activity.

Seung Bong Hong, MD, PhD Sungkyunkwan University School of Medicine Samsung Medical Center Korea Dr. Hong reported no financial relationship with a commercial interest relevant to this activity.

Julia Jacobs, MD, PhD University Medical Center Freiburg Germany Dr. Jacobs has received consulting fees from UCB and Zogenix, and the CME Program has determined there is no conflict of interest.

Prasanna Jayakar, MD, PhD Nicklaus Children’s Hospital USA Dr. Jayakar reported no financial relationship with a commercial interest relevant to this activity.

Philippe Kahane, MD, PhD University Hospital of Grenoble Michallon France Dr. Kahane reported no financial relationship with a commercial interest relevant to this activity.

Giridhar Kalamangalam, MD, DPhil University of Texas Health Sciences Center McGovern Medical School USA Dr. Kalamangalam reported no financial relationship with a commercial interest relevant to this activity.

Andres Kanner, MD University of Miami Health System Miller School of Medicine USA Dr. Kanner reported no financial relationship with a commercial interest relevant to this activity.

Karl Martin Klein, MD, PhD Epilepsy Center Frankfurt Rhine-Main University Hospital, Goethe-University Frankfurt Germany Dr. Klein has received honoraria from UCB, Novartis and Eisai, and the CME Program has determined there is no conflict of interest.

Suzanne Knake, MD, PhD University Hospitals Marburg Philipps-University Marburg Germany Dr. Knake has received honoraria from UCB, Desitin and Eisai, and the CME Program has determined there is no conflict of interest.

Nuria Lacuey, MD, PhD Case Western Reserve University University Hospitals Cleveland Medical Center USA Dr. Lacuey reported no financial relationship with a commercial interest relevant to this activity.

Samden Lhatoo, MD Case Western Reserve University University Hospitals Cleveland Medical Center USA Dr. Lhatoo reported no financial relationship with a commercial interest relevant to this activity.

Brian Litt, MD, PhD Perelman School of Medicine, University of Pennsylvania Hospital of the University of Pennsylavania USA Dr. Litt has stock options in and is co-founder of Blackfynn, Inc., and the CME Program has determined there is no conflict of interest.

Hans Lüders, MD, PhD Case Western Reserve University University Hospitals Cleveland Medical Center USA Dr. Luders reported no financial relationship with a commercial interest relevant to this activity.

Louis Maillard, MD, PhD Centre Hospitalier Régional Universitaire de Nancy France Dr. Maillard has received honoraria from Eisai and UCB, and the CME Program has determined there is no conflict of interest.

Jayanti Mani, MD Kokilaben Dhirubhai Ambani Hospital & Medical Research Institute India Dr. Mani reported no financial relationship with a commercial interest relevant to this activity.

Jonathan Miller, MD Case Western Reserve University University Hospitals Cleveland Medical Center USA Dr. Miller reported no financial relationship with a commercial interest relevant to this activity.

Dang Nguyen, MD University of Montreal Notre-Dame Hospital Canada Dr. Nguyen reported no financial relationship with a commercial interest relevant to this activity.

Soheyl Noachtar, MD University of Munich Germany Dr. Noachtar has received consulting fees and/or honoraria from Eisai, UCB and Desitin, and the CME Program has determined there is no conflict of interest.

Cormac O’Donovan, MD Wake Forest Baptist Health USA Dr. O’Donovan has received research support from Sage Therapeutics, Sunovion and Upsher-Smith, and the CME Program has determined there is no conflict of interest.

Sylvain Rheims, MD, PhD Institute for Children and Adolescents with Epilepsy France Dr. Rheims reported no financial relationship with a commercial interest relevant to this activity.

Felix Rosenow, MD Epilepsy Center Frankfurt Rhine-Main University Hospital, Goethe-University Frankfurt Germany Dr. Rosenow has received honoraria from UCB, Eisai, Certomed, Shire and Desitin, and the CME Program has determined there is no conflict of interest.

Philippe Ryvlin, MD, PhD Lyon University Institute for Children and Adolescents with Epilepsy France Dr. Ryvlin reported no financial relationship with a commercial interest relevant to this activity.

Ley Sander, MD, PhD University College London National Hospital for Neurology and Neurosurgery UK Dr. Sander has received honoraria for speaking from UCB, Eisai and Janssen, and the CME Program has determined there is no conflict of interest.

Stephan Schuele, MD, MPH Northwestern University Feinberg School of Medicine USA Dr. Schuele reported no financial relationship with a commercial interest relevant to this activity.

Andreas Schulze-Bonhage, MD University Hospital Freiburg Germany Dr. Schulze-Bonhage has received honoraria from UCB and Eisai and a consulting fee from Precisis, and the CME Program has determined there is no conflict of interest.

Michael Sperling, MD Sidney Kimmel Medical College of Thomas Jefferson University Thomas Jefferson University Hospital USA Dr. Sperling reported no financial relationship with a commercial interest relevant to this activity.

Nitin Tandon, MD University of Texas Health Sciences Center McGovern Medical School USA Dr. Tandon reported no financial relationship with a commercial interest relevant to this activity.

William Theodore, MD National Institute of Neurological Disorders and Stroke National Institutes of Health USA Dr. Theodore reported no financial relationship with a commercial interest relevant to this activity.

Maria Thom, MD, PhD University College London Institute of Neurology UK Dr. Thom reported no financial relationship with a commercial interest relevant to this activity.

Samuel Wiebe, MD University of Calgary Canada Dr. Wiebe reported no financial relationship with a commercial interest relevant to this activity.

Shasha Wu, MD, PhD University of Chicago USA Dr. Wu reported no financial relationship with a commercial interest relevant to this activity.

Organizing Committee Alexis Arzimanoglou, MD; John Duncan, MD; Hajo Hamer, MD; Edouard Hirsch, MD; Philippe Kahane, MD, PhD; Andres Kanner, MD; Susanne Knake, MD, PhD; Samden Lhatoo, MD; Hans Lüders, MD, PhD; Jonathan Miller, MD; Philippe Ryvlin, MD, PhD; Felix Rosenow, MD Dr. Hamer has received honoraria from UCB, Desitin, Eisai, Novarits and Bial; Dr. Rosenow has received honoraria from UCB, Eisai, Certomed, Shire and Desitin. The CME Program has determined there is no conflict of interest. Other committee members reported no financial relationship with a commercial interest relevant to this activity.

Faculty Disclosure The policy of Case Western Reserve University School of Medicine CME Program requires that the Activity Director, planning committee members and all activity faculty (that is, anyone in a position to control the content of the education activity) disclose to activity participants all relevant financial relationships with commercial interests. Disclosure will be made to activity participants prior to commencement of the activity. Case Western Reserve University School of Medicine also requires that faculty make clinical recommendations based on the best available scientific evidence and that faculty identify any discussion of “off-label” or investigational use of pharmaceutical products or medical devices.

Acknowledgments Educational grants from the following companies are gratefully acknowledged

UCB Nihon Kohden Supernus Eisai LivaNova

Exhibits provided by Platinum – Eisai Gold – Sunovion FHC

Bronze PMT Nihon Kohden

UCB

Standard Ad-Tech Courtagen Micromed Supernus Zimmer Biomet We gratefully acknowledge their support and hope you will visit their displays during a break in the meeting.

Posters 1. Electroencephalogram features of seizure prediction in patients with generalized periodic discharges with and without triphasic morphology Ayham Alkachroum, MD; Haifa Al-Abri, MD; Alok Sachdeva, MD; Sarita Maturu, MD; Jennifer Waldron, DO; Han Wang, MD; Macym Rizvi, MD; Guadalupe Fernandez-Baca Vaca, MD; Hans Luders, MD, PhD 2. Frequency of status epilepticus in women with epilepsy G. Odintsova; K. Abramov, A. Chugunova 3. Temporal lobe seizure causing asystole Faizan Aslam, MRCP 4. Language inhibition and motor response thresholds during extra-operative cortical stimulation mapping Gewalin Aungaroon, MD; Alonso Zea Vera, MD; Paul Horn, PhD; Katherine Holland, MD, PhD; Ravindra Arya, MD, DM 5. After-discharges and seizures during functional brain mapping with extra-operative electrical cortical stimulation Gewalin Aungaroon, MD; Alonso Zea Vera, MD; Paul Horn, PhD; Katherine Holland, MD, PhD; Ravindra Arya, MD, DM 6. Intracranial HFOs in patients with drug-resistant seizures and focal cortical dysplasia Carmen Barba; Federico Mealni; Gianpiero Di Giacomo; Flavio Giordano; Matteo Lenge; Annamaria Buccoliero; Chiara Caporalini; Francesco Mari; Renzo Guerrini 7. Alternating the polarity of 50Hz biphasic stimulation allows recovering physiological EEG responses during intracranial stimulation Andrea Barborica; Ioana Mindruta; Mihai Maliia; Irina Popa; Anca Arbune; Andrei Daneasa; Cristian Donos 8. Prognostication challenges after anoxic brain injury, A case report Alireza Bozorgi, MD; Benjamin Miller, MD; Shahram Amina, MD; Wei Xiong, MD 9. Long term follow up in pharmacoresistant temporal lobe epilepsy operated patients. A functional connectivity study. Lilia Morales Chacon; Karla Batista; Abel Sanchez Coroneaux; Margarita Baez Martin; Juan E. Bender; Kenris Morales; Sheila Berrillo 10. Experience with short video EEG in small town, Nashik, India – (Yield and cost effectiveness) Anand Diwan; Ashok Pillai 11. Cataplexy in a young girl, mistaken for epilepsy Claire E.H.M. Donjacour, MD, PhD 12. Antiepileptic drug withdrawal and timing of seizures in the epilepsy monitoring unit Phan Duy; Emily Johnson, MD

13. Neocortical electrophysiological patterns of memory formation – an intracranial EEG study S. Gollwitzer; S. Rampp; M. Fellner; G. Kreiselmeyer; B. Diehl; T. Wehner; J. Lang; S. Schwab; S. Schwarz; K. Rossler; S. Hanslmayr; H.M Hamer 14. Levosimendan exerts anticonvulsant properties against PTZ-induced seizures in mice through activation of nNOS/NO pathway: Role for KATP channel Gooshe M; Tabaeizadeh M; Aleyasin AR; Mojahedi P; Ghasemi K; Yousefi F; Vafaei A; Amini-Khoel H; Amiri S; Dehpour AR 15. Clinical profile, EEG patterns and anti-seizure drug response in patients with malformations of cortical development Swapan Gupta; Madhukar Dhondji; Sudhindra Vooturi; S. Sitajayalakshmi 16. Cat scratch disease with encephalopathy Samir Karia, MD 17. Ohtahara syndrome, left hemimegalencephaly with lobar migration and myelination abnormalities and novel NPRL3 splice alteration Samir Karia, MD 18. Right parietal region as the symptomatogenic zone for the ictal hiccup Sanaz Ahmadi Karvigh; Soroor Advani 19. Six year single center experience of invasive electroencephalography in patients with refractory hypermotor seizures K.A. Klotz; D. Altenmuller; A. Schulze-Bonhage; J. Jacobs 20. Surgical management strategies and seizure outcome in medically refractory pediatric epilepsy with large gliotic foci Naresh Kumar; Siby Gopinath; K.P. Vinayan; Arun Grace Roy; K. Radhakrishnan; Anand Diwan; Ashok Pillai 21. Brodmann area 25 is a cortical structure for human blood pressure control Nuria Lacuey 22. Comparing intellectual and behavioral functioning of children with medically intractable epilepsy to treatment-responsive epilepsy A.R. Lucchetti; T. Owens; J. Fields; E. Wirrell; M. Zaccariello 23. Systemic autoimmune diseases in idiopathic epilepsy Yitao Ma, MD 24. Multi-institutional AMED study of epilepsy and glia in patients with intractable focal epilepsy – A case presentation Taketoshi Maehara; Motoki Inaji; Satoka Hashimoto; Akiyoshi Kakita; Akio Ikeda; AMED Study Group of epilepsy and glia 25. Convulsive status epilepticus in Vilnius: ten-year retrospective analysis Ruta Mameniskiene; Jurgita Grikiniene 26. New Onset Refractory Status Epilepticus (NORSE) presenting with gelastic seizures in a 3 year old girl Ahmad Marashly, MD

27. Plasma serotonin levels in patients with epileptic seizures Arun Murugesan; MR Sandhya Rani; Johnson Hampson; Bilal Zonjy; Samden Lhatoo 28. MR-guided laser interstitial thermal imaging in epilepsy Lidia Mayumi Nagae; Justin M. Honce; Eric Nyberg; Steve Ojemann; Aviva Abosch; Cornelia Drees 29. Migration of epileptic discharges during medication withdrawal in presurgical evaluation: 2 clinical cases Y. Novitskaya; M. Hintz; A. Schulze-Bonhage 30. Seizure outcome in non-lesional frontal lobe epilepsy surgery Sumana Pallegar; Siby Gopinath; K.P. Vinayan; Arun Grace Roy; K. Radhakrishnan; Rajesh Kannan; Manjit Sharma; Ashok Pillai 31. Hippocampal transection in SEEG-proven, dominant mesial temporal lobe epilepsy in childhood Jun T. Park; Guadalupe Fernandez Baca Vaca; Rachel Tangent; Jonathan Miller 32. Perception of body scheme mapped with high frequency stimulation (HFS) during Stereo-electroencephalography (SEEG) Popa I; Donos C; Barborica A; Bartolomei F; Lagarde S; Maliia MD; Hirsch E; Scholly J; Valenti-Hirsch MP; Mindruta I 33. Functional mapping by somatosensory evoked potentials during frontal lobe epilepsy surgery in Cuba L. Portela Hernandez; L. Morales Chacon; A. Santos Santos; R. Perez Lalana 34. Psychogenic non-epileptic seizures (PNES) in persons with drug refractory epilepsy (DRE) due to a surgical substrate Ramanujam B; Tripathi M; Sharma S; Ahmed FU; Wadhawan GV; Chandra PS 35. High frequency oscillations and spikes running-down after SEEG-guided thermocoagulations in the epileptogenic network of periventricular nodular heterotopia Scholly J; Pizzo F; Timofeev A; Valenti-Hirsch MP; Behr C; Ollivier I; Proust F; Roehri N; Hirsch E; Bartolomei F 36. Surgical approach for Lennox-Gastaut syndrome in a child: A case report Hannah Grace Segocio; Susan Acosta 37. Focal nonconvulsive status epilepticus associated with peri-ictal water-drinking: A case report and review of the literature Huang Shuo, MD, PhD; Haifa AlAbri, MD; Alok Sachdeva, MD; Ayham M. Alkhachroum, MD; Stephanie Shatzman, BS; Mark Scher, MD; Hans Luders, MD, PhD 38. A new platform for human brain functional mapping in epilepsy patients Yinchen Song; Kevin Hartstein; Abigail Hellman; Peter Ulric Tse; Krzysztof Bujarski; Erik Kobylarz; Vijay Thadani; George Thomas Jr.; Barbara Jobst 39. Analysis of semiology components of hypermotor seizure and their anatomical correlation Sikawat Thanaviratananich

40. Capturing of events during inpatient monitoring is unlikely in patients with infrequent events. Video-EEG monitoring is also not readily available in many underserved communities. Sikawat Thananviratananich, MD, MSc; David Chen, MD 41. Seizure freedom solely with resection of sphenoid wing temporal encephalocele in patient with proven independent hippocampal seizures Carol Ulloa, MD 42. Neurosurgical treatment of mesial temporal sclerosis – our experience Sulentic Vlatko; Nankovic Sibila; Mrak Goran; Bazadona Danira 43. An alternative to collodion Esperanza Wagner, R. EEG T; Dr. Carlos Gama 44. Combination of corpus callosotomy and vagus nerve stimulation for treatment of the most difficult cases with medically refractory epilepsy Takamichi Yamamoto, MD

5/25/17

FOCAL EPILEPSY IN THE 21ST CENTURY: How far have we really come? Samuel Wiebe MD FRCPC 10TH International Epilepsy Colloquium, Miami Beach, June 15-18, 2017

Outline Where are we now? • Evidence safari Medical and Surgical therapy • What has (not) been achieved

What’s in the horizon? • Precision in epilepsy requires prediction • Challenges with prediction

EPILEPSY DEFINITIONS Conceptual Operational 1993

A disorder of the brain: -enduring predisposition to generate epileptic seizures, -neurobiologic, cognitive, psychosocial consequences -requires at least one epileptic seizure.

>2 unprovoked seizures 24 hours apart Independent of Risk of recurrence Excludes Status epilepticus or clusters of seizures within 24 hours

>2 unprovoked seizures 24 hours apart, or

Operational 2014

1 uprovoked seizure plus Risk of recurrence >60%,* or Reflex Epilepsy, or Epilepsy Syndrome *if risk unknown default to > 2 unprovoked seizures >24 hours Fisher et al, Epilepsia 2005 and Epilepsia 2014

1

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Epilepsy RESOLVED 1993

NO provision for classifying people as no longer having Epilepsy

2014

Resolved Age-dependent epilepsy syndrome and now past the applicable age, or Seizure-free for the last 10 years, with no seizure medicines for the last 5 years

Fisher et al, Epilepsia 2014

Incidence trends – No change over 40 years

Sillanpaa et al, JAMA Neurol 2016

Incidence trends – more focal epilepsy


2

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Focal Epilepsy CAROLE (2001) N=434

Parietal 5%

Occipital 4% Temporal 45%

Unlocalized 19%

Frontal 27%

Jallon et al, Epilepsia 2001

Epilepsy in the elderly INCIDENCE TRENDS OVER 40 YEARS – Finland entire population


Change in emphasis

Perampanel Retigabine Eslicarbazepine Lacosamide Rufinamide Pregabalin Stiripentol Levetiracetam

20

Number

Tiagabine

15

Topiramate Felbamate Zonisamide

10

Oxcarbazepine Fosphenytoin Gabapentin

Lamotrigine Vigabatrin

Sodium Valproate

Carbamazepine Benzodiazepines

Ethosuximide

5 Phenobarbital

Phenytoin

Primidone

Bromide

0 1840

1860

1880

1900

1920

1940

1960

1980

2000

Year

3

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50% seizure reduction 0.5

Absolute Difference between AED and Placebo

Proportion

0.4 0.3 0.2 0.1 0 Before 2001 or 2001 later

Children Adults

✔ Remember 20% (NNT=5)

High Focal dose adults & adults children

Beyenburg et al, Epilepsia 2010

Seizure Free 0.5

Absolute difference between AED and Placebo

0.4

Proportion

0.3 0.2 0.1 0

Before 2001 or 2001 later

Children

Adults

✔ Remember 6% (NNT=17)

High dose Focal adults adults & children Beyenburg et al, Epilepsia 2010

Seizure Frequency & QOL Is Seizure Reduction Meaningful? Percent Seizure reduction ¯100%

¯75-99%

¯50-74% ¯ 10 seizures Present Present Present

OR (95%CI) 1.7 (1.4– 2.0) 1.3 (1.1 – 1.5) 1.4 (1.3 – 1.7) OR (95%CI) 1.9 (1.2– 3.0) 3.4 (1.6 – 7.2) 2.8 (2.0 – 3.9) 2.2 (1.3 – 3.6) 4.3 (2.0 – 8.9) 2.7 (1.6 – 4.7)

(1) Schiller, Neurology 2008. (2) Hitiris, Epil Res 2007. (3) Berg, Ann Neurol 2009

OUTCOME OVER TIME WITH AEDs 1,098 patients, median follow-up 7.5 years Early Sustained Seizure Freedom Late Sustained Seizure Freedom

37% 59% 22%

Relapse & Remit

16%

Never Seizure Free

25%

Time Brodie et al, Neurology 2012

How do we get new ASDs? Target ID Hit generation Lead generation Animal studies

Efficacious, safe, “druggable”, molecule, protein, gene, other. Data mining, multiple sources Compound with desired activity, confirmed upon retesting Further testing and “refinement” of most promising hits Animal models, disease efficacy, some safety

Phase I

Humans, small “n”, safety, dose range

Phase II

Humans, larger “n”, efficacy, further safety

Phase III

Humans, large “n”, efficacy, further safety, regulatory approval

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Animal Studies: Interpretable? Reproducible? • 76 animal studies, cited >500 times, published from 1980 to 2000 • 7 top journals (Science, Nature, Cell, Nature genetics, Nature medicine, Nature immunology, Nature biotechnology) • Assessed – Quality of the studies – whether findings were replicated in human trials

Hackam et al, JAMA 2006

REPRODUCIBLE IN HUMAN TRIALS? Hackam et al, JAMA 2006

45% REMAIN UNTESTED

38% REPLICATED IN HUMAN TRIALS

Predict replication Does not Predict replication

18%

10%

CONTRADICTED IN APPROVED FOR HUMAN TRIALS USE IN HUMANS

Animal study found dose-response (OR=3.3)

Type of disease or therapy, journal, citation rate, year of publication, length of follow-up

The NIH Core Set of Standards – Study design Landis, Nature 2012

Randomization

Blinding

Assign animals at random

Blinded caretakers and researchers

Report randomization method

Blinded outcome assessment

Concealed allocation

Blinded analyses

Sample Size

Statistical estimation of sample size Before experiment begins Account for repeated analyses

Data handling

Eligibility criteria Missing data, outliers and data exclusion Prospective endpoint selection Interim analyses Pseudo-replicates (many samples from same data set)

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Introducing Preclinical randomized trials Proposal to Derisk Clinical Trials • • • • •

Focus on Efficacy & treatment gap Rigorous blinding Multicentre, site monitoring Central coordinating site Compare with inactive control and if possible with known active • At least 2 different models • True models of epilepsy (spont recurrent seizures) • Best model for syndrome • Endpoints defined a priori • Expert statisticians • Sample size, analyses

O’Brien Epilepsia 2013; Simonato et al, Lancet Neurol 2014

Antiepileptogenesis 20 Agents with preclinical proof of concept Compound

Mechanism

Adv Eff

Erythropoietin

EP receptor

?

FGF-2, BDNF

Gene therapy

?

Yes

Rapamycin

antineoplastic

Inflammation

?

Adenosine

DNA methylation

Fingolimod

Inflammation

?

1NMPP1

antineoplastic

Melatonin

Antioxidant

Yes

WP1066

antineoplastic

Compound

Mechanism

Celecoxib

Inflammation

?

Parecoxib

Inflammation

Adv Eff No

α-4 integrin Ab

Inflammation

Aspirin

Compound

Mechanism

Levetiracetam

SV2A

Ethosuximide

Ca-channel

Yes

Zonisamide

Na-channel

No

Carbamazepine

Na-channel

Vigabatrin

GABA inhibitor

Ceftriaxone

Glutamate agonist

?

Atipemazole

Adrenergic agonist

?

SR141716A

Cannabinoid antagonist

?

? ? Yes

Adv Eff ?

Yes

Pitkanen, Neurotherapeutics 2014

Opportunities for Antiepileptogenesis

The problem is time and cost

Years

French et al, 2013

7

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From Rats to Fish and Flies for Drug Screening Drosophila

Seizure rats and mice

• Many more animals • Fast drug screening • Clemizole repurposing

SCN1A Zebra fish

Molecular Medicines Targeted to Mechanism

Perampanel

AMPA receptor

Nature, 2014

Temporal Lobe Surgery 40%

?

60%

Difference NNT = 2

Wiebe et al, NEJM, 2001

Early Surgery: 2-year Sustained Seizure Freedom Not seizure free

with AEDs

73% with Surgery 1.4 NNT

p = 0.001

Seizure free 0

20 Number of patients

0%

25

15 10

11

23

5 0

4 Surgery

Medical

Engel et al, JAMA 2012

8

EPILEPSY

Outcome patterns in epilepsy surgery—the long-term view Samuel Wiebe

Predicting response to therapy in individual patients with epilepsy is not straightforward. An exploration of long-term surgical outcomes in an epilepsy cohort has identified seven patterns of remission and relapse, and the probability of each outcome has been calculated. The study provides new predictors of postoperative outcomes in epilepsy. Wiebe, S. Nat. Rev. Neurol. advance online publication 31 January 2012; doi:10.1038/nrneurol.2012.9

Clinicians who communicate the diagnosis of epilepsy to their patients can say with confidence that the evidence-based probability of achieving seizure freedom with a variety of antiepileptic drugs (AEDs) is about 70%.1 If medication fails to control seizures, clinicians can assert that resective brain surgery has achieved impressive seizure-free outcomes in selected patients: the available evidence demonstrates that long-term seizure freedom is achieved in about 60% of patients who undergo temporal lobe surgery, and in 30–40% of those who undergo extratemporal surgery.2,3 Moreover, if a patient becomes seizure-free after surgery, they will have a 30% probability of being able to discontinue their AEDs.4 The evidence regarding predictors of outcomes is also congruent. Long-term seizure freedom is more likely if discrete seizure-producing zones and MRIdetected abnormalities are resected in their entirety, if the postoperative EEG shows no epileptiform discharges, and if patients are completely seizure-free in the early postoperative period.2,5,6 However, these neatly packaged probabilities of outcome conceal a more-complex reality. In their recent analysis of long-term outcomes after epilepsy surgery, de Tisi et al.7 have improved both our understanding of the various outcome patterns and our interpretation of postoperative seizure-freedom. Understanding a patient’s likelihood of long-term outcome is important, because this could, where appropriate, enable clinicians to advise decreased or discontinued medication, and to arrive at a decision regarding surgery. As reported in The Lancet, de Tisi and colleagues performed a year-by-year analysis to

investigate seizure outcomes in a cohort of 615 adults who underwent resective surgery for epilepsy. Annual outcome was determined as either freedom from or persistence of seizures that impaired the patient’s awareness. The researchers characterized seven patterns of long-term seizure relapse and remission (Figure 1).7 Although the authors reported on all types of surgery, the majority of their analyses and comments pertained to patients with temporal lobe resection (81% of their cohort).

Seizure freedom was highest in patients who underwent hemispherectomy (64%), followed by those who had temporal lobe surgery (55%) and extratemporal surgery (40%), but the risk of seizure recurrence was increased up to threefold in patients with nonspecific pathology or cortical dysplasia.7 The findings support previous observations that linked postoperative outcomes with type of surgery and etiology, and also confirm the idea that seizure recurrence in the years immediately after surgery confers a poor long-term outcome. Consistent with other studies,8 de Tisi et al. found that the absolute proportion of seizure-free patients changed little over time, but that this proportion comprised different patients at each time point investigated, with up to 15% of individuals shifting between the different seizure outcome patterns each year.7 Some of the findings from the current study question existing views on postoperative seizure outcomes. For example, previous reports contend that occurrence of simple partial seizures (SPSz) in the immediate postoperative years has no impact on the long-term likelihood of seizure

5/25/17

SURGERY: Long-term seizure outcome patterns

Seizure outcome pattern

Percentage of patients who experience seizure outcome (%)

59%

1–

51

2–

18

3–

8

4–

8

5–

7

6–

6 2

7– Remission

Time

Relapse

Figure 1 | Long-term postoperative seizure outcome patterns in patients with epilepsy. Bar heights represent probability of developing the particular outcome pattern after surgery. Lengths Wiebe, S. (2012) of colored bars illustrate course of seizure freedom (green) versus seizure occurrence (blue). Bar lengths only illustrate the time frame of relapse or remission, and do not show the actual outcome duration. Outcome patterns: 1, seizure-free since surgery; 2, never seizure-free; 3, initially seizure-free, then relapse; 4, initial seizures, then terminal remission; 5, seizure free with transient relapse, then remission; 6, complex pattern of remissions and relapses; 7, initial seizures with transient remission, then relapse.

NATURE REVIEWS | NEUROLOGY

ADVANCE ONLINE PUBLICATION | 1 © 2012 Macmillan Publishers Limited. All rights reserved

JAMA. 2015;313(3):285-293 2 2 5 3 3 3

Randomized trials Systematic reviews with controls Systematic reviews without controls Pediatric systematic reviews Long-term studies Large cohorts

62% (34-74)

Long term Outcomes Percent'Seizure'Free' Subpial#Trans# Frontal# Grouped#Xtemp# Callosotomy# Pariet=Occip# Temp#&#Xtemp# Hemispherectomy# Temporal#

16%# 27%# 34%# 35%# 46%# 59%# 61%# 66%#

Tellez-Zenteno et al, Brain 2005

9

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Long Term Seizure Freedom Percent Seizure Free 64

63

61

54

76 62

45

After 1980

41

Before F/U 5-10 F/U >10 1980 years years

Adults

Children Tumours

Older

(>50)

Tellez-Zenteno et al, Brain 2005

Non-Lesional vs Lesional Meta-analysis 40 studies Lesional

Non-Lesional

80%

Percent Seizure Free

60% 40%

0%

75%

70%

60%

51%

46%

20%

Temporal & Xtemporal

35%

Temporal & Xtemporal

Xtemporal

Tellez-Zenteno et al, Epilepsy Res 2010

Pre 1997

FEWER

MORE

Multilobar resections Non-specific Gliosis Intracranial EEG Complications Reoperations Seizure Free Lobar – Focal resections Tuberous sclerosis AEDs Continued

90 80 70

Percent Seizure Free

POST - 1997

83 67

Post 1997

81 63

77

74

58

60

45

50 40 30 20 10 0 0.5

1

2

Years Post-surgery

5 P20 patients, 1990 to 2008

Adults Children

Major neuro

Total

Minor 3 months

Minor neuro 0

5 10 Percent

15

Epilepsia 2013

VISUAL MEMORY

Percent of Patients

VERBAL MEMORY

Percent of Patients

STATISTICALLY RELIABLE CHANGE Meta-Analysis 20 0 -20 -40 -60

20

7

Left T

Right T 14

-20 -44

Left T 15

Right T 10

0 -20 -40

Gain Loss

-21

Gain Loss

-23 Sherman, Wiebe et al, Epilepsia 2011

COGNITIVE REHABILITATION Systematic review N= 577, No randomized trials • Techniques – – – – –

Internal compensatory strategies Memory aids Psychoeducation Verbal and visual Memory training Exercises for attention and executive function

• Results – May improve verbal memory • Using visual imagery in particular

– – – – –

Less helpful in dominant surgery Figural Memory less benefited Decline in cognitive function avoided May improve function and QOL Effect of timing is unclear

Mazur et al Epilepsia 2015

11

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DOES SURGERY CURE?

AED WITHDRAWAL Long Term

22% Seizure Free Off AEDs

Tellez & Wiebe, Brain 2007

AED WITHDRAWAL – CHILDREN AND ADULTS 50%

Recurrence

40%

Pooled

30%

33% Children

25% Adults

20%

Seizure Free Off AEDs

10% 0% Individual Studies

Schmidt, et al, Epilepsia 2004

12

5/25/17

Seizure recurrence % (95%CI)

AED withdrawal - medical and surgical, up to 2014

Medical = 45 studies, 7,082 patients Surgical = 16 studies, 2,441 patients

34% 29%

28%

Main problems • No controls • Incomplete reporting • Too many analyses for too few patients • Results highly variable

24%

22%

21%

14%

Lamberink et al, Epileptic Disord 2015

Predictors Of Seizure Recurrence Post-surgery AED Withdrawal Feature

Number of studies (positive/total)

Shorter time from surgery to reduction of AEDs

3/3

Longer duration of epilepsy

2/4

Postop spikes on EEG prior to withdrawal

4/5

Seizures between surgery and withdrawal

2/4

Older age

1/1

Normal MRI

1/1

Multifocal MRI

1/1

Etiology (Mesial temporal sclerosis)

1/5

Incomplete resection

1/2

Multiple surgeries

1/1

Lamberink et al, Epileptic Disord 2015

AED WITHDRAWAL What neurologists say they do… Questions

USA

Canada

EEG

57%

62%

MRI

14%

10%

AED level

39%

11%

1 year

25%

10% Mono, 20% Poly

>2 years

62%

3% Mono, 60% Poly

Use nearly always

2 SURVEYS • USA, 66 epilepsy centres, • n=151, response rate 68% • Canada, all epileptologists • n= 66, response rate 81%

57

When to taper

Factors in favor

Patients’ wishes, Unilateral MTS, Normal EEG

Factors against

Epileptiform EEG*, early seizures*, persistent auras, wants to drive, multifocality*

Berg, E&B 2007; Tellez-Zenteno, Epilepsy Res 2012

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AED WITHDRAWAL – Surgical Therapy 6 non-controlled studies

4 Controlled studies

Median recurrence Withdraw No Withdraw

Percent recurrence

41% Temporal 22%

Extratemporal

Ratio = 2

65% regain control

28% Time to start taper Highly variable Immediate to 2 years post surgery

© MASSON

29%

No difference!

**Recurrence higher in no withdrawal group in 2 studies

Rev Neurol (Paris) 2004 ; 160 : 4, 4S00-4S00

4S1

Conférence de consensus Texte des experts Évaluation médico-économique de la chirurgie des épilepsies partielles pharmaco-résistantes de l’adulte. Étude coût-efficacité - Résultats préliminaires M.-C. Picot1, D. Neveu1, P. Kahane2, A. Crespel3, P. Gélisse3, E. Hirsch4, P. Derambure5, S. Dupont6, E. Landré7, F. Chassoux7, L. Valton8, J.-P. Vignal9, C. Marchal10, A. Rougier11, C. Lamy12, F. Semah12, A. Biraben13, A. Arzimanoglou14, J. Petit15, P. Thomas16, P. Dujols1, P. Ryvlin14 Unité de biostatistiques et épidémiologie, CHU Arnaud de Villeneuve, Montpellier Service de neurophysiopathologie de l’épilepsie, CHU Hôpital Nord, Grenoble Service d’Explorations Neurologiques et Epileptologie, CHU Gui de Chauliac, Montpellier Service de neurologie, CHU Hôpital Hautepierre , Strasbourg Service de Neurophysiologie Clinique, CHU Hôpital R. Salengro, Lille 6 Service de Neurologie, Hôpital LaPitié-Salpêtrière, AP-HP, Paris 7 Service de Neurochirurgie, Hôpital Saint Anne, AP-HP, Paris 8 Service d’Explorations Neurologiques et Epileptologie, CHU Rangueil, Toulouse 9 Service de Neurologie, CHU Hôpital Neurologique, Nancy 10 Service de Neurologie, CHU Hôpital Pellegrin-Tripode, Bordeaux 11 Service de Neurochirurgie, CHU Hôpital Pellegrin-Tripode, Bordeaux 12 Service de Neurologie, Hôpital Saint Anne, AP-HP, Paris 13 Service de Neurologie, CHU Pont-Chaillou , Rennes 14 Service de Neurologie, Hôpital Robert Debré AP-HP, Paris 15 Service de Neurologie, Etablissement médical La Teppe, Tain l'Hermitage 16 Service de Neurologie, Hôpital Pasteur, Nice 17 Neurologie Fonctionnelle et Epileptologie, CHU Hôpital neurologique, Lyon 1 2 3

5

Cost Effectiveness

4

RÉSUMÉ

Years after surgery

Une analyse coût-efficacité a été réalisée sur une cohorte prospective de patients adultes présentant une épilepsie pharmacorésistante parPicot et al, Rev Neurol (Paris) 2004 tielle opérable. Les données économiques et cliniques ont été recueillies à l’inclusion, puis tous les six mois durant deux ans chez les patients opérés et ceux traités médicalement. L’efficacité est définie par une année sans crise. Le rapport coût-efficacité incrémental (RCEI), incluant les coûts directs médicaux (CDM) et non médicaux, est estimé pour les deux premières années après chirurgie et extrapolé sur la vie entière grâce à une simulation de Monte-Carlo. Les coûts indirects ont été mesurés en unités physiques. La qualité de vie a été évaluée (QOLIE-31, SEALS). Les données ont été comparées avant et après chirurgie. Cette analyse préliminaire porte sur 89 patients opérés et 78 traités médicalement. Les patients opérés présentent une épilepsie plus sévère. Un an après la chirurgie, 83 p. 100 des patients sont libres de crise. Le RCEI à un an et deux ans après chirurgie est égal respectivement à 23 531 et 9 533 euros par année supplémentaire sans crise. À moyen terme, la chirurgie devient coût-efficace entre 7 et 8 années après l’intervention. Ce délai est peu sensible aux variations du taux d’escompte et à l’âge d’intervention des patients. Mots-clés : A VENIR.

Tirés à part : M.-C. PICOT, CHU, Hôpital Arnaud-de-Villeneuve, Département de l’Information Médicale, 291, avenue du Doyen-G.-Giraud, 34295 Montpellier Cedex 5, France. E-mail : [email protected]

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Cost Effectiveness in Children

Kene et al, Child’s Nerv Dis 1999

J Neurosurg 87:20–28, 1997

A cost-effectiveness analysis of anterior temporal lobectomy for intractable temporal lobe epilepsy

J. T. King, Jr., et al.

JOSEPH T. KING, JR., M.D., M.S.C.E., MICHAEL R. SPERLING, M.D., AMY C. JUSTICE, M.D., PH.D., AND MICHAEL J. O’CONNOR, M.D. Section of Neurosurgery, Department of Veterans Affairs Medical Center, Cleveland, Ohio; Department of Neurosurgery, Case Western Reserve University and University Hospitals, Cleveland, Ohio; Program in Health Care Research and Division of General Internal Medicine, Case Western Reserve University, Cleveland, Ohio; Comprehensive Epilepsy Center and Departments of Neurology and Neurosurgery, Graduate Hospital, Philadelphia, Pennsylvania; and Division of Neurosurgery, University of Cost per QALY = $37,000 Pennsylvania Medical Center, Philadelphia, Pennsylvania

Surgical = Medical at 15 years

U Patients with medically intractable temporal lobe epilepsy are potential candidates for anterior temporal lobectomy (ATL), in which epileptogenic temporal lobe tissue is localized and surgically removed. This surgical approach can eliminate or drastically reduce seizures in the majority of patients. The authors used a decision-analysis model to examine the cost-effectiveness of a surgical evaluation and treatment protocol for medically intractable temporal lobe epilepsy. This model compared a cohort treated with the new protocol with a continuation of their immediate preoperative medical management and projected these differences over the patient’s lifetime. The Markov model incorporated postoperative seizure status, patient quality of life, death from surgical and natural causes, discounting, and the direct medical costs associated with outpatient evaluation, hospitalization, surgery, antiepileptic drugs, and lifetime outpatient treatment. The intent-totreat analysis included patients who underwent evaluation but were not eligible for ATL. Sensitivity analyses were also performed on the variables in the model. Data from the baseline model indicated that evaluation for ATL provided an average of 1.1 additional quality-adjusted life years (QALYs) compared with continued medical management, at an additional cost of $29,800. Combining the clinical and economic outcomes yielded a cost-effectiveness ratio of $27,200 per QALY. This value is comparable to other accepted medical or surgical interventions, such as total knee arthroplasty ($16,700/QALY) or coronary artery balloon angioplasty ($40,800/QALY). Sensitivity analyses demonstrate that the results are critically dependent on postoperative seizure status and improvement in quality of life. Although further work is necessary to quantify the improvement in quality of life after epilepsy surgery better, the present data indicate that ATL for treatment of intractable temporal lobe epilepsy is a cost-effective use of medical resources.

KEY WORDS • epilepsy • temporal lobe epilepsy • cost-effectiveness analysis • decision analysis • Markov process • surgery

T

HERE are an estimated 400,000 people with epilepsy in the U.S. who continue to have seizures despite medical management with antiepileptic medications.34 Some of these patients are candidates for epilepsy surgery, which entails the localization and surgical removal of epileptogenic tissue. Anterior temporal lobectomy (ATL) is the most common operation for refractory epilepsy.25 Numerous series have demonstrated the effectiveness of this procedure in reducing or eliminating seizures in appropriately selected patients with temporal lobe epilepsy.10,14,17,20,23,29,69,75 Although it is effective, surgery is an expensive undertaking; the charges for the surgical workup and treatment of epilepsy are estimated to range from $25,000 to $100,000.46 Cost-effectiveness analysis incorporates clinical and economic outcomes to assess an intervention.19,22,70,71 This report

J Neurosurg, 1997

examines the cost-effectiveness of ATL as a treatment for medically refractory temporal lobe epilepsy. Using an intent-to-treat analysis, we detailed the clinical effectiveness and costs associated with ATL and determined which factors had a critical impact on the cost effectiveness of this procedure. Clinical Material and Methods Surgical Evaluation Protocol

Patients were eligible for evaluation if they suffered from medically intractable temporal lobe epilepsy, defined as persistent complex partial or secondarily generalized seizures occurring at a rate of at least one every 1 to 2 months, and failure to respond to at least three different

20

J. Neurosurg. / Volume 87 / July, 1997

Quality of Life

FIG. 1. Graphs showing the influence of altering various assumptions on the cost-effectiveness ratio of the evaluation and treatment protocol for medically intractable epilepsy. A higher cost-effectiveness ratio indicates a greater cost

Clinically Important Improvement (expressed in 1994 U.S. dollars) per unit benefit (expressed in QALYs). Fifty thousand dollars per QALY (horizontal dotted line) has been proposed as a guideline for determining if an intervention is cost effective. Upper Left: Graph showing that the cost-effectiveness ratio is directly related to the age of the patient. The asterisk indicates the baseline 30-year-old patient. The cost per QALY remains below the $50,000 threshold for patients 20 to 60 years old. Upper

Percent of patients

80"

NNT Right: Graph NNT showing that NNT NNT the cost-effectiveness ratio NNT is inversely related to the quantitative improvement in quality of 2 life following 2 successful surgery. 4 3 3 baseline value of 0.15 U improvement. The cost per QALY The asterisk shows the

remains below the $50,000 threshold provided the improvement in quality of life is greater than or equal to 0.08 (0.0–1.0 scale). Lower Left: Graph showing that the cost-effectiveness ratio is inversely related to the increase in income after successful surgery. The asterisk corresponds to the baseline assumption of no income increase despite successful surgery. If the average annual income of seizure-free patients increases more than $5400 compared with preoperative levels, the evaluation and treatment protocol is actually cost saving. Lower Right: Graph showing that the cost-effectiveness ratio is inversely related to the surgical mortality rate. Discounting reduces the present value of costs and benefits accrued in the future. Because many of the benefits of the ATL evaluation and treatment protocol accrue in the future, lower discount rates increase the cost-effectiveness ratio of the protocol. The asterisk indicates the baseline 5% discount rate. The cost per QALY remains below the $50,000 threshold provided that the discount rate stays below 9%. If the discount rate falls below 0.6%, the evaluation and treatment protocol is actually cost saving.

60" 40" 20" 0"

QOLIE,89"

QOLIE,31"

HUI,III"

SF,36"PC"

SF,36"MC"

is shown in Table 2. The Surgical" model is quite robust; alterations patient, and the discount rate. There is a marked inverse Medical" relationship between postoperative improvement in the in most variables across clinically meaningful values proquality of life and the cost per QALY of ATL (Fig. 1 upper duce only slight changes in the cost per QALY. For examWiebe et al, 2001, right). Fiest et alPerturbations 2015 in two variables significantly deple, there is little change in the cost per QALY in patients creased the cost per QALY: the average annual income between 20 and 60 years of age (Fig. 1 upper left). increase in seizure-free patients, and the discount rate Extreme values of three variables produced a marked (Fig. 1 lower left and right). increase in the cost per QALY: improvement in quality of life with successful surgery, average protocol cost per In the range of variables that we examined, in only one 24

J. Neurosurg. / Volume 87 / July, 1997

15

5/25/17

Mortality: Surgery vs Medical Deaths per 1,000 patient years Ratio = 4.1 Epilepsy cause

Surgical Medical

Ratio = 2.5 All cause

0

2

4

6

8

10

12

14

Adapted from: Bell, JNNP 2010

8.6 deaths/1000

1,006 surgical patients, 104 medical patients,

P 0.8

58

41 Jehi et al, Lancet 2015

EPILEPSY SURGERY GRADING SCALE

Patients presented at conference

All p7.5 Grade 2 >4 to 2 years) • No response to 2 AEDs • Structural lesions • Greater number of seizures in early stages Kwan & Sander, 2004

Chronic Epilepsy • Active 2 years after onset • Failed 2 first line AEDs • Great number of seizures in early history But beware of:

• “Pseudo”- Chronicity – Misdiagnosis – Mistreatment – Non-treatment (lack of adherence)

Epilepsy Surgery • Important treatment option – Should not be seen as last resort • Not available in many areas – major treatment gap

• Around since late 19th century but better take up since deployment of modern imaging • Many centres (too many?) set up last 20 years • Initially increasing number of cases • Rapid clearance of pool; mostly low hanging “cases” • Increasing “severity” of cases

• Recent stagnant or declining numbers Jette, Sander & Keezer, Lancet Neurol 2016

Recent Stagnant or Declining Numbers • In the UK: – 422 surgeries in 1998/9

- 246 surgeries in 2010/1

• In Sweden: – 78 surgeries in 1991;

- 50 surgeries in 2007

• In Germany: – Increase in surgeries until 2004 but evident decline since despite increasing pre-surgical evaluations

• In US: – Evaluations increased between 1998 & 2009 but surgeries remained stable • Redistribution ? Lhatoo et al, Epilepsia 2003; Kumlien et al, Seizure 2010; Neligan et al, Epilepsia 2013; Englot et al, Neurology 2012; Schiltz et al, Epil Res 2013; Helmstaedter et al, Eur J Neurol 2014; Jehi et al, Epilepsia 2015; Cloppenborg et al, JNNP 2016; Jette, Sander & Keezer, Lancet Neurol 2016

Recent Stagnant or Declining Numbers

Cloppenborg et al, JNNP 2016

Recent Stagnant or Declining Numbers

% change in total & MTS surgeries in 9 centres in Australia, Germany & US from peak Jehi et al, Epilepsia 2015

Recent Stagnant or Declining Numbers • The disappearing sclerotic hippocampus ‒ Clear trend reported from most locations • Why ? ‒ Changing natural history ? ‒ Following demographic trends ? ‒ Better management of FS & brain infections ? ‒ Better AED treatment ?

Schiltz et al, Epil Res 2013; Helmstaedter et al, Eur J Neurol 2014; Jette, Sander & Keezer, Lancet Neurol 2016

Epilepsy Surgery • Clear downward temporal trend in numbers • Underutilisation ? – Lack of referral ? – Redistribution ? – Increasing barriers to surgery ?

• Decreasing pool of eligible surgical candidates ? – – – –

Demographic shift ? Better AED outcomes now ? Better management of Febrile Seizures & infections ? Less pseudo chronicity ?

• Increase in numbers of refuseniks ? • Premature mortality ? • Over inflated numbers when setting up case ?

Underutilisation of Surgery • Evidence unclear for under use • Evidence for under-referral & substantial delays in referrals of suitable candidates for assessment • Epilepsy a dynamic condition alternating between drug-responsive & drug-resistant states for some – Temporary remission might reduce eagerness for surgery by individuals & health professionals – Awaiting for the next “incoming magic bullet’’

Jette, Sander & Keezer, Lancet Neurol 2016

The Role of “Redistribution” • Pre-surgical assessments moving from high-volume to middle-volume & to low-volume centres – Less likely to proceed to surgery as resources and expertise more limited

• No evidence for redistribution happening in a large scale

Englot, Epilepsy Res 2015; Jette, Sander & Keezer, Lancet Neurol 2016

Possible Barriers to Surgery • Patient and family factors – Lack of knowledge & misconceptions • Poor health literacy, stigma; misconceptions, fear & risk anxiety

– Poor behaviours or cultural issues • Poor self-management; parents wanting child to be old enough to take decision; mistrust of physician

– Access issues • Lack of transport; inability to miss work or school; lack of child care; social disparities

– Research gap • Insufficient knowledge and understanding about reasons patient refuse to have surgery Jette, Sander & Keezer, Lancet Neurol 2016

Possible Barriers to Surgery • Physician and health system factors – Lack of knowledge & misconceptions • Definition & indications for surgery; misconceptions about risks

– Poor behaviours or cultural issues • Negative attitudes surgery; reluctance to refer; poor patient– physician relationship; poor communication

– Access issues • Lack of surgery programme; inadequate health resources; complex health insurance programmes & policies; not funded or reimbursed

– Research gaps • Need for better tools to delineate focus; comparative studies of surgical approaches; extent of resection to optimise outcome & minimise adverse events Jette, Sander & Keezer, Lancet Neurol 2016

Epilepsy Surgery • Decrease in pool of eligible candidates not discordant with persistent underuse – This might reflect that identified & generally considered pool of eligible individuals is decreasing while an even larger pool of individuals, who would be potential candidates, never considered

• Huge treatment gap worldwide – Less than a quarter of low income countries have epilepsy surgery programmes Jette, Sander & Keezer, Lancet Neurol 2016

The Shrinking Numbers: Fact or Myth ?

So How Many are Really Intractable? • So is the 30 to 40% of intractable tenable ? Was it ever ?

patients still

• Are we now better spotting & managing pseudo-chronicity ? – (Misdiagnosis) – Mistreatment – Non-treatment (lack of adherence)

• Is the prognosis for seizures control better that previously estimated ? Is it now ? Has it changed ?

Incidence, Prevalence & Cumulative Incidence Age-specific incidence rate, cumulative incidence rate & prevalence rate of epilepsy in Rochester, Minnesota (1935–1974)

Incidence per 100,000

3.0

Cumulative incidence Incidence

100

2.0

Prevalence

50

1.0

25 0

0.5 0

10

20

30

40 Age

50

60

70

Prevalence / cumulative incidence (%)

150

80 Hauser et al, 1983

Major Demographic Shift

Hauser et al. Epilepsia 1993

Demographic Shift in Last 4 Decades • Change on age-specific incidence – Significant increase in the elderly – Slight increase on first year – Decrease in childhood incidence

• Total number hasn’t changed but proportions have! • Reasons unclear but coincides with – – – – –

Expectant mothers adopting healthier lifestyles Improvements in pre & perinatal care Sander et al, Lancet 1993 Management of FS & CNS infections Everitt & Sander, BMJ 1998 Immunisation programmes Increase life expectancy

Demographic Shift in Last 4 Decades • Reasons unclear so all speculative

•

Increase in elderly – Cerebrovascular disease ?

• Decrease in childhood – Less malformations of cortical development ? – Less birth hypoxia and trauma ?

• Probably wont ever find out!

Sander et al, Lancet 1993 Everitt & Sander, BMJ 1998

Last NGPSE Results • 792 incident cases enrolled in mid-80s • Seizures recurred in 61 – 73%

– Median FU 16.6 years • 255 people (37%) died - SMR 2.07

– Median FU 23.6y in those alive

• 82% (95% CI 77,86) in terminal remission of 5 years or more – 76% off AEDs

• No difference in terminal remission between adults & children Bell et al, JNNP 2016

Decreasing Pool of Eligible Candidates • Improved efficacy of newer AEDs – Some evidence a modest improvement over older drugs – With increasing number of available AEDs total numbers who benefit from drugs increased even if effects of each individual drug modest ?

• Improved management of febrile seizures – Less HS ?

• Pool of adult candidates may have decreased as more successes in paediatric populations – Some evidence for increase number of paediatrics surgery Jette, Sander & Keezer, Lancet Neurol 2016

The Increasing Refuseniks •

Increasingly more opt against surgery

•

In one German centre increased over time

•

Not clear why but now more detailed information on risks provided •

Will you consent? No thank you, I refuse!!!!

•

And Dr Google ?

•

This needs further research! Cloppenborg et al, JNNP 2016

Epilepsy Surgery • Decreasing number of adults partially offset by increase in paediatric cases – Unlikely to be spurious or due to incomplete or biased data

• Clear gradient towards complexity – Low hanging fruits mostly gone

• Reason most likely multifactorial – The perfect storm!!

The Perfect Storm!! • Multifactorial: – Demographic shift • Potential target decreased: highest incidence in the elderly

– Changes in aetiological mix • Less HS / Developmental abnormalities – Altered natural history – Over estimation of number • 1990: 10k new patients a year in the UK alone!

• Numbers in 10 years from now ? – Epilepsy surgery: a mainly paediatric endeavour ?

Intractability: What Next? • Better understanding of natural history of syndromes • Realistic assessment of number of potential surgical candidates in general population • Better understanding of referral patterns – Enhancing referral networks

• Better understanding of decreasing facilitating factors or barriers • Better understanding of number of rufuseniks & reason for refusing surgery • Closing the treatment gap Jette, Sander & Keezer, Lancet Neurol 2016

Intractable Epilepsy: Have the New AEDs Made a Difference

Frank Gilliam, MD, MPH Professor of Neurology University of Kentucky

Considerations for the Value of Newer Seizure Medications • Historical Considerations • Safety and Quality of Life • Intractability and Consequences

New Antiepileptic Drugs? Antiepileptic Drug Clobazam Oxcarbazepine Zonisamide

Date of European Approval

Date of US Approval

1975

2011

Denmark 1990

2000

2005 (Japan 1989)

2000

Definite or probable SUDEP, all SUDEP, and all causes of death were significantly less frequent in the efficacious AED group than in the placebo group, with odds ratios of 0·17 (95% CI 0·05-0·57, p=0·0046), 0·17 (0·05-0·57, p=0·0046), and 0·37 (0·17-0·81, p=0·0131), respectively. Rates of definite or probable SUDEP per 1000 personyears were 0·9 (95% CI 0·2-2·7) in patients who received efficacious AED doses and 6·9 (3·8-11·6) in those allocated to placebo.

Syndrome

Year

First Choice

First Line

Focal Seizures – Dyscognitive Features

2016

Lamotrigine Levetiracetam Oxcarbazepine

Lacosamide Carbamazepine

2005

Carbamazepine Lamotrigine Oxcarbazepine

Levetiracetam

2001

Carbamazepine

Lamotrigine Phenytoin Oxcarbazepine

Epilepsy and Behavior, 2017


AED Hypersensitivity Syndrome  Characterized by rash, systemic involvement  Arene oxide intermediates ‐ aromatic ring  Lack of epoxide hydrolase  Cross‐reactivity • • • •

phenytoin carbamazepine Phenobarbital oxcarbazepine

 Relative cross reactivity ‐ lamotrigine American Epilepsy Society 2011

AED Inducers: The Cytochrome P-450 Enzyme System  Broad Spectrum Inducers: – – – –

phenobarbital - CYP1A2, 2A6, 2B6, 2C8/9, 3A4 primidone - CYP1A2, 2B6, 2C8/9, 3A4 phenytoin - CYP2B6, 2C8/9, 2C19, 3A4 carbamazepine - CYP1A2, 2B6, 2C8/9, 2C19, 3A4

 Selective CYP3A Inducers: – oxcarbazepine - CYP3A4 at higher doses – topiramate - CYP3A4 at higher doses – felbamate - CYP3A4

 Tobacco/cigarettes - CYP1A2 American Epilepsy Society 2011

AEDs and Drug Interactions  Although many AEDs can cause pharmacokinetic

interactions, several agents appear to be less problematic.  AEDs that do not appear to be either inducers or inhibitors of the CYP system include:

gabapentin lamotrigine levetiracetam zonisamide lacosamide American Epilepsy Society 2011

AED Side Effects and Depression Predict Health Status in Epilepsy Correlation of QOLIE-89 summary scores with NDDI-E and AEP

QOLIE-89 summary scores

100 80 60 40 20

R2 = 0.72 0 00

10

20

30

40

50

60

70

AEP and NDDI-E summary scores ∆ Neurological Disorders Depression Inventory-Epilepsy  Adverse Events Profile

Gilliam et al. Lancet Neurol 2006;5:399‐405. 3

Determinants of Subjective Health in Pharmacoresistant Epilepsy Memory 8% Adverse AED effects 36%

Other 29%

Seizure rate 2% Depression 25% Perrine et al. Arch of Neuro, 1996. Johnson et al. Epilepsia 45:5 544, 2004 Gilliam Neurology 58:9-19, 2002 Gilliam et al. Lancet Neurology, 2006

Adverse AED Effects: A European Study AEP Item

Carbamazepine

Valproate

Phenytoin

Tiredness

54%

49%

55%

Difficulty Concentrating

41%

38%

45%

Sleepiness

40%

35%

38%

Baker et al. Epilepsia, 38:353-362, 1997

Volume 313

1985

p 145-152

Comparison of carbamazepine, phenobarbital, phenytoin, and primidone Mattson R, Cramer J, Collins J, Smith D, Delgado-Escueta A, Browne T, et al

“ The outcome of this project underscores the unsatisfactory status of antiepileptic therapy with the medications currently available. Most patients whose epilepsy is reasonably controlled must tolerate some side effects. These observations emphasize the need for new AEDs and other approaches to treatment.”

AED Toxicity and Subjective Health 100

QOLIE-89 QOLIE-89 Total Score

80

60

40

20

0 15

30

45

60

75

Adverse Event Profile Score

(n=200, r = -0.78, p< 0.0001)

Gilliam et al. Neurology 2004;62:23-27

% Improvement in AEP Score

Improvement in Adverse Effects with Systematic Screening

30 25 20

t test p value = 0.01

15 10 5

Yes

No

Physician Received AEP

Gilliam et al. Neurology 2004;62:23-27

Adverse Events Profile Study Results

AED Changes

AEP change >15

Seizure Rate

AEP Provided n=32

Standard Care n=30

p value

21

4

7

1

12 months at last follow up

J Neurol Neurosurg Psychiatry 83: 810-813, 2013

Long-Term Prognosis of Childhood Epilepsy n=220 -Sillanpaa et al, NEJM 1998 • •

76 (36%) were refractory. Initial response to AED within 3 months and idiopathic epilepsy were best predictors.

Early Identification of Refractory Epilepsy n=525 -Kwan and Brodie, NEJM 2000 • •

192 (37%) patients were refractory. Only 11% of patients became seizure-free if the first drug was ineffective.

“Intractable epilepsy may be delayed, especially in focal epilepsy. It often is preceded by a quiescent period, followed by further remissions. These findings help explain why surgically treatable epilepsies may take 20 years or longer before referral to surgery.”

Berg et al. Ann Neurol 2006;60:73–79

Berg et al. Ann Neurol 2006;60:73–79

Epilepsia 49: 1440-1445, 2008

“Repeated remissions and relapses were common…” “Although these brief remissions may encourage optimism, in fact, they are often not enduring.” Ann Neurol 65:510–519, 2009


Keezer et al. Neurology 86:704, 2016




Note: SMR is not the same of risk of dying

Thurman et al. Epilepsia 58:17, 2017

Results confounded by age and etiology

Thurman et al. Epilepsia 58:17, 2017

Devinsky et al. Lancet Neurol 15:1303, 2016

Devinsky et al. Lancet Neurol 15:1303, 2016

1106 surgically treated patients and 104 non‐surgical patients Patients who had surgery had lower mortality than non‐ surgical patients Conclusion: Lower mortality with surgery than continuing ineffective medical therapy

Sperling et al. Neurology 87:2067, 2016

Conclusion: Stopping seizures is associated with reduced mortality


1‐2 TCS / year Less than one TCS / year More than 2 TCS / year


Patient Group All Resections and Transections Temporal lobe surgery Extratemporal surgery Non ‐ surgical


Number of Patients 555 Seizure Recurrence 354 Seizure Free

Observed deaths 47

421 Seizure Recurrence

38

306 Seizure Free

11

5.3 (2.65 ‐ 9.49)

70 Seizure Recurrence

5

9.7 (3.14 ‐ 22.62)

30 Seizure Free

0

0

N/A

104 Total

16

25.3 (14.50 ‐ 41.17)

3.43 (1.96 ‐ 5.56)

12

Deaths/1000 p‐y SMR (95% CI) (95% CI) 10.4 (7.67 ‐ 13.89) 2.11 (1.55 ‐ 2.81) 1.17 (0.60 ‐ 5.2 (2.67 ‐ 9.02) 2.04) 11.1 (7.58 ‐ 15.22) 2.09 (1.48 ‐ 2.87) 1.16 (0.58 ‐ 2.07) 2.07 (0.67 ‐ 4.82)

Ryvlin et al. Lancet Neurol 10:961

Case discussion: Latency to Surgery – Fact or Fiction? Felix Rosenow, MD Epilepsy Center Frankfurt Rhine-Main Goethe-University Frankfurt/Main, Germany

Overview     

Case A.B. Data from trials on latency to surgery Reasons for a long latency Consequences of a long latency to epilepsy surgery Conclusions

Case A.B., male *1976 with structural right temporal lobe epilepsy  Epilepsy onset at age 11 (1987)  Initially only “mild” dialeptic seizures without motor      

symptoms Seizure free for 1 year under VPA-therapy Since age 15 (1991) automotor seizures Semiology: Unspecific aura (change in perception)  automotor seizure. Postictal phase: Inadequate behavior: walks around, undresses, moves objects. (On one occasion twists an arm of our neuropsychologist). Duration 10-15 mins Postictal Amnesia Seizure frequency: 1-2/month

Drug resistant epilepsy  Previous seizure suppressive treatment:  Valproic acid 2000 mg/d  Phenobarbitol 150 mg/Tag  Phenytoin 300 mg/Tag  Vigabatrin 2000 mg/Tag  Carbamazepin 800 mg/Tag  Lamotrigine 500 mg/Tag  Topiramate 900 mg/Tag  Oxcarbazepin 1200 mg/Tag  Zonisamide 400 mg/Tag  Pregabalin 600 mg/Tag  Medication in 2008:  Oxcarbazepin 1200 mg/Tag  Pregabalin 600 mg/Tag  Lamotrigine 500 mg/Tag

Treatment up to 2008  1993 (age 17) – 1st neurosurgery, MRI-lesion right temporal, no presurgical video-EEG-monitoring

 Neuropathology: „Chronic encephalitis most likely of viral etiology“

 Outcome: Seizures: no change, incomplete resection T1+contrast

Treatment up to 2008  1995 (age 19) – „2nd resection - no presurgical video-EEGmonitoring

 Neuropathology: „Increased number of glial cells with

lymphomonocytic infitrates, no tumor suggestive findings.“

 Post-resection MRI (1997): remaining tumor  Outcome: seizures not changed T1+contrast

Treatment up to 2008  2002 (age 26) – Implantation of a

Vagus-NervStimulator because of seizure persistence – no presurgical video-EEG-monitoring  Outcome: Little change

2008 (age 32) 1st Presurgical Video-EEG-monitoring  Interictal EEG:  Multiregional epileptiform discharges (IED) bitemporal. 60 % max. Sp1, 30% Sp2 and 10 % R parietal max. P8 + R frontal max. F4>F8  Seizure semiology:  Dialeptic seizure (x5)  left versive seizure (x1)  generalized tonic clonic seizure (x1, sign of 4 left extended)  Ictal EEG:  4 of 5 seizure onset patterns bitemporal L>R  1 lateralized seizure onset right  Repetitive, righthemispheric IED max F4, F8 and Sp2 before seizure onset

Bitemporal Sharp wave max Sp1 and Sp2

MRI 18/JUN/2008  R temporal defect + contrast-enhancing lesion R mesiotemporal increasing in size since 2000 and 2002  No other pathology

T1+contrast

Ax T1 mit KM

FLAIR

Ax T2 Flair

Management and Outcome  2008 (age 32) Classic TLR including 2/3 of the R TL and the mesial structures

    

Diagnosis: Ganglioglioma WHO I Engel Ia, ILEA 1 for 7 years (last FU 2015) Improved QoL (QOLIE-31: T41  T51) Reduced Depression (BDI: 16  5) Fully employed at a job center („On the right side of the table now!“) GFAP

NeuN

Factors leading to long latency to presurgical epilepsy diagnosis in case A.B.  Seizures initially mild  Seizure free under initial drug  Insufficient treatment by less qualified center without presurgical epilepsy diagnostic work-up

 Following 2 unsuccessful surgical treatments indication for VNS  Patient comes from a state whithout no epilepsy center at the time



Literature

 Based on a prevalence of 5/1,000 persons with epilepsy, 4,500 patients in the U.K. require epilepsy surgery.  Every year, 450 patients with newly diagnosed epilepsy who may eventually require surgery are added to this “surgical pool.”  At the current annual rate of operations, a large number of refractory patients remain untreated.  This is probably partly because many patients are not referred for specialist care and therefore remain underinvestigated. Lack of referral as cause of long latency.

Lhatoo S. et al. Epilepsia 2003

Literature  American Academy of Neurology practice parameter in 2003    

recommends “referral to a surgical epilepsy center on failing appropriate trials of first-line antiepileptic drugs.” We compared referral data for patients with TLE at our center for 1995 to 1998 (group 1, n 83) and 2005 to 2008 (group 2, n 102) Results: Duration from the diagnosis of habitual seizures to referral (17.1 vs 18.6 years, p 0.39) Nonepileptic seizures were referred significantly earlier than TLE in either group or when combined. Conclusions: Our analysis does not identify a significantly earlier referral for epilepsy surgery evaluation as recommended in the practice parameter, but suggests a hopeful trend in this direction. Haneef Z et al. Neurology 2010

Literature

Latency to evaluation is increasing with time at +0,2 year/year P=0.001 Bien CG et al. JNNP 2013

Literature CONCLUSIONS:  Long latency of 15 years to surgery  Increasing volume of the presurgical work-up  Decreasing numbers of surgically remediable syndromes  Growing rate of informed choice against epilepsy surgery.  Although diagnostic evaluation is offered to a larger group of epilepsy patients, surgical numbers remain stable. Cloppenburg T et al JNNP 2016



Selection & Referral

„Selection is a very powerful tool!“  Of patients for a specific form of treatment  Used extensively in medicine as a whole  Used by epileptologists and epilepsy surgeons – of course!  Used by referring colleagues – clearly!  Depends on information available and judgment and attitude

Survey of 512 MDs from Austria, Germany and Switzerland regarding there attitude towards epilepsy surgery Beantwortet: 512

Übersprungen: 0

Germany

men women

Austria

Switzerland

Strzelczyk & Knake in preparation

512 MDs: Board certification and subspecialties Beantwortet: 512

Übersprungen: 0

Neurology

Neurology and Psychiatry

Neuropediatrics

Pediatrics


Do you have access to adequate expertise, technology and ressources to adequately select candidates for epilepsy surgery? Beantwortet: 506

Übersprungen: 6

Yes

No


Which factors are relevant for your decision to refer to presurgical diagnosis? Beantwortet: 456

Übersprungen: 56

Seizure frequency

Epilepsy syndrome, seizure type Number of AED tried

MRI findings Localization of the EZ


A candidate for presurgical diagnosis should have a minimum of one seizure per... Beantwortet: 447

Übersprungen: 65

Year

3 months month week

Irrelevant


Which exclusion criteria do you use regarding referral to epilepsy surgery? Beantwortet: 466

Übersprungen: 46

Age>65

Low seizure frequency Psychiatric comorbidity Low seizure frequency

Non of the above


Problems with referral patterns  Referral relies on MRI, but routine-MRI is frequently not

reliable and repeat MRI in an epilepsy center frequently show lesions.

 Referral relies on seizure frequency but seizure counts by

patients are unreliable and frequently are underestimates.

1. Von Oertzen T et al. Standard magnetic resonance imaging is inadequate for patients with refractory focal epilepsy. J Neurol Neurosurg Psychiatry. 2002 Dec;73(6):643-7. 2. Cook MJ et al. Lancet Neurol. 2013:563-71

Medical doctors at an epilepsy center – referral to presurgical diagnosis (VEM) Survey outpatient clinics Epilepsy-Center Berlin-Brandenburg Patients n = 185

Cortesy of Martin Holtkamp Steinbrenner et al. in preparation

Referal to VEM – Medical Doctors Survey outpatient clinics Epilepsy-Center Berlin-Brandenburg Patients n = 185 Referred by MD yes

Referred by MD no

n = 80 (43%)

n = 105 (47%)

Steinbrenner et al. in Vorbereitung

Referal to VEM – Medical Doctors Survey outpatient clinics Epilepsy-Center Berlin-Brandenburg Patients n = 185 Referred by MD yes

Referred by MD no

n = 80 (43%)

n = 105 (47%) Seizure frequency too low

30%

Low chance of success

24%

psychiatric comorbidity

23%

Seizure severity

22%

To high age

13% Steinbrenner et al. in Vorbereitung

Referral to VEM – Patients Survey outpatient clinics Epilepsy-Center Berlin-Brandenburg Referred by MD yes n = 80

Steinbrenner et al. in Vorbereitung

Referral to VEM – Patients Survey outpatient clinics Epilepsy-Center Berlin-Brandenburg Referred by MD yes n = 80 Patient approval yes

Patient approval no

n = 24 (30%)

n = 56 (70%)

24 / 185 = 13%

Fear of brain surgery in general

49%

Illdefined reasons

33%

Fear of postoperative disability

33%

Hope for new antiepileptic drugs

27%

Low chance of success

24%

Steinbrenner et al. in preparation



Consequences of long latency to surgery

 Benfits of seizure freedom postponed  Increased cumulative mortality and SUDEP risk, especially when GTCSz  Decrease in social and economic participation  Increase in cost  Reduced likelyhood to obtain seizure freedom

Bethel series on mTLE

   

171 of 184 patients at 0,5yrs 161 of 173 patients at 2yrs 88 of 95 patients at 3yrs 71 of 86 patients at 5yrs

80% 71% 66% 58%

Engel Engel Engel Engel

1A+B 1A+B 1A+B 1A+B

Uni- and multivariate analysis of predictors of seizure freedom at these follow-up times

Latency to surgery vs. seizure outcome

Bethel-series: Conclusions  Epilepsy duration prior to surgery is a major

predictor for the longterm seizure freedom at 5years post surgery.  Operate ASAP!  MTLE is a progressive disease.

 Other findings:  Psychiatric comorbidity – negative predictor  Pat. able to push seizure button - positive predictor

Conclusions  Fact not fiction: The latency to presurgical

diagnosis and epilepsy surgery is long and decreases only in the pediatric population (adults 20 years, children 5years)

 There are many reasons including:     

Selection / nonreffereal Doctors attitude Patients preference Initial pharmacoresponse Treatment at a center without expertise in epilepsy surgery

 …………….

Thanks!

Epilepsy Surgery – Has the Post‐Resection Era Begun?

Philippe Ryvlin, MD, PhD

Seizure Tracking – Personalized Care of Intractability

William Theodore, MD, PhD

What Big Data Can Do for Intractability

Brian Litt, MD, PhD

Epilepsy and Seizure Classification – A Pragmatic Look Hans O. Lüders

Talk Organization • • •

•

Short introduction of the 2017 ILAE seizure and epilepsy classification Short introduction of a multiaxis epilepsy classification Cases # 1, 2, 4, 8 and 11 which were published with the ILAE classification of seizure types will be presented and classified according to the ILAE classification and the multiaxis classification The two classifications will be compared and the strength and shortcomings of the two classification systems will be discussed

Three level epilepsy classification (ILAE)

Multiaxial Epilepsy Classification • • • •

Seizures (pure semiological classification) Epileptogenic zone (all available information) Etiology(as precisely defined as possible) Comorbidities

Comments: 1. With very few exceptions this classification applies classical terminology that has been used in epileptology fr decades or centuries 2. The term “dialeptic seizures” is introduced. It refers to episodes of altered ictal responsiveness with postictal amnesia. 3. The classification assumes that each seizure type can be just a component of a seizure. The seizure evolution is expressed by joining components with an arrow (Example: abdominal aura generalized tonic-clonic seizure)

Case #1 (example in ILAE Instruction manual) • “A woman awakens to find her husband having a seizure. The onset is not witnessed but she is able to describe bilateral stiffening followed by bilateral shaking. EEG and MRI findings are normal.”

Case #1

ILAE Epilepsy Classification Seizure type: Unknown onset tonic-clonic seizure Epilepsy type: Unknown onset epilepsy Epilepsy Syndrome: None Etiology: Unknown

Case #1 (example in ILAE Instruction manual) ILAE Epilepsy Classification Seizure type: Unknown onset tonic-clonic seizure Epilepsy type: Unknown onset epilepsy Epilepsy Syndrome: None Etiology: Unknown

Multiaxial Epilepsy Classification Seizures: Generalized tonic-clonic seizure Epil. Zone: Unknown Etiology: Unknown

Case #1 (example in ILAE Instruction manual) ILAE Epilepsy Classification Seizure type: Unknown onset tonic-clonic seizure Epilepsy type: Unknown onset epilepsy Epilepsy Syndrome: None Etiology: Unknown

Multiaxial Epilepsy Classification Seizures: Generalized tonic-clonic seizure Epil. Zone: Unknown Etiology: Unknown

Problem: All available information is used to classify seizure type and epilepsy type  no need to classify epilepsy type because it is already defined by seizure type

Case #2 (example in ILAE Instruction manual) • “A woman awakens to find her husband having a seizure. The onset is not witnessed but she is able to describe bilateral stiffening followed by bilateral shaking. EEG shows a right parietal slow wave focus and MRI shows a right parietal region of cortical dysplasia.”

Case #2

ILAE Epilepsy Classification Seizure type: Focal to bilateral tonic-clonic Epilepsy type: Focal onset epilepsy Epilepsy Syndrome: None Etiology: Structural and genetic

Case #2 (example in ILAE Instruction manual) ILAE Epilepsy Classification Seizure type: Focal to bilateral tonic-clonic Epilepsy type: Focal onset epilepsy Epilepsy Syndrome: None Etiology: Structural and genetic

Multiaxial Epilepsy Classification Seizures: Generalized tonic-clonic seizure Epil. Zone: Right parietal lobe Etiology: Right parietal cortical dysplasia

Case #2 (example in ILAE Instruction manual) ILAE Epilepsy Classification Seizure type: Focal to bilateral tonicclonic Epilepsy type: Focal onset epilepsy Epilepsy Syndrome:None Etiology: Structural and genetic

Multiaxial Epilepsy Classification Seizures: Generalized tonicclonic seizure Epil. Zone: Right parietal lobe Etiology: Right parietal cortical dysplasia

Problems: 1. Epilepsy type is redundant 2. Unclear if the expression “focal to bilateral” implies focal semiology or expresses focality in other tests (EEG, MRI, etc) 3. Location of epileptogenic zone is undefined 4. “Structural and genetic” etiology is extremely vague

Case #4 (example in ILAE Instruction manual) • “A child has brief seizures with stiffening of the right am and leg, during which responsiveness and awareness are retained.”

Case #4

ILAE Epilepsy Classification Seizure type: Focal aware tonic seizure Epilepsy type: Focal onset epilepsy Epilepsy Syndrome: None Etiology: Unknown

Case #4 (example in ILAE Instruction manual) ILAE Epilepsy Classification

Multiaxial Epilepsy Classification

Seizure type: Focal aware tonic seizure Epilepsy type: Focal onset epilepsy Epilepsy Syndrome: None Etiology: Unknown

Seizures: Right arm and leg tonic seizure Epil. Zone: Left frontal lobe Etiology: Unknown

Case #4 (example in ILAE Instruction manual) ILAE Epilepsy Classification Seizure type: Focal aware tonic seizure Epilepsy type: Focal onset epilepsy Epilepsy Syndrome:None Etiology: Unknown

Multiaxial Epilepsy Classification Seizures: Right arm and leg tonic seizure Epil. Zone: Left frontal lobe Etiology: Unknown

Problems: 1. Epilepsy type is redundant 2. Location of tonic seizure is undefined  location of most likely epileptogenic zone is undefined

Case #5 (example in ILAE Instruction manual) • “A 25-year-old woman describes seizures beginning with 30 seconds of an intense feeling that “familiar music is playing.”She can hear other people talking, but afterwards realized that she could not determine what they were saying. After an episode , she is mildly confused, and has to “reorient herself.”

Case #5

ILAE Epilepsy Classification Seizure type: Focal impaired awareness seizure Epilepsy type: Focal onset epilepsy Epilepsy Syndrome: None Etiology: Unknown



Seizure type: Focal impaired awareness seizure Epilepsy type: Focal onset epilepsy Epilepsy Syndrome: None Etiology: Unknown

Seizures: Experiential aura  dialeptic seizure Epil. Zone: Temporal lobe Etiology: Unknown

Case #8 (example in ILAE Instruction manual) ILAE Epilepsy Classification Seizure type: Focal impaired awareness seizure Epilepsy type: Focal onset epilepsy Epilepsy Syndrome:None Etiology: Unknown

Multiaxial Epilepsy Classification Seizures: Experiential aura  dialeptic seizure Epil. Zone: Temporal lobe Etiology: Unknown

Problems: 1. Epilepsy type redundant 2. Expression “focal impaired awareness seizure” is extremely vague just indicating that during a focal seizure the patient lost consciousness. Symptoms or signs occurring before the loss of consciousness, namely auras, focal motor signs, etc. are all “neglected”. 3. The location of the epileptogenic zone is not defined. The history, however, allows us to define with relative confidence the location of the epileptogenic zone.

Case #8 (example in ILAE Instruction manual) • “A seizure begins with tingling in the right arm of a 75-year-old man. The patient says that it then progresses to rhythmic jerking of the right arm lasting about 30 seconds. He retains awareness and memory for the event.”

Case #8

ILAE Epilepsy Classification Seizure type: Focal sensory seizure with somatosensory features progressing to right arm clonic activity Epilepsy type: Focal onset epilepsy Epilepsy Syndrome: None Etiology: Unknown



Seizure type: Focal sensory seizure with somatosensory features progressing to right arm clonic activity Epilepsy type: Focal onset epilepsy Epilepsy Syndrome:None Etiology: Unknown

Seizures: Right arm somatosensory seizure  right arm clonic seizure Epil. Zone: Left parietal lobe Etiology: Unknown

Case #8 (example in ILAE Instruction manual) ILAE Epilepsy Classification Seizure type: Focal sensory seizure with somatosensory features progressing to right arm clonic activity Epilepsy type: Focal onset epilepsy Epilepsy Syndrome:None Etiology: Unknown

Multiaxial Epilepsy Classification Seizures: Right arm somatosensory aura  right arm clonic seizure Epil. Zone: Left parietal lobe Etiology: Unknown

Problems: 1. Epilepsy type is redundant 2. Location of somatosensory aura is undefined 3. Location of epileptogenic zone is undefined

Case #11 (example in ILAE Instruction manual) • “A 14-month-old girl has sudden extension of both arms and flexion of the trunk for about 2 seconds.These seizures repeat in clusters. EEG shows hypsarrhythmia with bilateral spikes most prominent in the left parietal region. MRI shows a left parietal dysplasia. Resection of the dysplasia terminated the seizures.”

Case #11

ILAE Epilepsy Classification Seizure type: Focal epileptic spasm Epilepsy type: Focal onset epilepsy Epilepsy Syndrome: West syndrome Etiology: Structural and genetic



Seizure type: Focal epileptic spasm Epilepsy type: Focal onset epilepsy Epilepsy Syndrome: West syndrome Etiology: Structural and genetic

Seizures: Generalized epileptic spasm Epil. Zone: Left parietal lobe Etiology: Left parietal dysplasia

Case #8 (example in ILAE Instruction manual) ILAE Epilepsy Classification Seizure type: Focal epileptic spasm Epilepsy type: Focal onset epilepsy Epilepsy Syndrome: West syndrome Etiology: Structural and genetic

Multiaxial Epilepsy Classification Seizures: Generalized epileptic spasm Epil. Zone: Left parietal lobe Etiology: Left parietal dysplasia

Problems: 1. Epilepsy type is redundant 2. It is unclear if the epileptic spasms had focal semiology or the expression “focal” refers to the results of other ancillary tests (EEG, MRI, etc.) 3. The location of the epileptogenic zone is undefined 4. The term “structural and genetic etiology” is vague and of little practical value

General comments • •

All proposals for classification of seizures and epilepsies should be submitted to extensive “field tests” to assess its practicality before it is approved. The exercise discussed above reveals the following shortcomings of the ILAE classification: – The classification of epilepsy type is implicit in the classification of seizure type – An essential condition for a multiaxial (multidimensional) classification is that each axis defines a different (independent) seizure/epilepsy characteristic. That is not the case for the ILAE’s seizure, epilepsy, and syndrome types. – Seizure terminology is oversimplified dropping essential semiological information – No attempt is made to define the location of the epileptogenic zone – Etiological groupings lead to vague terms (like structural and genetic etiology) that are of little help in epilepsy management

Conclusions •

•

•

•

The ILAE classification of seizures and epilepsies should be submitted to an extensive “field test” before it is submitted for approval by the epilepsy community It seems that a multiaxis classification would be most helpful for management purposes. The axes should be – totally independent (not redundant) – cover all the essential features of the epilepsies (semiology, epileptogenic zone, etiology) The classes within any given axis should be “meaningful.” Example: – “Left visual aura” pointing to a right occipital epilepsy (instead of focal aware sensory seizure) – Left frontal astrocytoma instead of structural etiology Classification with different degrees of precision should be possible. Detailed classification should be possible if essential for patient management.

Case Discussion: Classification Conundrums Hajo Hamer, MD

This "case conundrum" will be on "falls". History taking may be very challenging in cases presenting with falls as the only or primary sign, and it may be very difficult to come to the correct diagnosis. Videos of various falls beyond syncope will be presented. Different epileptic semiology leading to falls will analyzed and differential diagnoses will be discussed.

7T MRI in Presurgical Assessments – What Are We Chasing?

Renzo Guerrini, MD

10th International Epilepsy Colloquium: State of the art: Surgical and medical management Neuroimaging of intractability ‐ Functional Imaging – where do we stand now – Susanne Knake MD Functional imaging has been initially introduced to delineate the eloquent cortex: Today, functional MRI (fMRI) is a reliable technique to predict typical language localization in the presurgical workup. However, it is still challenging to predict atypical language dominance. Results for presurgical memory lateralization are promising. However, in recent years, functional imaging has been used to demonstrate networks of epilepsy and function. Especially resting state network analysis might be helpful to demonstrate the extent of epileptic networks and might help to even modify our understanding of focal epilepsies towards a more extended network disease. In future, functional imaging might be used as a biomarker to predict the individual patient´s prognosis. The talk will summarize the use of different functional imaging techiques in the clinical diagnosis of intractable epilepsies.

Oxygen Enhanced Magnetic Resonance Imaging and Related Techniques in Focal Epilepsy

Giridhar Kalamangalam, MD DPhil International Epilepsy Colloquium Miami FL, June 15-17, 2017

Where should epilepsy research go in the next 10 years?

1. Understand the mechanisms of epileptogenesis. 2. Understand the mechanisms of neuronal synchronization and triggering of seizures. 3. Determine the genetic risks for non-Mendelian epilepsies. 4. Understand the role of brain development in epilepsy. 5. Characterize the role of glia and immune mechanisms in seizures. 6. Develop drugs targeted to disease mechanisms. 7. Explore nonconventional treatments for epilepsy. 8. Understand pharmacoresistance. 9. Develop new targeted approaches for treatment.

__________________________________________________ Noebels JL et al (2012). Jasper’s Basic Mechanisms of the Epilepsies. 4th Edition.

Biomarker Imaging of Epilepsy

________________________________ Vliet et al (2017). Epilepsia 58(3):315-330

The BOLD Brain

Oxygen and magnets

Linus Pauling (1901-93)

Oxygen-enhanced MRI

Because fMRI fundamentally follows oxgenation profiles in the blood, MRI signal fluctuation can be produced by both tissue activation, or ‘artificially’, by changing the gas constituents in the blood

Question 1: Can oxygen response be used to distinguish normal from epileptic cortex? Question 2: Is the method of use in nonlesional epilepsies to identify the region/laterality of disease?

Physiology Hb

dHb

Air (21% O2) ↓dHb (dHb → Hb)

Hb

BOLD signal

100% O2

100% O2 Air

100% O2 Air

Time

Air

Hypometabolic tissue shows less robust O2 response Hb

dHb

Air (21% O2) minimal ↓dHb (dHb → Hb)

Hb

BOLD signal

100% O2

100% O2 Air

100% O2 Air

Air

Normal Abnormal

Time

Robust ‘activations’

Left (blue), right (red) aggregate in 11 canonical brain areas.

Single voxel dynamics;TR = 5s. Air-O2-air-O2-air

Spectral pattern in a normal versus TLE

_____________________________________ Kalamangalam et al. (2012). Ep Res 98: 50-61

Aside: The O2MRI signal – a closer look

The mean is larger with OE, but so is the variance…

O2-fMRI air

Difference image

_______________________ Kalamangalam & Ellmore, 2012. ANA.

100% O2

Intermission

Imaging magnetic susceptibility

MRI for epileptologists 2

1

B0

B1

3

t=0

t=0

Gradients & susceptibility

B0

ΔB

Phase shift of the signal

B0 ΔB

ΔB from differing magnetic susceptibilities

Magnetic fields (ΔB )from electric currents

The phase image

Suggestive Results

Right HS

R TL phase homogeneity

Nonlesional ______________________________ Kalamangalam (2014). AES Platform.

R TL phase homogeneity

Shim-field dependence

Quantitative susceptibility imaging

Proposal Nonlesional

SEEG

Constructing the epileptic susceptibility field

Perspectives

There is nothing nuclear spins will not do for you – as long as you treat them as human beings.

-Erwin Hahn (1921-2016) Discoverer of spin echo

Acknowledgements

UCL INSTITUTE OF NEUROLOGY DCEE

Multimodality imaging – how it helps John Duncan UCL Institute of Neurology National Hospital for Neurology and Neurosurgery London, UK


The key need • Refractory epilepsy is potentially curable with advanced neurosurgical planning

and intervention, cost effective, improves quality of life • Delayed referrals, complex pathway


The solution • Image-guided solution to the epilepsy surgery pathway

• Computer-assisted planning • Robotic placement of intracranial electrodes • 4D Visualization of seizure onset/spread • 3D image-guided resections • Increased precision, speed and safety • Applicable to all cranial neurosurgery


EpiNav™ solution 5 workpackages covering the epilepsy surgery pathway

…. Dissemination of the complete EpiNavTM solution


3D visualisation of lesion and motor fMRI


Placing electrodes, plan resection



3D MMI: placing electrodes, planning resection


EpiNav™ Strategy •

Library of 160 commonly used intracranial electrode targets and cerebral entry points

•

Pick from parcellated and labelled structures

•

Adapt to individual patients

•

Add bespoke trajectories

Benefit •

Quick, consistent strategies


EpiNav™ Strategy and planner


EpiNav™ Strategy: ROI notation

76 152 184 154 126 166 206 144

LEFT hemisphere Left Frontal Left-Basal-Forebrain Left-precentral-gyrus-medial-segment Left-precentral-gyrus Left-superior-frontal-gyrus-medialsegment Left-gyrus-rectus Left-orbital-part-of-the-inferior-frontalgyrus Left-triangular-part-of-the-inferiorfrontal-gyrus Left-middle-frontal-gyrus

LFBR LFCM LFCm, LFCs, LFCc, LFCi LFFa, LFFc, LFFp LFGR

LFIO LFIT LFMa, LFMc, LFMp


Integration of multimodal 3D imaging in the epilepsy surgery pathway.


EpiNavTM Planner


EpiNavTM Planner


EpiNavTM Planner Computer-assisted electrode trajectory planning • Preset constraints of proximity to blood vessels, sulci, angle crossing skull, entry zones, other electrodes • Optimize grey matter sampling

Benefit • Precise planning of trajectories • Improved safety profile

• Greater efficiency • 4 hr reduced to 56 s to compute • 30 min total

• Reduced risk in 83% trajectories • Increased GM sampling in 57%


EpiNav™ Planner Computer-assisted electrode trajectory planning - Managing risk


EpiNavTM Planner Computer-assisted electrode trajectory planning

Outline strategy to 3D structures


EpiNavTM Planner Computer-assisted electrode trajectory planning Example patient imaging dataset containing (a) CT with skull segmentation (orange), (b) MRV with vessel segmentation (red), (c) 3D T1-weighted MPRAGE with brain parcellation, (d) 3D T1-weighted MPRAGE with GM segmentation (orange) , and (e) 3D T1-weighted MPRAGE with sulci segmentation (green).


EpiNavTM Planner Computer-assisted electrode trajectory Centre and inferior border ROI targets in posterior insula . Sagittal view of posterior insula with blood vessels (red)

Heat map: blue is a low risk and red is a high risk

Electrode trajectories: inferior border, centre


EpiNavTM Planner Computer-assisted electrode trajectory planning Measures of trajectory suitability for manual (X) versus CAP(Y) (a) Angle crossing skull (b) Risk score

(c) Distance to nearest critical structure (d) Grey matter ratio


EpiNavTM Planner Computer-assisted electrode trajectory planning: Target point clusters Anterior insula

Hippocampus

arteries (red) and veins (cyan)


Risk stratification of target


EpiNavTM Planner Probe’s eye view (POV) to check trajectory


EpiNav™ Placement Robot-assisted electrode placement •

Integrate with EpiNavTM trajectory planning

•

Randomized comparison with manual placement

•

Bone fiducials

•

Sub-millimetre accuracy

Benefit •

Quick, precise execution of multiple electrode placements anywhere in brain

•

Improved safety profile

•

Reduce operating time by >25%


EpiNavTM Placement A Randomised Control Trial of SEEG Electrode Insertion • • • •

Biopsy and phantom data Multiple approvals: MHRA, HRA, REC, JRO Commence July 2017


MGS trajectory guidance system


EpiNav™ 3D SEEG analysis


EpiNav™ SEEG display and analysis •

Link electrode positions in EEG display to 3D MMI


EpiNav™ 3D SEEG analysis: work in progress Link Micromed BrainQuick with EpiNav Re-ordering display montage 3D display of parametric SEEG data, eg Gamma power

HFO Epileptogenicity Index Videos to display temporal and spatial propagation in 4 Dimensions


EpiNavTM Resect Resection planning in 3D • Design resection of epileptogenic zone, • with or without icEEG

Benefit • Plan made in context of : eloquent cortex critical structures gyral and skull anatomy • Plan saved for later use • Upload resection plan to neuronavigation system


EpiNavTM Resect Resection planning in 3D


EpiNavTM Resect 3D multimodal imaging and resection planning

Blue : CST Yellow: seizure onset White : primary motor Red : lesion Brown : resection volume


3D Multimodal imaging and resection planning

Blue : CST Brown : resection


Resection planning in 3D  Develop from SEEG data


EpiNavTM Laser interstitial thermal therapy planning in 3D


EpiNavTM Disseminate Beta sites at present: • Cardiff • London hospitals (GOSH, Kings) • Edinburgh • Utrecht • Geneva • Vienna • Goteborg • Kuopio • Grenoble • Marseilles • Cleveland, Ohio • Leuven


EpiNavTM Conclusion • Evolving image-guided solution to the entire epilepsy surgery pathway • Techniques also applicable to all cranial neurosurgery

• Beta versions available


EpiNavTM Acknowledgements • Seb Ourselin • Rachel Sparks • Gregor Zombori • Roman Rodionov • Vejay Vakharia • Mark Nowell • Andrew McEvoy • Anna Miserocchi • Martin Schweiger • Sharzhad Shapoori • Sofia Eriksson • Beate Diehl

• David Simon, Leslie Holton

Support Wellcome Trust EPSRC NIHR

Case discussion: How imaging helps / does not help me Andreas Schulze‐Bonhage, Freiburg‐Germany The increasing importance of imaging techniques in the diagnosis of epilepsies is reflected in the new term “structural epilepsy” in the present epilepsy classification. Identifying structural abnormalities in presurgical evalution has been a major incentive for utilizing high‐ quality imaging in the diagnostic workup of epilepsy patients. Evidence for potentially epileptogenic lesions greatly facilitates the establishment of proper hypotheses with regard to a suspected epileptogenic zone, reduces the need for invasive diagnostics and tends to improve surgical outcome. In practice there are, however, a number of constellations in which imaging findings are not only helpful but may lead to erroneous conclusions as to appropriate treatment options. These constellations include: 

   

Negative imaging findings (“normal MRI”) due to insufficient quality of MR imaging or due to a lack of specific information for the rater with regard to appropriate target areas of the brain resulting in non‐referral for presurgical evaluation Rating of normal variants of brain morphology as epileptogenic Erroneous classification of brain lesions as epileptogenic without sufficient concordant evidence from other clinical information Wrong inference of multifocal epilepsy in multilesional patients Focus of attention to an identified lesion without considering dual pathologies

Representative cases reflecting these constellations will be used to develop a strategy for planning and interpreting imaging in the individual clinical context.

Epilepsy Colloquium, Miami, June 2017

Early ictal spread – What it means for surgery Fabrice Bartolomei Hôpital de la Timone APHM Institut de Neurosciences des Systèmes (INS) INSERM /Université, Marseille, France

Introduction / The EZ network / Speeds and epileptogenicity / Ictal Estimation of ES / Conclusions

StereoElectroEncephalography (SEEG) • Intracerebral Macro Electrodes • Method that aims to record seizures • Problem of the extension of ictal discharges and variable range of propagation speeds of epileptic discharges • « propagation précoce » • Pattern of the Epileptogenic Zone (EZ)

•Talairach & Bancaud (1965)

Introduction / The EZ network / Speeds and epileptogenicity / Ictal Estimation of ES / Conclusions Temporal spread

Early propagation patterns

Occipital onset

Bancaud, Takeda et al, 1969

Late Propagation pattern

Introduction

Occipito temporal seizure SEEG recordings


Spatial extent and the concept of « Epileptogenic Networks »: EZ network and PZ networks • The concept of « Epileptogenic networks » describes subnetworks engaged in epileptic activity genesis/propagation • Anatomical specificity (classification)

Wendling et al, 13; Bartolomei et al, Epilepsia, 2017,

Introduction / The EZ network / Speeds and epileptogenicity / Ictal Estimation of ES / Conclusions Amygdala Hippoc Ant

Entorhinal C Hippoc Post

Epileptogenic Zone Network A AR. Case with MTLE and FCD type I

Propagation Zone network


Mesio-lateral seizures « Early propagation » in both mesial and lateral cortex


SEEG: Temporo-frontal network eTP iTP A OFC DLPFC BA32 C24

Introduction / The EZ network / Speeds and epileptogenicity / Ictal Estimation of ES / Conclusions SEEG Parietal Cortical Lesion Large Fronto-Parietal NEtwork

P P

F

F

Large fronto-parietal network

Gamma Map (Wendling, Bartolomei et al, 03)


A Definition of early/ late ? • No clearcut definition • 1.5 second in duration

Recording IFA using depth electrodes TP

HB

AM

PT

HH

TP

temporal pole

AM

amygdala

HH

hippocampal head

HB

hippocampal body

PT

posterior temporal

Case Western Reserve University

Conventional EEG-ictal onset (LFF 1Hz, HFF 120Hz, 100 μV/mm, 15 sec/page) TP AM

HH

HB

PT

500 uV 1 sec

Recording of Ictal IFA (LFF 0.016 Hz, HFF 15 Hz, 100 μV/mm, 60 sec/page) TP

AM

HH HB

PT

3 mV

10 sec

Recording of ictal IFA (LFF 0.016 Hz, HFF 15 Hz, 100 μV/mm, 300 sec/page) TP AM

HH

HB

3 mV 30 sec

Ictal IFA in TLE • 75 seizures from 15 patients with TLE – 94% clinical seizures – 78% subclinical seizures

(Wu, Epilepsia 2014)

Ictal IFA in TLE • Both negative and positive IFA are recorded – Dipole-like pattern along amygdala/hippocampal complex AM

IFAHH

IFA+

AM

HH

HB

HB

500 μV 30 sec


Ictal IFA in TLE • Ictal IFA could occur at, before, or after the conventional seizure onset

Ictal EEG onset

Ictal EEG onset

Ictal IFA onset (8 sec later) Ictal IFA onset (3 sec earlier)

Ictal IFA in TLE • Ictal IFA has a smaller spatial distribution c/w conventional spikes • Earliest onset (100%) and highest amplitude (60%) of ictal IFA co-localize with SOZ TP AM

HH

HB


IFA and seizure localization • Ictal IFA – confirms seizure onset zone TP AM

HH

HB

IFA and seizure localization • Ictal IFA – confirms ictal onset – helps in localization when conventional seizure onset is diffuse

Seizure onset is widely distributed on subdural grid in a neocortical seizure

1 mV

(Ikeda, 1996)

1 sec

Ictal IFA has smaller field distribution

(Ikeda, 1996)

Roles in seizure localization • Ictal IFA – confirms ictal onset – helps in localization when conventional seizure onset is diffuse – better surgical outcome with resect area including ictal IFA

(Ikeda, 1996)

Ictal IFA are consistent in all seizures from one patient LHD

LHD

RHD

RHD

RATS

RATS

RITS

RITS

RPTS

RPTS

LHD

LHD

RHD

RHD

RATS

RATS

RITS

RITS

RPTS

RPTS

LHD

LHD

RHD

RHD

RATS

RATS

RITS

RITS

RPTS

RPTS

Roles in seizure localization • Interictal IFA – associated with interictal spikes (irritative zone) LHD

RHD

RATS

RITS

RPTS

Roles in seizure localization • Interictal IFA – associated with interictal spikes – ? suggests of network process

(Thompson, 2016)

What generates IFA? • Summation of excitatory postsynaptic potentials (EPSP)

(Gumnit, 1965 & 1970 )

Generated by depolarization of glia cell

(Neidermeyer’s Electroencephalography)

Generated by both neurons and glial cells

(Speckmann and Caspers, 1979)

What generates IFA? • • • •

? Pyramidal neurons ? Glia cells ? Both neurons and glia cells ? Non-neuronal origin

( Caspers and Speckmann, 1969, 1972; Gumnit, 1965 & 1970 )

Summary • IFA can be recorded with DC amplifier or an AC amplifier with long TC • IFA can be in positive or negative polarity • A negative polarity at anterior, positive polarity at posterior of AHC observed in TLE • Ictal IFA could occur at, before or after conventional EEG seizure onset

• Ictal IFA are more localized than conventional EEG • The ictal IFA with the earliest onset or highest amplitude often co-localize in SOZ

Remaining Questions • What is the association between IFA and epileptogenesis? • What is the role of IFA in epilepsy surgery? • What is the exact mechanism of IFA? • What does interictal IFA mean? • What does the “dipole-like” pattern at AHC mean?

Thank you

Abstract for Case Discussion: Utility of HFOs and Infraslow in surgical practice Julia Jacobs

This presentation will focus on several cases in which HFO and infraslow activity were used to improve the delineation of epileptogenic areas. The following case scenarios, that are representative for the use of HFO and infra-slow activity in a presurgical clinical setting will be discussed. ‐ ‐

‐

Patients with extended and multifocal lesions, in whom the above EEG markers result in a more precise localization of the SOZ. Patients in whom widespread increases in HFOs are seen. It will be discussed whether these HFO generating areas really reflect epileptic areas or might also represent brain areas in which physiological HFO occur and which should not be considered for epilepsy surgery Patients in whom simultaneous scalp and intracranial EEGs were performed and in which scalp as well as intracranial HFOs can be analyzed and provide additional information about the epileptic network

In all cases the postsurgical seizure outcome will be used as validation for information obtained by analyzing HFO and infra-slow activity. The talk aims to fulfill the following learning objectives: ‐ Identify clinical situations in which the use of new EEG biomarkers may ameliorate the EEG analysis ‐ Understand the technical requirements necessary for these analyses ‐ Raised awareness about challenges in analysis and interpretation of information obtained from HFO and infra-slow activity

The Epileptogenic Zone J. Engel UCLA

Definition of abnormal brain areas Definition

Measures

Irritative zone

Area of cortex that generates interictal spikes

Electrophysiological (invasive and noninvasive)

Ictal onset zone

Area of cortex where seizures are generated (including areas of early propagation under certain circumstances)

Electrophysiological (invasive and noninvasive)

Epileptogenic lesion

Structural abnormality of the brain that is the direct cause of the epileptic seizures

Structural imaging and tissue pathology


Measures

Symptomatogenic zone

Portion of the brain that produces the initial clinical symptomatology

Behavioral observation and patient report

Functional deficit zone

Cortical area of nonepileptic dysfunction

Neurologic examination neuropsychological testing, EEG, PET, SPECT


Measures

Epileptogenic zone

The area of brain that is necessary and sufficient for initiating seizures and whose removal or disconnection is necessary for abolition of seizures

Theoretical concept

Epileptogenic network

The area of brain that supports the generation of seizures, without which seizures do not develop or occur. Disconnections may have beneficial effect.

Theoretical concept

Types of seizure onsets in hippocampus in patients with MTLE Low Voltage Fast (p348) 0.5 mV

Hypersynchronous (p367)

0

20

40

60

80 sec 100

Depth electrode with 40 µ microelectrodes

Rat LEC

LdHip

LpHip REC

RdHip 2 mV 1 sec

RpHip 390 Hz

100 ms 100 msec

2 mV mV 15 2ms 15 msec

Human LAH LAH LEC LEC LEC

LEC

ROF ROF REC REC

.5mV 5 mV REC REC 1 sec 300 Hz

100 msec

15 msec

Interictal Events in KA rats with spontaneous SZ Interictal Spikes

A

1

2

Fast Ripples 3

B 1 mV 10 ms

~300 Hz

50 msec

C

D

Tail Gamma

Fast Ripple-Tail Gamma Complex

1 2 mV 50 msec

30-50 Hz

Neuronal correlates of Fast Ripples

field

1

2

3

4

5

6

7

n=466 2 ms

-200

ms

-150

-100

-50

0

Voltage versus depth profiles of evoked and spontaneous fast ripples A

B

C

1

1 2

.

2

3 5 7 9

18 * 19 *

11 13

24*

15

29

17 19

* *

21

23 * 25

200mm

27 29

20msec

2mV

Influence of hippocampal atrophy upon Ratio of FR to Ripple rates (human)

Are Fast Ripple generating sites associated with local anatomical disturbances ? Microelectrode registration

Atrophy map

Analysis of local atrophy

Fast Ripple-generating sites strongly associated with local atrophy Significantly higher rates of Fast Ripple occurrences in local atrophic vs. nonatrophic areas. Higher rates of Fast Ripple discharge correlate with greater atrophy.

Ogren et al. In preparation

No significant association between Ripple occurrence and local atrophy

Unfolding the human mesial temporal lobe

Reduced MTL GM thickness correlates with higher single neuron firing rates that contributes to greater neuronal excitability in the SOZ

Fast Ripple and Tail Gamma Components of Seizure Discharge A LdHip LpHip RPir REC RdHip RpHip 2 sec

B

1

2

3

LdHip LpHip RPir REC RdHip

1 mV RpHip 260 Hz

36 Hz

100 msec

Fast Ripples at the Spontaneous Seizure Onset

Strength of Paired Pulse Inhibition in Areas Generating FR and Areas Not Generating FR (rats) A

B

200

FRPS noFRPS

FR

100 FRPS

0.5 mV

1

0 10 ms

30

C 1.5 mV

2 10 ms

noFRPS

50

70

80

100

200

500 1000

70

80

100

200

500 1000

600 FR

500 400 300 200 100 0 30

50

msec

Influence of Bicuculline on the Size of Area Generating Fast Ripples 1 12 12

2

11

11

1

10 2

3 3

9 8

4

4

10

5

7 6

9 300mm

Stim

5

8 6

7

LaDG

LpDG

1 mV

RaDG

1 min

RpDG

µV/mm2

1.5

20ms 1 mV

4 1 3 2

0.5

1 0 1

2

3

4

22

266

510

1 mV

SZ onset

5 sec

Hz

HYP & LVF seizure onsets associated with unique patterns of damage HYP or LVF seizure onsets associated with significant atrophy. Atrophy in patients with HYP onset resembles classical hippocampal sclerosis. Atypical pattern of atrophy associated with LVF onsets compared to HYP onsets. Ogren et al. In press

Contralateral damage in patients with LVF seizure onsets HYP onsets associated with isolated areas of damage, but overall not significantly different with respect to control subjects. Significant contralateral atrophy in patients with LVF onsets. Ogren JA, Bragin A, Wilson CL, Hoftman GD, Lin JJ, Dutton RA, Fields TA, Toga AW, Thompson PM, Engel J, Jr., Staba RJ. Three-dimensional hippocampal atrophy maps distinguish two common temporal lobe seizure-onset patterns. Epilepsia, 2009; 50: 1361-70.

Lin JJ, Salamon N, Lee AD, Dutton RA, Gaeaga JA, Hayashi KH, Luders E, Toga AW, Engel J, Jr., Thompson PM. Reduced neocortical thickness and complexity mapped in mesial temporal lobe epilepsy with hippocampal sclerosis. Cereb Cortex, 2007; 17: 2007-18.

Connectivity of the epileptogenic network • DTI and tractography • fMRI • Gamma event coupling

BIOMARKERS Dynamic changes that indicate the presence of an epileptogenic process with a sufficiently high degree of reliability to warrant intervention • Biomarkers of epileptogenesis • Biomarkers of epileptogenicity

MARKERS OF CLINICAL EPILEPSY • • • • • •

Risk factors Precipitating factors Seizure prediction and detection Outcome measures Surrogate markers Biomarkers

TARGET MECHANISMS • • • • • • • • •

Cell loss (e.g., hippocampal atrophy) Axonal sprouting Synaptic reorganization Altered neuronal function (e.g., gene expression profiles, protein products Neurogenesis Altered glial function and gliosis Inflammatory changes Angiogenesis Altered excitability and synchrony

POTENTIAL BIOMARKERS • Hippocampal changes on MRI • Interictal spike features, including fMRI • Pathological high-frequency oscillations (pHFOs) • Excitability – TMS • AMT-PET imaging • Gene expression profiles

BIOMARKERS FOR SURGERY • Identify the epileptogenic zone (define its boundaries). • Identify the epileptogenic network (? Suggest disconnection, provide prognosis)

Epilepsy Surgery in the USA: Under‐ or Overutilized IEC Collocquium Miami Beach, FL June 15‐18,2017

Stephan Schuele, MD, MPH, FAAN, FACNS

Disclosures Speaker Bureau: Eisai, Sunovion 30% salary EMU related

Stephan U. Schuele

Outline  Introduction  Surgical Trends  Unter‐utilization  Over‐utilization  Summary

Stephan U. Schuele

High Hopes  Epilepsy surgery has been described as “arguably the most underutilized of all accepted therapeutic interventions in the entire field of medicine” (Engel J Jr.)  “surgical activity must more than triple again just to accommodate the annual increment, let alone to address the backlog.” Engel Jr 1993 Stephan U. Schuele

Evidence of Efficacy  First RCT showing efficacy of ATR 2001  Guidelines recommending referral for complex partial seizures 2003  2nd RCT demonstrating efficacy of early resection 2012

Stephan U. Schuele

Wiebe S. et al. 2001; Engel J Jr. et al, 2003; Engel J Jr. et al. 2012

Epilepsy Surgeries: Stagnant

Stephan U. Schuele

Englot et al. Neurology 2012; Schiltz et al. Epil Res 2013

Study Limitations  Nationwide Inpatient Sample  Random sample of only 20% of entire hospital discharges  Relying on ICD 9 Coding  No distinction of type of surgery

Stephan U. Schuele

Epilepsy Surgery at Academic Centers 1991 – 2001 ‐ 2011

Stephan U. Schuele

Jehi L et al. Epilepsia 2015

Trends at Academic Centers  TL Epilepsy Surgery:  True decrease more likely than artificial drop or leakage

 XTLE Surgery:  Increase, driven by better diagnostic techniques and imaging

 3.3 fold increase of invasive studies not leading to surgery (0.7%/year). Stephan U. Schuele

Jehi L et al. Epilepsia 2015

Theories  Leakage to non‐academic centers  1998‐2003: 1.9%  2004‐2008: 9.2%

 Depletion: Prevalent pool 50% in 2 months • Invasive evaluation is not yet cost effective method for patient selection • Improving multimodal imaging techniques may better selection for invasive evaluation better, and thus improve the cost benefit ratio of the procedure J Mani IEC June 2017

39

Conclusion • In premier epilepsy centers of resource rich nations, about 25% of patients undergo invasive evaluation for epilepsy surgery, many are non lesional cases • In Resource poor nations, annual epilepsy surgeries have increased in last 5 years. Less than 10% of patients have invasive evaluation before surgery, so most chosen non invasively, most are lesional cases • In the current method of practice, the cost benefit ratio of invasive evaluation in non lesional cases is low. • Hence for resource poor countries, it is cost effective to invest in non invasive techniques for patient selection • Invasive evaluations to be considered in a few cases on a individualised basis, at predesignated centres J Mani IEC June 2017

40

Thank you

J Mani IEC June 2017

41

Is ECoG Sufficient Enough in Difficult Cases?

Michael Duchowny, MD

Is ECOG sufficient enough in difficult cases? Prasanna Jayakar MD., PhD

ECoG “Difficult” Cases Literature

Strategies

Strengths & limitations

When to use and how

Green vs red patterns

When NOT to use and why

Definition of “Difficult cases”  Epileptogenic Zone [EZ] localization:  Extent is unclear  Multifocal or bilateral possibilities  Divergent multimodal non‐invasive data  Electrocortical stimulation mapping [ESM]:  Children  Atypical representation

Off hand , you have a dipolar source, but lets do a MEG to confirm.

Literature ‐ Background • NO level I/II data • Center biases and resource limitations influence utilization that ranges from “always” to “never” • Lack of standardized procedure for recording, anesthesia, stimulation • Variable interpretation of abnormalities [Singh et al., 2015. Ictal onset on intracranial EEG: Do we know it when we see it? State of the evidence]

ECoG – Inherent Strengths • Avoids the discomfort, risks and costs of staged implantation, extra‐operative IEEG monitoring and a second surgical procedure. • Flexible electrode placements allow EEG recording and ESM mapping prior to, periodically during, and at the end of resection to maximize removal of all regions revealing significant abnormality while preserving function.

ECoG ‐ Limitations • Time constraint generally limits study to 20‐60 mins and thus records mainly inter‐ictal epileptiform discharges [IEDs] Asano et al., Epilepsia 2004 Sep;45(9):1091-9

ECoG ‐ Limitations • Fewer electrodes are generally used, and while large areas may be sampled, these are generally recorded sequentially rather than simultaneously. • Limited analyses of propagation patterns, network characteristics, coregistration with other data, detailed mapping

ECoG ‐ Limitations • Placement of electrodes within specific deep targets is less accurate without stereotactic guidance.

• Lastly, the effects of anesthesia are unpredictable and may occasionally impede recording of abnormalities or ESM.

ECoG: the quest for Green vs. Red patterns • Typical IEDs prior to resection or “rim” spikes [Wray et al., 2012; Tran et al., 1995; Kanazawa et al., 1996; Yang et al., 2014] • Pharmacologically activated discharges [Ebrahim et al., 1986; Gancher et al., 1984; Gronlykke et al., 2008; Kjaer et al., 2010; Rampp et al., 2014; Tempelhoff et al., 1992] • HFO [Jacobs et al., 2010; Wu et al., 2010; Zijlmans et al., 2012] • Bursts [Greiner et al., 2016] or discharges lasting >2 s [Terra et al., 2014] • Paroxysmal fast activity admixed with spikes [Greiner et al., 2016] • Continuous Epileptic Discharges [CEDs] : Repetitive or periodic discharges, Recruiting/derecruiting rhythms ‐ Bridge the gap between the irritative and ictal onset zones [Palmini et al., 1995; Turkdogan et al 2005; Ferrier et al., 2006; Greiner et al., 2016 ]

Perceived reliability of ECoG patterns to define EZ ILAE survey of 40 pediatric centers worldwide [Jayakar et al., 31st IEC, 2015]

Least

Most

Perceived reliability of Extra‐operative IEEG patterns

Least

Most

ECoG example– Continuous epileptic discharges [CEDs]

CEDs example

CEDs leading to Ictal onset

How do specific ECoG patterns relate to IOZ ? • Greiner et al., Epilepsia 2016 – 103 children – compared ECoG findings with extraoperative IOZ and outcomes. – IED [63%] and CEDs [83%] correlated with IOZ – Outcome correlation

• Korzeniewska et al. Neuroimage; 2014: Ictal propagation of high frequency activity is recapitulated in interictal recordings

ECoG “Difficult” Cases Literature

Strategies

Strengths & limitations

When to use and how

Green vs red patterns

When NOT to use and why

ECoG: When and how to use • IEDs: – Use in specific lesional substrates such as discrete developmental tumors, acquired/low‐flow vascular lesions, or Sturge‐Weber syndrome is equivocal. • Some centers advocate primarily a lesionectomy [Rowland et al ‐ Meta‐analyses. 2012] • Others opt for ECoG [Giulioni et al. 2009; Chang et al., 2010; Ogiwara et al., 2010; Tripathi et al., 2010; Gelinas et al., 2011; Englot et al., 2012] – Use in MRI negative cases with convergent non‐invasive functional data including ESI/MEG, PET, SPECT [Lee et al., 2003; Jayakar et al., 2008; Schneider et al. 2012; Kudr et al., 2013; Burkholder et al 2014]

• HFOs: Pre‐resection [Jacobs et al., 2010; Wu et al., 2010; Zijlmans et al., 2012; van Klink et al., 2104 ] or post‐resection [van 't Klooster et al., 2015] found to correlate with outcome.

ECoG: When and how to use • CEDs: Periodic ECoG is being increasingly used till all tissue revealing CEDs is removed • Scenarios where CEDs on ECoG are likely: – FCD: type IIB, IIA, or I [Palmini et al., 1995;Greiner et al., 2016] – TS where the culprit tuber is known‐ [Mohamed et al., 2012; Harvey et al., 2015] – Also seen with non‐dysplastic lesions: ulegyria, encephaloclastic [Turkdogan et al., 2005; Pascoal et al., 2013; Schilling et al., 2013] – When non‐invasive data shows: • Scalp EEG: frequent rhythmic IED runs, or ESES • PET shows hyper‐metabolism

HYPER PET

 Namer et al., Clin Nucl Med. 2014 Jul 3. [Epub ahead of print]‐ FCD Intrinsic epileptogenicity  Talanow et al.. Clin Nucl Med. 2009 Oct;34(10):670‐4. MCD [6/71 pts]  Luat et al. Brain Dev.. 2006 Oct;28(9):592‐6. LKS  De Tiège et al. Neurology.2004 Sep 14;63(5):853‐7. [ESES]  Alkonyi et al. Epilepsia. 2011 Jul;52(7):1265‐ 72. Sturge Weber syndrome[9/60 pts]  Bansal et al. Epilepsia 2016 Mar; 57(3):436-44.

Case example‐ Progressive aphasia, Bipeds on scalp EEG

MRI: Suspect left frontal FCD

PET

ECoG

Subdural Depth

Post‐resection ECoG

2 wks post op‐ No aphasia No BIPEDS

Intraoperative Mapping & Monitoring Flexible electrode placements allow:  Combined cortical and sub-cortical mapping throughout surgery  Documentation of atypical representations

Awake surgery with clinical testing maximizes safe resections when feasible Seidel et al J Neurosurg. 2013 118(2):287-96; Schucht et al. Hum Brain Mapp. 2012 Jun 19. doi: 10.1002/hbm.22122.

Where ECoG is NOT sufficient  IEDs:  NOT found to be useful in typical MTLE [Tran et al., 1995; Kanazawa et al., 1996; Yang et al., 2014]  Post‐resection “rim spikes”:  Do not correlate with outcome [Wray et al., 2012; El Tahry et al., 2016]  Trend toward good outcome [OR 2.03, p=0.099‐ Greiner et al., 2016]

 Ictal capture required  Divergent multimodal non‐invasive data  Multifocal irritative zones without clear IOZ eg., dual pathology, Tuberous Sclerosis or nodular heterotopia  Bilateral IEEG exploration indicated for possible lateralized IOZ  Hemispheric syndromes with preserved function eg., Polymicrogyria [Wang et al., 2015]

 ESM not feasible

Factors limiting intraoperative ESM

Anesthesia effect

Ojemaan et et al. 1989

Age effect

Jayakar et al. 1992

Awake surgery for language mapping

Diagnostic Commission IEEG Indications and Utility Recommendations Jayakar et al., Epilepsia 2016; 57:1735‐ 1747

Conclusions  Intra‐operative ECoG is clearly insufficient when ictal capture is required, where ESM is not feasible, or detailed post‐processing is considered essential  However, it is being increasingly used worldwide in many difficult cases under specific scenarios where it averts the need for extraoperative IEEG studies and maximizes safe resections.  When the ECoG is uninformative, the electrodes may be implanted for extra‐operative IEEG studies ‐ a flexible cost‐effective strategy  Further validation of ECoG patterns is required

Epilepsy Program Team •

•

•

•

•

• • •

Epileptology/Neurophysiology:  Ian Miller MD  Michael Duchowny MD  Trevor Resnick MD  Prasanna Jayakar MD., PhD  Ann Hyslop MD  Kalyani Karkare MD Neurosurgery  Sanjiv Bhatia MD  John Ragheb MD  Travis Tierny MD Neuroradiology  Nolan Altman MD  Santiago Medina MD  Esperanza Pacheco MD  Martha Ballesteros  Byron Bernal MD Neuropsychology  Brandon Korman PhD  Reshma Naidoo PhD Nursing specialist  Pat Dean  Aileen Rodriguez  Claudia Garcia Neurointensivists NeuroAnesthesiologists NeuroPathologist

Thank You

Building Epilepsy Surgery Programs – The Iranian Experience

Shahram Amina, MD

Epilepsy Surgery in Korea Seung Bong Hong, MD, PhD Department of Neurology Samsung Medical Center, Sungkyunkwan University, Seoul, Korea

History of Epilepsy Treatment in Korea Korean Neuropsychiatric Association: 1945  Korean Neurosurgical Society: 1961  Rose Club (later renamed to Korean Epilepsy Association in 1964  Korean Neurological Association: 1982  Epilepsy patients were treated mostly by medication until early 1990’s 



Korean Epilepsy Society: 1996

20th Anniversary Book of Korean Epilepsy Society

Published in 2016

History of Epilepsy Surgery in Korea Anecdotal brain surgery for epilepsy patients until early 1990’s

Professor Bo Sung Sim (1924 – 2001) performed hemispherectomy for cerebral paragonimiasis in 1958.

Dr. Chu Kul Lee (1914 – 2006)

Beginning period of EEG 



  



Dr. Soo-Ik Lee from University of Virginia came to Korea in 1969. 8 channel Grass EEG in 224 patients in 1969 16 channel EEG in 1976 Dr. Soo-Ik Lee returned to Virginia in 1975 Dr. Young-Choon Park came back to Korea after Neurology training in USA in 1970 In those days, only small number epilepsy patients were able to visit hospitals due to low economic level and low awareness of epilepsy and stigma.

Terminology of Epilepsy in Korea 

Seizure 발작 發作, 경련 痙攣



Epilepsy 간질 癎疾, 전간 癲癎(てんかん)

2011 renaming 

Electro-cerebral disease 뇌전증 腦電症

A car accident of epilepsy patients in Korea July 31, 2016 in Busan city 51 year-old man with epilepsy skipped drugs for 2-3 days before the accident. The patient was driving a car by speed of 150km/hr during the crash at a crossroad. 3 persons were killed and 14 injured.

All media blamed epilepsy for the accident 

 



Actually many people with epilepsy received disadvantages from media report on epilepsy-induced traffic accident. Many patients called Korean Epilepsy Society to help them from discrimination of society and biased blaming. I communicated with 59 colleagues in other countries and received many information about the car accident risk of epilepsy patients compared to other groups of population. Korean Epilepsy Society released a urgent statement about this accident and low risk of well controlled epilepsy patients to media

Introduction of Modern Epilepsy Surgery in Korea    

 



1988: Dr. Byung-In Lee and Dr. Kyun Hur came back to Korea from USA (Yonsei University Hospital). 1989: Dr. Lee started epilepsy monitoring unit. 1st epilepsy surgery was done in 1989. 1992: Dr. Sang-Do Lee and Dr. Eun-Ik Son did an epilepsy surgery in Kyemyung University Hospital in Dae-Gu city, Korea. 1992: Dr. Hyung-Il Kim started epilepsy surgery in Junbook Unversity Hospital in 전주, Korea 1994: Dr. Seung Bong Hong and Dr. Seung Chyul Hong started epilepsy surgery in Samsung Medical Center, Seoul, Korea Thereafter, 6 more epilepsy centers began epilepsy surgery.

Epilepsy Surgery New start in early 1990s Seoul National University Hospital (1994)  Yonsei University (1989)  Samsung Medical Center (1994)  Asan Medical Center  Dongsan Medical Center (1991)  Cheonbuk National University (1991) 

Epilepsy Symposium in 1994 with Dr. Luders

Epilepsy Symposium in 1995

Epilepsy Program of Samsung Medical Center

Neurology

Pediatric Neurology

Neurosurgeon

Recent Epilepsy Surgeries in Korea

✓ Decreasing epilepsy surgery cases ✓ Decreasing activity of epilepsy surgery centers ✓ Increasing neurostimulation surgery (VNS, DBS)

Why surgery decrease?  

 





Still not well known to both patients and doctors Number of surgery centers are limited. More difficult cases, less easy cases Labored presurgical evaluation and surgery, but less medical cost Still high cost for presurgical evaluation and surgery in Korea for PWE with low income Difficult epilepsy surgery is not well recognized and appreciated in hospitals.

Recent improvement of national insurance coverage in Korea 



Until 2016 (patient’s payment rate) • Outpatient: drugs(30%), tests(60%) • Inpatient: drugs(20%), tests(20%), surgery(20%) After January 2017 • Additional support for Severe Drug Resistant Epilepsy (SDRE): ≥1 CPS or motor SPS per month drugs(10%), tests(10%), surgery(10%)



• But there is still non-reimbursed portion. • Admission fee (1 - 3 bed room) • Special fee (professor): 50% of test, 100% of surgery

Surgery in Samsung Medical Center Etc.(VNS,DBS,callotomy 등)

120

Resective surgery Invasive surgery

2

100

1

80

0

0

5

67

60 47

4 3 9

49

60

57

49

0

33

27 18

27 16

21

23

24

12

15

13

21

16

40

14

21

47

47

43 40

33

26

33

25

54

57

40

20

4

7

62

61

11

9

7 56

43

12

18

38

46

20 11

39

40

24

23

20

16

21

1 0

94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12 13 14 15 16

Ictal-Interictal SPECT subtraction Ictal SPECT

Subtracted SPECT

Localization of epileptic focus by SISCOM Right SMA epilepsy

Brain MRI, FDG-PET: normal, EEG: non-lateralized

LJW

FLAIR

SISCOM

Neuroimaging studies

No epileptogenic lesion

Functional deficit zone

R

R

Brain MRI

Brain FDG-PET

MRI-PET PET-MRI fusion fused image

FDG-PET/MRI coregistration for detection of cortical dysplasia

Salamon N, Neurology 2008

Intracranial EEG recording

3D Mapping of Intracranial Electrodes

Co-registration of 3MRI, lesion, SISCOM and subdural grid electrodes

MRI lesion

SISCOM hyperperfusion

Subdural grid electrodes

Brain Electrical Stimulation of Intracranial Electrodes

Samsung Medical Cente

Co-registration of 3MRI, lesion, SISCOM and subdural grid electrodes + EEG + brain stimulation results Toe motor Negative motor

2nd – 5th finger motor Thumb motor

Tongue motor

Interictal spikes

Ictal onset zone

Intracranial Electrodes Placement CT-MRI fusion

Simultaneous Scalp-Intracranial EEG Recording

Scalp EEG

SScalp

Cortical EEG

Cortical EEG onset

Non-visualization on scalp EEG

False localization on scalp EEG

두피 뇌파 Scalp EEG

피질 뇌파 Cortical EEG

False ictal onset zone on scalp EEG

Ictal onset zone on subdural grid = concordant to SISCOM

SISCOM: left occipital hyperperfusion during seizures

10/F HSY with aura and automotor seizures (3D MRI, FLAIR, PET, SISCOM fusion)

Flair + PET1 + PET2 + SISCOM Ictal onset zone by scalp EEG

MRS – What we can see… 

Long TE



Short TE NAA

NAA Cr Cho

Cho Cr

mI

Glx Lipids

MRS in MCD

(Malformation of Cortical Development)

NAA

NAA

Cho Cho

CSI in Focal Cortical Dysplasia 

FCD at Lt middle frontal gyrus 

Epileptogenic lesion vs. chemically abnormal region

Streamline Tractography

DTI in MCD

(malformation of cortical development)

Epilepsia, Vol. 48, No. 8, 2007

DTI in Cortical Dysplasia

• Fiber connection의 이상 보다는 FA 가 감소한 것으로 추정됨. NeuroImage 2004;22:1826-1829

MEG center in Seoul National University Hospital, 2005 Neuromag 300 channels

152 channel MEG system made in Korea (KRISS) MSI : Magnetic Source Imaging MSI = MEG + MRI 3D coordinate exported to Curry SW patients’ individual realistic head model generation

MEG recording

CURRY (Version 7, Neuroscan, USA) MRI

Image data parameter setting

Realistic Head Model

Landmark & Talairach setting

Samsung Medical Center

MEG BEM(Boundary Element Method)

42

MEG dipole analysis in SMC ▪ ECD(Equivalent Current Dipole) model 1 Fixed MUSIC (MUltiple SIgnal Classification) algorithm ▪ GOF(Goodness of Fit) ≥ 70 Spike detection Dipole in patient’s brain and time selection from MEG record model

MEG source localization using MUSIC algorithm

Source analysis using MUSIC algorithm

Dipole in patient’s MRI

Samsung Medical Center

Superimposed dipoles in a patient’s brain MRI

Comparing MEG source localization result with presurgical evaluation

Presurgical Evaluation result

MEG Source localization

Video EEG

Brain MRI

Ictal SPECT

SISCOM

ISAS

Lesion Rendering

PET

Samsung Medical Center Samsung Medical Center

44

MEG recording (101)

(128) (27) No Spike

Spike

Well Concordant

Partially Concordant

Not Concordant

No Fitting

(69)

(11)

(11)

(10)

Compared with presurgical evaluation result

* ( ): number of patients

• 90% of the patients’ dipoles were fitted Total pts

Well Concordant pts

Partially Concordant pts

Not Concordant pts

91 (100%)

69 (76%)

11 (12%)

11 (12%)

• 10% of the patients’ dipoles were not fitted well  low SNR(Signal to Noise Ratio) or generalized spike Samsung Medical Center

45

• 13 patients underwent epilepsy surgery Pt #

Sex

1 2 3 4 5 6 7 8 9 10 11 12 13

M M M M M M M M M F M F M

Age (yr) 41 34 20 41 20 18 29 50 33 17 20 55 38

Onset Lesion (yr) 18 N 5 Y 0 N 20 Y 13 N 9 Y 20 Y 5 Y 4 Y 0 Y 6 Y 19 Y 10 Y

Presurgical evaluation Bi (R>>L) T LT Bi (R>>L) FT Bi (R>>L) T LT R TO Bi (R>>L) FT RT L FT Bi (R>>L) F LT LT Bi (RL) T RT L FT Bi (R>>L) F LT L ant T LT

Concordance Outcome rate 1 IA 1 IIIA 1 IA 0 IA 1 IA 1 IA 1 IA 1 IA 1 IA 1 IB 1 IA 1 IA 1 IA

• MEG sources were well concordant and had good outcome in 12 patients (F/U 0.6~2.9yr) - pt #4: poor concordance rate (few dipoles analyzed case) • Lesional: 10 patients / Non-lesional: 3 patients  IA ~ IIIA outcome Samsung Medical Center

46

High resolution EEG dipole source localization

Frequency Spectrum of EEG waves High Frequency Oscillation (HFO)

Oscillations

Representative Function

Ultra-slow / Slow (DC~1 Hz)

Cyclic Modulation of Gross Excitability

Delta (1~4 Hz)

Slow-wave Sleep

Theta (4~8 Hz)

Learning and Memory (especially in MTL)

Alpha (8~12 Hz)

Synchronous, coherent activity of thalamic pacemaker cells (predominantly in occipital lobe)

Beta (12~30 Hz)

Movement control, Long-range Synchrony

Gamma (30~80 Hz)

Perception, Memory, Consciousness (?)

Ripple (80~200 Hz) Memory consolidation Fast ripple (200-500Hz) Epileptic, ??

Clinical Utility of High Frequency Oscillations in Neocortical Epilepsy

HFO highly concentrated in SOZ compared to control regions

Surgical removal of HFO-generating region correlates with seizure outcome

Experiences at Samsung Medical Center 120

100

80

Total number of Epilepsy surgery

60

Resection 40

20

VNS, DBS Electrode insertion

0 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12 13 14 15 16

51

VNS number in Korea VNS 年度別 case Updated at Dec 20th, 2016 Year

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

Total

Case

18

2

5

6

8

13

89

58

37

30

36

23

30

34

64

69

104

77

703

Case 120 104 100

89 77

80 64 58

60

Case 37

40

20

69

36 30

30

34

23

18 2

5

6

8

13

0 1999

2000

2001

2002 2003 2004 2005 2006 2007 2008 2009

2010

2011

2012

2013

2014

2015

2016

Deep Brain Stimulation

New Scans for Stereotactic Targeting

Short tau inversion recovery (STIR) image

New Scans for Stereotactic Targeting

Fast Gray Matter Acquisition T1 inversion recovery (FGATIR) image

Inserted tips of bilateral electrodes in the ATN (T2WI)

Summary of Outcome of ATN DBS trials in CMC of Korea since 2005 (n = 29 pts) ▪

Median seizure reduction: 70.0%

▪

≥ 50% seizure reduction: 22 / 29

(75.9%)

▪

Sz free for more than 6 months: 7

(24.1%)

▪

Sz free for more than 1 year: 2

(13.8%)

▪

▪

Major complication after operation ▪ 1 case – IPG infection, resolved after device removal at post-op. 4th month) ▪ No peri-operative major bleeding Lack of Efficacy

▪ 2 cases – Removal of DBS apparatus d/t lack of efficacy after at least 1 year ▪ Patient with LGS (1 patient) & post-infectious epilepsy (1 patient) ▪

Minor complaint ▪ Pain sensation related to device : 8,

all recovered

Submitted to Epilepsy Research

Centromedian thalamic DBS for Intractable Epilepsy

CM DBS in Epilepsy 

ATN

Rationale • CM has widespread projections to the cortex and plays a central role in wakefulness & cortical excitability (Miller R, 1996), and it plays a role in sz generation & propagation (Detre JA, 1996; Mondragon S, 1990)

• Velasco group reported positive results in 13 patients with LGS (77%, responder rate)(Velasco F, 1987;Velasco FMD, 2000; Velasco AL, 2006)2010)

• Effectiveness of CM DBS in 11 pts (single blinded Tx, 3M on/ 3M off, followed by 6M open-label stimulation). • All 6 pts with GE had >50% sz reduction • But, in 5 FLE pts only one showed >50% improvement (Valentin, 2013)

Long term outcome of patients with CM DBS ( > 1 year) at CMC of Korea Patient Sex/Age F/U (months)

Dx

Mean Sz reduction (%)

KWJ

M/19

40

B T-PLE, crypto

71.9

LSJ

F/34

36

B schizencephaly

72.9

YJS

F/32

36

B schizencephaly

58.2

CYJ

F/21

34

LGS

75.8

OMY

F/32

34

B schizencephaly

79.0

LWJ

M/24

34

LGS

53.7

Ree

F/16

32

92.9

CYH

M/42

32

SDB

F/27

23

B FLE or cingulate E R schizencephaly, multifocal E LGS

PJH

M/28

24

LGS

35.7

NHM

F/34

22

Multifocal E

94.2

OYS

M/25

18

Multifocal E

91.7

SJH

M/23

4

B (or L>R) C-PLE

93.1

66.9 70.4

Sz reduction: Avg. 73.5%, Median 78.3%

« Lesion Negative Intractable Epilepsy » « Mesio-Temporal Lobe Epilepsy » Julia Scholly, Maria Paola Valenti F Bartolomei Marseille, Edouard Hirsch Strasbourg

Lesion Negative = MRI Negative = Neuro-Path. Negative ?

Intractable = Drug Resistant ?

Mesio-Temporal Epilepsy = Mesio-Temporal Seizure Onset ?

Mesio-Temporal Lobe Syndrome? = Hippocampal Sclerosis ?

« Lesion Negative Intractable Epilepsy » « Mesio-Temporal Lobe Epilepsy »  “Typical MTLE” without mesial temporal sclerosis (other lesion or normal MRI)

 “Typical MTLE with MTS” is not necessarily strictly mesial temporal MTS lesions often extends outside the mesial temporal regions  Functional neuroimaging often shows maximal abnormalities over the temporal pole  SEEG demonstrates initial involvement of the temporal pole in up to 30% of “MTLEs”  “Typical MTLE with MTS” is not a homogeneous syndrome  Variability in past-history and electroclinical findings  Various aspects of MTS  Large spectrum of response to surgery P Ryvlin with permission

Historical Perspective Temporal lobe seizures described as “uncinate fits” in 1881 by John Hughlings Jackson

ILAE 2017 Classification of Seizure Types Expanded Version1 Generalized Onset

Focal Onset Aware

Impaired Awareness

Descriptors

Non-Motor Onset autonomic behavior arrest cognitive emotional sensory

Motor

Motor

Motor Onset automatisms atonic2 clonic epileptic spasms2 hyperkinetic myoclonic tonic

Unknown Onset

?

focal to bilateral tonic-clonic

tonic-clonic clonic tonic myoclonic myoclonic-tonic-clonic myoclonic-atonic atonic epileptic spasms2

tonic-clonic epileptic spasms

Non-Motor behavior arrest

Non-Motor (absence) typical atypical myoclonic eyelid myoclonia

Unclassified3

1 Definitions, other seizure types and descriptors are listed in the accompanying paper and glossary of terms. 2 These could be focal or generalized, with or without alteration of awareness 3 Due to inadequate information or inability to place in other categories

From Fisher et al. Instruction manual for the ILAE 2017 operational classification of seizure types. Epilepsia doi: 10.1111/epi.13671

Sophie, 28 Years, Right Handed

Interictal EEG

Ictal EEG

EEG Onset

Vertigo

Ictal EEG

Increased mortality in epilepsy Historical Perspective

 « Vertigo » a descriptor of focal seizure: Anatomo-functional correlation (Electrical Cortical Stimulation)  Intraparietal sulcus (rotation, “flottement”, Foerster, 1936; Blanke et al., 2000)  Temporal superior gyrus (« sensations labyrinthiques », Penfield and Jasper, 1954, Penfield, 1957)  Angular Gyrus, BA 39 (« sensation vertigineuse non-spécifique», Smith, 1960, Blanke et al. 2002)  « Vestibular Cortices » Temporo-périsylvien, BA 21, 22, 40 (rotation, translation, Aspecific feeling of movment of body, Kahane et al., 2003)  Parietal mesial (Linear displacement, Kahane et al., 2003, Wiest et al., 2004)  Posterior Insula (rotation, translation, “sensation vertigineuse aspécifique”, Isnard et al., 2004; Mazzola et al. 2014)  Others: Thalamus, Cerebellum… ?

Lopes & Blanke, Brain Res. Rev. 2011

 Seizures with vestibular phenomenology  Temporal Superior Gyrus, Temporo-parietal junction (Penfield and Kristiansen, 1951; Smith, 1960)  Temporo-Parieto-Occipital Junction (Barba et al., 2007; Hewett et al., 2011 )  Parietal Superior Region (Bartolomei et al., 2011 )  Insula (Isnard et al. 2004)  Frontal Region (Lopez et al., 2010)  Primary or secondary of multiple cortical area participating in multimodar vestibular processing

 Sub-Cortical Structures ?

The Human Central Nervous System by R. Nieuwenhuys, J. Voogd, C. van Huijzen

MRI 3 Tesla

Sophie, 28 Years, Right Handed

 VIQ: 82; PIQ: 98; GIQ : 87  Visual and Verbal Memory Deficit  Attention Deficit  Fronto-Temporal and Temporal Mesial Dysfunction L>R

Seizure types*

Co-morbidities

Focal

Generalized

Etiology Unknown

Structural Genetic

Epilepsy types Focal Focal

Generalized

Combined Generalized & Focal

Infectious Unknown

Metabolic Immune

Epilepsy Syndromes

Epilepsy Syndromes ? Scheffer I et al. 2017

Unknown

Lesion Negative ?

« Concept » of MTLE Hippocampal Sclerosis = Biological Markers ≠ Etiology

«Classical» Syndrone ?

« Immune » Hashimoto LGI1-VGKC GAD……

Febrile Seizure Genetic Anoxic Trauma

« Alzheimer »

Conclusion Phase I:  Symptomatogenic Zone:  Temporal mesial, Basal antrior, Lateral Cortices  Temporo-parietal Junction / Parietal Cortices (Vestibular Area?)  Insular Inferior and Anterior Cortices  Parietal Late involvment (taste?)  Mainly Non-dominant Hemisphere  Irritative Zone :  Temporal anterior and medial Right >> Left; Fronto-basal Right  Functional deficit Zone :  FDG-PET: Temporal anterior, Basal, Medial Right>>Left; Insular Right, OrbitoFrontal lateral Right  Neuropsychology: Fronto-temporal, Temporal medial, Right>Left  Lesional Zone: MRI? Malformative (Cerebellum Hamartoma?)

« Non Lesional" Right Mesio-Temporal + with Vestibular Symptom, No cortical lesion on MRI Actual Epileptogenic Zone Potential Epileptogenic Zone

Temporo-parietal Junction Right?

Left Mesio-temporal?

Temporoinsulo-perisylvian Right? Temporal antérieur Mesio-lateral Right?

Role of Left Cerebellum Lesion ? Sub-cortico-cortical Network ? L Cerebellum -> R Thalamus (N. ventral lateral) -> R Thalamus (N. lateral dorsal or lateral posterior) -> R Parietal and /or Posterior Gingulate Cx-> Limbic

Video-SEEG Bilateral Right: 13 electrodes

Left: 5 electrodes DL S

OP H

O

C

A’

A B I

F

B’

I’ E’

D E

Cb’

S VL

LD

O

Electrodes Dixi® (5–18 contacts, longueur 2 mm, diameter 0.8 mm, espace 1.5 mm); Implantation Robot ROSA ™. Neuroiumaging post processing fusion IRM/scanner post-implantation (logiciel OsiriX)

Cb’

Interictal EEG

Interictal EEG

First Clinical Sign «Epigastric » AMY D Hc ant D Hc post D

INS inf Temp sup Cingulaire Supramarg Th LD Th VL INS post Op Par

Cx Cérébel G

«J’ai une crise!» AMY D Hc ant D Hc post D


Cx Cérébel G

«J’ai chaud»

Network cortico-sub-cortical: parietal, insula, thalamus (N. latero-dorsal) et Cx Cerebellum contra-lateral «J’ai une crise!»

«J’ai chaud»

«Les poumons «ça tangue!» s’ouvrent»

AMY D Hc ant D Hc post D


Cx Cérébel G

Remote Verbal Memory

Stimulations Results : 

Electroclinical Seizures:

Right:

A 1-2 chocs 2 mA; B’ 3-4 chocs 2 mA



Symptomatic Post Discharge OP

 “Arrêt sur l’image, tête qui tourne” I’ 1-2, chocs, 1 et 1,5 mA

H

S

O C A

 “Sensation thoracique, Ascending Paresthesia” B’ 2-3, chocs, 1mA

B D

I

F

E

 Functional Zones  Auditive primary and Associative cortex  H’ 1-2; H 5-9, chocs, 1 et 2mA

Left:

 Cingular posterior cortex  S 2-3 à 1mA et à 1,5mA:  Ascending paresthesia A’

 Orbito-frontal cortex • O 11-12 0 3mA ; Executives dysfunction during STROOP Test.

I’

B’ E’ Cb’

Seizure onset Zone Symptomatogenic Zone Irritative Zone

Epileptogenic Lesion

Electrical Irritative Zone (SWs, poly-SWs, low amplitude polyspikes) Left:

Right:

OP H A’

S

O

B’

C I’

B

A

E’

F

D I Cb’

E

S VL

O

N. ventral latéral

DL N. latérodorsal

Pour Background Activity Electrical Lesional Zone ( Gamma activity) Right: Right:

Left:

OP H

S

O

A’

C

B’ B

A I’

F

D

E’

I

E

Cb’

S VL

O

N. ventral latéral

DL N. latérodorsal

Phase II Conclusion Right:

Left::

OP H A’

O

B’

C B

A I’

S

E’

F

D I

E

Cb’

Electrical Irritative Zone Actual Practical Epileptogenic Zone

S VL

Potential Epileptogenic Zone O

Role of Left Cerebellar Hamartoma?

N. ventral latéral

DL N. latérodorsal

Resection Proposal: • Standard temporal lobe resection non dominant hemisphere • No AED withdrawal after surgery ? Risk of further memory loss? -> fMRI language before surgery Right: Left:

OP

H A’

S

O

B’

C

I’

B

A

E’

F

D I Cb’

E

S VL

O

N. ventral latéral

DL N. latérodorsal

Follow up 3 Years after Surgery:  Seizure Outcome Engel Ia  Improvement of long-term memory performances  AED schedule simplification: actually on monotherapy LTG 200mg/day Histology: • Amygdala & Hippocampus: normal; • Temporal pole: mMCD type II (Palmini) (small groups of heterotopic neurons in subcortical white matter Subtests Immediate Verbal Memory Immediate Visual Memory Mémoire immédiate Remote Verbal Memory Remote Visual Memory Remote Verbal Recognition General Memory Working Memory

Post op 70*

Pre Op 72*

77*

97

71* 72*

82 69*

75*

68*

96

86

80* 94

69* 79

« Non Lesional" Right Mesio-Temporal + with Vestibular Symptom, No cortical lesion on MRI

16

Seizure onset

14

Averaged z-scores

12 10

*

8 6 4 2

*

0 -2

Brain regions

Role of Left Cerebellum Lesion ? Sub-cortico-cortical Network ? Cerebellum G -> Thalamus D (N. ventral lateral) -> Thalamus D (N. lateral dorsal ou lateral postérior) > Cortice parietal and /or G. Gingulate posterior -> Limbic

Symptomatogenic Zone Irritative Zone Actual Epileptogenic Zone Lesion Non Epileptogenic

Potential Epileptogenic Zone ?

Seizure Onset

Case Discussion & Conclusion:  Our data suggest an epileptogenic network with inititial implication of mesiotemporal structures followed by temporal lateral, insuloparietal, thalamus and cerebellum involvement when vertigo occurred.

Insula post. inf. G. temp. sup.

G. temp. moyenHip anter Amygd ale

G. cinguli post. G. supramargin Thalam al (inf.) us N. LD

Pôle temp Cx cérébelleux

Opercule par. G. supramarginal ThalamusInsula post. N. VL sup. (sup.)

Seizure Core Cx entoInsula post. inf. rhinal G. temp. sup.

 Actual Epileptogenic Zone does not include cerebellar lesion despite “vertigo” as early symptom.

Cx entorhinal

G. cinguli post. G. supramargina Thalamu l (inf.) s N. LD G. supramarginal (sup.)

G. temp. moyen Hip anter

Amygda le Pôle temp Cx cérébelleux Opercule par. Thalamus Insula post. N. VL sup.

Merci!

Clotilde Boulay Julia Scholly Françoise Mielcarek Edouard Hirsch Josiane Roehm Paola Valenti-Hirsch Christel Dentel, C Behr

Pierre Kehrli, F Proust Mustapha Benmekhbi Alexander Timofeev

Thank You!

Bernhard Steinhoff Anke Staack Anne-Sophie Wendling Alexander Schmidt

Fabrice Bartolomei Fabrice Wendling

Lesion Negative Intractable Epilepsy Neocortical Temporal Lobe Epilepsy

Epileptogenic Zone Lateral neocorKcal vs. mesial temporal

Epilepsy Colloquium Miami/FL

1

1

17.6.2017

Epilepsy Center Dept. of Neurology University of Munich Ludwig-Maximilians-Universität LMU Munich / Germany

NeocorKcal temporal epileptogenic zone

Mesial temporal epileptogenic zone

Epilepsy Surgery Evaluation

Epilepsy Surgery

Lateral neocortical vs. mesial temporal

no

MRI lesion

yes mesiotemporal

Extramesiotemporal

yes

Adjacent eloquent cortex (fMRI)

no Convergence of seizure semiology, EEG & Neuropsych

no NeocorKcal temporal resecKon

1

Temporal resecKon

no

Mesial temporal resecKon

Localization of the Epileptogenic Zone Symptomatogenic zone (Semiology, FDG-PET) FuncKonal deﬁcit zone (neuropsych. FDG-PET)

Invasive EEG

PET & SPECT convergent

yes

yes

Resection

Syndrome: Lt. neocortical temporal lobe epilepsy Etiology: Lt. lateral temporal cavernoma

Epileptogenic lesion (MRI)

Aura → automotor seizure → Lt. face clonic seizure → generalized tonic-clonic seizure

Seizure onset zone (ictal EEG & SPECT)

MRI lesion

IrritaKve zone (interictal EEG)

1

Ictal EEG Interictal EEG

1

Syndrome: Lt. neocortical temporal lobe epilepsy Etiology: Unknown Auditory aura → dialepKc seizure → Rt. versive seizure → gen. tonic-clonic seizure

1

Ictal EEG Interictal EEG

EEG in Neocortical & Mesial temporal Epilepsy

Seizure Semiology in Neocortical & Mesial temporal Epilepsy

Pfänder et al., Epilep1c Disord 2002

Pfänder et al., Epilep1c Disord 2002

Lesion Negative Intractable Epilepsy

Neocortical Temporal Lobe Epilepsy Interictal Non-invasive EEG

NeocorKcal Temporal Lobe Epilepsy

•  42 y/o M.B.A. •  Epilepsy since age 10 •  Auditory aura → dialepKc seizure → Rt. versive seizure → gen. convulsive •  EEG: Lt. mesial temporal spikes •  MRT: normal •  Refractory to mulKple AEDs •  EEG-Video-Monitoring: Interictal: Lt. mesial temporal spikes Ictal: EEG seizure pa\ern, Lt. temporal

DialepKc Seizure

Fp2-F8 F8-FT10 FT10-T8 T8-P8 P8-O2 Fp1-F7 F7-FT9 FT9-T7 T7-P7 P7-O1 Fp2-F4 F4-C4 C4-P4 P4-O2 Fp1-F3 F3-C3 C3-P3 P3-O1 Fz-Cz Cz-Pz EKG

2

Lesion Negative Intractable Epilepsy FDG-PET

Neocortical Temporal Lobe Epilepsy Ictal Non-invasive EEG Fp2-F8 F8-FT10 FT10-T8 T8-P8 P8-O2 Fp1-F7 F7-FT9 FT9-T7 T7-P7 P7-O1 Fp2-F4 F4-C4 C4-P4 P4-O2 Fp1-F3 F3-C3 C3-P3 P3-O1 Fz-Cz Cz-Pz EKG

Invasive Evaluation

Neocortical Temporal Lobe Epilepsy Ictal Non-invasive EEG Fp2-TP10 AF8 F8 FT8 SP2 F12 T8 TP10 P8 P12 PO8 FC6 F4 C4 P4 AFZ FZ CZ PZ Fp1 AF7 F7 FT7 SP1 F11 T7 TP9 P7 P11 PO7 FC5 F3 C3 P3 O1 RS EKG

G

F

StereotacKcally implanted depth electrodes

E

D A

B

C

Spikes

Spikes & Seizures

L

1 1

1

10

A

1

10 1

5

G

6

E

B

10

C

R R

Neocortical Temporal Lobe Epilepsy Interictal Invasive EEG (Depth Electrodes)

L

L

Neocortical Temporal Lobe Epilepsy Interictal Invasive EEG (Depth Electrodes)

3

Neocortical Temporal Lobe Epilepsy

Ictal Invasive EEG during auditory aura (Depth Electrodes)

Invasive Evaluation StereotacKcally implanted depth electrodes failed to idenKfy speech areas

G F

E


Ictal Invasive EEG Seizure Onset (Depth Electrodes)

Interictal Epileptiform Discharges Subdural Electrodes = 56% = 24,3%

8

D A

B

7

C

16

6

24

5

= 9,6%

32

4 3

40

2

L

= 2,1%%

48

1

56 10

19

64 27

= 1,6% = 1,1%

63

35

62 43

61 60

51 59

Neocortical Temporal Lobe Epilepsy Ictal Invasive EEG Seizure Onset

Neocortical Temporal Lobe Epilepsy Ictal Invasive EEG Seizure Pa\ern (Con‘t 2)

4





Cortical Mapping with Subdural Electrodes

MR negative, PET positive Neocortical Temporal Lobe Epilepsy

Ictal Invasive EEG Seizure Pa\ern (Con‘t 3)


3 years post-op seizure free

Motor face & throught



Histopathology: Focal corKcal dysplasia Typ Ia (microcolumns)

Speech Maximum Spikes

Auditory aura → dialepKc seizure; posKctal aphasia

R

Spikes

5

Temporal Plus Epilepsy – Case Discussion

Philippe Ryvlin, MD

Minimalist Surgery in TLE – Hippocampal Transection

Shahram Amina, MD

Orbital‐Frontal Epilepsy

Philippe Kahane, MD, PhD

Anterior Cingulate Epilepsy

Nuria Lacuey, MD

Miami, 15.-17.6.2017

= MRI negative 1

Klinische und elektroenzephalographische Zeichen von supplementärmotorischen Anfällen H.Holthausen in „Anfälle im Schlaf“; Hrsg. K. Meier-Ewert, H. Stefan, Gustav Fischer Verlag Stuttgart, 1995; 103-119 Supplementär-motorische Anfälle (SMA-Anfälle) und supplementär-motorische Epilepsie (SMA-Epilepsie) H. Holthausen, M. Hoppe in „Epilepsie 94“; Hrsg. U. Heinemann; Internationale Liga gegen Epilepsie, Berlin; 1995; 63-73 Präoperative Untersuchungsmethoden und postoperative Ergebnisse bei Patienten mit supplementär-motorischen Anfällen H. Holthausen, I. Tuxhorn, H. Pannek, A. Ebner, M. Hoppe, R. Schulz, F. Oppel, P. in „Aktuelle Neuropädiatrie“; Hrsg. D. Rating, Ciba-Geigy Verlag, Wehr, 1995; 182-195 Lennox-Gastaut-Syndrom (LGS) vs. Sekundäre Bilaterale Synchronie (SBS)

H.Holthausen in„Das anfallskranke Kind“ (11); Hrs. Gunter Groß-Selbeck, edition m+ p Dr.

Werner Rudat & Co. Hamburg, 1999; 77-115

3

The Supplementary Sensori-Motor Area (SSMA) - „History“, Localization and Organization of the SSMA – - SSMA-Seizures and SSMA-Epilepsies –

Hans Holthausen Neuropediatric Clinic and Clinic for Neurorehabilitation -Epilepsy Center for Children and AdolescentsVogtareuth / Germany 4

5

„stimulation of the SMA, or local epileptical discharge within it, produces:“ 1.body movements a) assumption of a posture b) maneuvers or rhythmic movements c) isolated movement of one extremity.“ 6

assumption of a posture

activation of proximal musculus

7

„stimulation may produce:“ 2. vocalization 3. slowing or complete inhibition of voluntary action 4. body sensation 5. pupillary alteration. Penfield and Jasper, 1954 8

Characteristics of SSMA-Seizures

- sudden onset (but frequently after arousal) - short duration - assumption of a posture/ asymmetric tonic - variable consciousness - occuring more in sleep than in wakefulness - relatively high seizure-frequency 9

further Characteristics

- vocalization - motor inhibition (negative motor; not epileptic negative myoclonus!) - somatosensory auras

10

further steps in the delineation of the SSMA

current knowledge about the organization of the SSMA

11

summary of numerous patients

12

13

SSMA as a „sink“for extratemporal seizures

SSMA

SSMA

SSMA-type seizures are frequent – SSMA Epilepsies are rare !!

J Neurol. Sci. 2002 Oct 15; 202 (1-2): 43-52 "Supplementary motor area (SMA) seizure" rather than "SMA epilepsy" in optimal surgical candidates: a document of subdural mapping. Ikeda A, Sato T, Ohara S, Matsuhashi M, Yamamoto J, Takayama M, Matsumoto R, Mikuni N, Takahashi J, Miyamoto S, Taki W, Hashimoto N, Shibasaki H.Department of Brain Pathophysiology, Human Brain Research Center, Shogoin, Sakyo-ku, Kyoto, 6060, Japan. [email protected] CONCLUSION: Among surgical candidates for intractable SMA seizures, frontal cortex other than SMA or even parietal cortex can be epileptogenic, and thus, the SMA itself may not necessarily have to be resected. This notion is clinically important when selecting surgical candidates as well as when planning presurgical invasive evaluation in patients with intractable SMA seizures. Copyright 2002 Elsevier Science B.V.

15

K. F.L., female, age 1 year Age at onset of epilepsy:

2 months

Seizures:

at onset eye-lid myoclonias and loss of contact later versions to the left; asymmetric tonic and myoclonic seizures

Frequency:

several per day 16

17

18

B.T., male

age 2 years

Age at onset of epilepsy:

5 ½ months

Seizures:

asymmetric tonic/ myoclonic

Seizure frequency:

several series per day

19

21

22

Epilepsy surgery in MRI-negative true SSMA Epilepsies

• anecdotical reports of succesfull surgeries but no systematic reports of larger series (no reports separatly from MRI-negative FLE series) • personal experience: - few cases 1990-1998 in Bethel/Bielefeld - none in Vogtareuth ( none in the last 20 years) 23

case report

Patient: P. Kristina, age 9 yearss • previous history: at age 2 years seizures with LOC, and „feeling“ of tension within the body, duration about 30 sec. Seizures at day time and during the night. No response to VPA and PB. • With CBZ seizure free for 4 years 24

case report – cont`d • Relaps at age 7 years, at time when entering school, every morning, usually in the car or while she is walking from the car to the classroom • Description by mother: kind of vertigo for about 15 sec., followed by a „deep breath“, staring, contraction of upper extremities, at times extension of arm and leg of one side (mother could not remember which side) • EEG at time of the consultation: normal (in EEGs at age about 3 years suspicion of „epileptic K´- complexes) • MRI: normal 25

case report – cont`d • DD by colleagues: 1. SSMA-Epilepsy 2. non-epileptic seizures • Interview with Kristina: - is aware of her attacks - is demonstrating that she has brief attacks with contraction of her shoulders Question: do you feel something bevor these attacks ?„Yes, I know when a seizure is coming – I have a sensation in the lower part of my right leg“. Question: does it stay there ? „No, it is raising, then jumping over to the left leg, then raising up and running over the 26 whole body, up to my head“

case report – cont`d • DD:

1. SSMA-Epilepsy 2. non-epileptic seizures Recommendation: withdrawal/reduction of medication and prolonged EEG/Video Monitoring Result: a) asymmetric tonic seizures b) EEG seizure pattern CZ/C3/P3 27

case report – cont`d

DD: 1. SSMA-Epilepsy

2. non-epileptic seizures

Re-evaluation of the MRI

28

possible scenarios after the re-evaluation of the MRI

1. additional tests (PET,SPECT,MSI -> invasive recordings = case will remain a MRInegative case 2. another, even better MRI, evtl postprocessing - > very good chance, that this 29 becomes a MRI-positive case

Small BOSDs are most likely the most frequent cause of MRI-negative SSMA-epilepsies

u

30

Harvey et al. 2015

Arch Neurol, 2009

31

Small BOSDs are most likely the most frequent cause of MRI-negative SSMA-epilepsies

u

32

Post-processing

34

Harvey et al. 2015

Discussion: how lateralizing and localizing are • somatosensory auras ? • motor signs ? • interictal EEGs ? • ictal EEGs ? • ancillary tests ? 39

40

41

42

43

44

Holthausen u. Hoppe, 1994 45

Holthausen u. Hoppe, 1994

46

47

SSMA-Seizures In the initial tonic phase are versions of the eyes and the head and more prominent tonic involvement (elevations) of the extremity(-ies) of one side of the body not absolutly reliable lateralizing signs

48

49

and small children or those with mental retardation do not report auras

EEG in SSMA-Seizures EEG in SSMA-Epilepsies - abnormal pattern outside of the SSMA  most likely SSMA-seizures, but not SSMA-epilepsy - EEG-seizure pattern and sharp waves over the SSMA-area (vertex, central paramedian)  no proof of SSMA-epilepsy, but…….. - interictal EEG often normal - normal ictal EEG does not rule out the possibility of the epileptic nature of the seizures!!

50

51

CED

53

Goldstandard: seizure free outcome

54

Knowlton et al. 2008

55

Knowlton et al.2008

56

Discussion type of invasive recordings • stereo EEG • strips/ grids • combinations

57

10th International Epilepsy Colloquium: The Surgical and Medical Management of Intractable Focal Epilepsy, 15th – 18th June 2017.

LESION NEGATIVE INTRACTABLE EPILEPSY: PRACTICAL CONSIDERATIONS Part 2: Frontal lobe epilepsy – case based discussions Dorsolateral frontal lobe epilepsy François Dubeau, MD Montreal neurological Hospital and Institute McGill University.


Complexity and variety of frontal lobe epilepsy The frontal lobe is a large lobe with extensive connectivity and multiple areas of epileptogenicity; Several gyri and functional regions accounting for the diversity of ictal semiology; Frequent widespread distribution of interictal and ictal epileptiform anomalies. EEG can mimick generalized epilepsy, but EEG can also be normal; Frontal lobe seizure semiology is complex and challenging. The degree of complexity varies according to: 1) the degree of involvement of primary and associative cortices; 2) cortico-cortical and cortico-subcortical interactions; and 3) neuronal synchronization (Bonini et al 2014; Chauvel & McGonigal, 2014).


Dorsolateral frontal lobe epilepsy premotor precentral

ANATOMY

prefrontal

Dorsolateral lobe can be subdivided in:

D D V

Primary motor cortex (area 4);

V

Pre-motor cortex divided in secondary motor cortex (area 6), frontal eye fields (area 8) and language area (areas 44 and 45);

premotor precentral

prefrontal

D

Dorsolateral pre-frontal cortex (areas 9 and 46).

V 8

lateral

9

46

12

44

45

47

medial

medial

9

10

24

25

32

11

13

lateral caudal

medial dorsolateral

ventrolateral

orbitofrontal

14


Dorsolateral frontal lobe epilepsy Seizure semiology from Quesney, Constain and Rasmussen, 1992.

FL seizures are diverse. In a nutshell: Seizures originating in the primary motor cortex usually consist of unilateral motor manifestations with preserved consciousness. Versive seizures (forced head deviation) indicate involvement of premotor cortex. Aphasic seizures indicate involvement of Broca’s language area. Seizures from the prefrontal cortex are often bizarre and complex.


Dorsolateral frontal lobe epilepsy A case presentation 33 yo R-handed man, electrical engineer, with seizures since age 16: •

Obstetrical history was uneventful. No past medical and surgical antecedents. No family history. Normal development and IQ;

•

Seizures started at 16 and rapidly became refractory. Typically, nocturnal or sleep-related, in clusters, of short duration, and followed by immediate recuperation;

•

1o VAP, 2o PTH ( LFTs), 3o CBZ (allergic skin rash), 4o LEV  LEV + GBP  LEV + GBP + PB  LEV + TPM.


Dorsolateral frontal lobe epilepsy A case presentation con’t Seizure semiology 





No aura or vague, poorly defined sensation  arousal  stares briefly, discreet  symmetric tonic posture, bilateral eyes blinking, pout  inconsistent H + E deviation to left. Almost immediate recuperation, goes back to sleep but amnestic for the event in spite of a short duration of 10-20 s. Important fatigue next morning particularly after a cluster. occ. 2ary G. Seizures are frequent, mostly nocturnal, in clusters.


Dorsolateral frontal lobe epilepsy A case presentation of a non-lesional dorsolateral frontal lobe epilepsy? con’t


Dorsolateral frontal lobe epilepsy A case presentation of a non-lesional dorsolateral frontal lobe epilepsy? con’t What’s next?

Surgical Outcomes of Frontal Lobe Resections

Jonathan Miller, MD

Neuropathology of lesion‐negative epilepsy. 10th International Epilepsy Colloquium ABSTRACT Maria Thom UCL Institute of Neurology Department of Neuropathology and Clinical and Experimental Epilepsy There has been a shift in recent years towards a greater proportion of MRI‐negative or non‐lesional focal epilepsies undergoing surgical resection [1]. In a varying proportions of these resections, a well characterised pathology as focal cortical dysplasia (FCD) type II, may ultimately be confirmed on neuropathological examination of the resected tissue [2]. However, it is estimated that in around 8% of cases in surgical series no specific microscopic lesion is identified, with some variation noted between reported series (2 to 26%) [3, 4]. The detection of localised and subtle pathological lesions in the resected material is dependent on appropriate laboratory specimen sampling protocols and adequate immunohistochemistry panels [5], minimising false‐negative rates. On the other hand, for more subtle developmental pathologies including FCD type I and mild malformations of cortical development (MCD), there may be a potential for over‐diagnosis (false‐positives). In particular, there is a lack of a tissue biomarker for FCD I which is based on the determination of cortical dyslamination only, is open to subjective interpretation and acknowledged to be less consistently reported between pathologists compared to FCD II [6]. For mild MCD, there is also a lack of universally agreed pathological criteria [7], in particular for extra‐temporal lobe resections. Nevertheless, new pathological entities and subtle microlesional pathologies continue to be recognised in cases with normal or mildly abnormal MRI [3, 8, 9]. Furthermore in cases lacking a distinct lesion, abnormalities of glial populations, including astroglia, oligodendroglia and myelination [10‐12] as well as inflammatory changes [13] are frequently noted and will continue to move to the forefront to investigate cellular alterations relevant to seizures as well as post‐surgical outcomes. The latter point is pertinent as around half non‐lesional cases will become seizure free. Furthermore, high resolution MRI and quantitative pathology correlative studies demonstrate that even subtle histological differences are potentially detectable in‐vivo [14‐16]. Finally, parallel investigations of molecular tissue alterations will enhance the detection and validation of any microscopic neuropathological abnormality [8, 9, 17]. 1.

Ryvlin, P. and S. Rheims, Predicting epilepsy surgery outcome. Curr Opin Neurol, 2016. 29(2): p. 182‐8.

2. 3.

4. 5.

6. 7. 8. 9. 10.

11. 12.

13. 14. 15.

16. 17.

Shi, J., N. Lacuey, and S. Lhatoo, Surgical outcome of MRI‐negative refractory extratemporal lobe epilepsy. Epilepsy Res, 2017. 133: p. 103‐108. Schurr, J., et al., Mild Malformation of Cortical Development with Oligodendroglial Hyperplasia in Frontal Lobe Epilepsy: A New Clinico‐Pathological Entity. Brain Pathol, 2017. 27(1): p. 26‐35. de Tisi, J., et al., The long‐term outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: a cohort study. Lancet, 2011. 378(9800): p. 1388‐95. Blumcke, I., et al., International recommendation for a comprehensive neuropathologic workup of epilepsy surgery brain tissue: A consensus Task Force report from the ILAE Commission on Diagnostic Methods. Epilepsia, 2016. 57(3): p. 348‐58. Coras, R., et al., Good interobserver and intraobserver agreement in the evaluation of the new ILAE classification of focal cortical dysplasias. Epilepsia, 2012. 53(8): p. 1341‐8. Liu, J.Y., et al., High‐throughput, automated quantification of white matter neurons in mild malformation of cortical development in epilepsy. Acta Neuropathol Commun, 2014. 2: p. 72. Liu, J.Y., et al., Early lipofuscin accumulation in frontal lobe epilepsy. Ann Neurol, 2016. 80(6): p. 882‐895. Dachet, F., et al., Predicting novel histopathological microlesions in human epileptic brain through transcriptional clustering. Brain, 2015. 138(Pt 2): p. 356‐70. Muhlebner, A., et al., Neuropathologic measurements in focal cortical dysplasias: validation of the ILAE 2011 classification system and diagnostic implications for MRI. Acta Neuropathol, 2012. 123(2): p. 259‐72. Scholl, T., et al., Impaired oligodendroglial turnover is associated with myelin pathology in focal cortical dysplasia and tuberous sclerosis complex. Brain Pathol, 2016. Shepherd, C., et al., A quantitative study of white matter hypomyelination and oligodendroglial maturation in focal cortical dysplasia type II. Epilepsia, 2013. 54(5): p. 898‐ 908. Alyu, F. and M. Dikmen, Inflammatory aspects of epileptogenesis: contribution of molecular inflammatory mechanisms. Acta Neuropsychiatr, 2017. 29(1): p. 1‐16. Garbelli, R., et al., Blurring in patients with temporal lobe epilepsy: clinical, high‐field imaging and ultrastructural study. Brain, 2012. 135(Pt 8): p. 2337‐49. Reeves, C., et al., Combined Ex Vivo 9.4T MRI and Quantitative Histopathological Study in Normal and Pathological Neocortical Resections in Focal Epilepsy. Brain Pathol, 2016. 26(3): p. 319‐33. Zucca, I., et al., Type II focal cortical dysplasia: Ex vivo 7T magnetic resonance imaging abnormalities and histopathological comparisons. Ann Neurol, 2016. 79(1): p. 42‐58. Kobow, K. and I. Blumcke, Epigenetics in epilepsy. Neurosci Lett, 2017.

Recognizing insulo‐opercular epilepsy –case discussion Dang K. Nguyen, MD, Ph.D., FRCPC Division of Neurology

Notre‐Dame Hospital Montreal University Health Centre

Disclosure statement • Advisory board UCB, Eisai, Sunovion, Novartis • Honoraria donated to the CHUM Foundation

Plan • Case study 1 • How to suspect IOE : – – – – –

Semiology Surface EEG MRI, MRS Ictal SPECT, Interictal PET MEG/MSI

• Case study 2

Case 1 • • • • •

10 y‐o ambidextrous girl No obvious seizure risk factors Mild language delay Onset of epilepsy: 4 y‐o Predominantly nocturnal once AED introduced • Frequency 2/wk to 10‐15/night despite several AED trials (6)

Semiology • Unpleasant feeling in back, R arm and both legs • ‘Bubbling, spinning’ in her head • Fear, mild agitation, low‐amplitude tremor • ± Pedalling • Aware most of the time

Investigations • MRI: normal • Video‐EEG

Interictal: R T

Interictal: R T‐F‐C

Ictal: R T‐C

…

…

…

…

…

Ictal SPECT

MEG

Genetic testing Heterozygous missense mutation (c.77C>T; p.T26M) in the CHRNB2 gene in the proband and her asymptomatic father. Functional testing: ‐In homozygous condition, increase in current density suggesting a gain of receptor function ‐Testing in heterozygous condition under way

Epilepsy surgery

Basic anatomy

Surbeck W, Bouthillier A, Nguyen DK. Refractory ICE: clinical features, investigation and treatment. Future Neurology 2010; 5(4): 491‐499

Structural connectivity

Ghaziri J, Tucholka A., Girard G., Houde JC, Boucher O., Gilbert G., Descoteaux M, Lippé S., Rainville P, Nguyen DK. Corticocortical structural connectivity of the human insula. Cerebral Cortex 2017; 27(2): 1216‐28.

Connectivity: A‐P gradient

Ghaziri J, Tucholka A., Girard G., Houde JC, Boucher O., Gilbert G., Descoteaux M, Lippé S., Rainville P, Nguyen DK. Corticocortical structural connectivity of the human insula. Cerebral Cortex 2017; 27(2): 1216‐28

A

B

Ghaziri J, Tucholka A., Girard G., Houde JC, Boucher O., Gilbert G., Descoteaux M, Lippé S., Rainville P, Nguyen DK. Corticocortical structural connectivity of the human insula. Cerebral Cortex 2017; 27(2): 1216‐28

Ghaziri J., Tucholka A., Houde J‐C., Girard G., Descoteaux M., Rainville P., Nguyen DK. The subcortical structural connectivity of the human insula (submitted)

Functions

Uddin LQ, Nomi JS, Hebert‐Seropian B., Ghaziri J., Boucher O. Structure and function of the human insula. JCNP 2017 (in press)

Clinical presentation of ICE:

(Penfield, 1955; Isnard J et al., 2000; 2004; Nguyen et al., 2009; Tran et al. 2014)

TLE

VISCEROSENSORY SX ICE FLE

HYPERMOTOR SX

(Ryvlin et al., 2006; Dobesberger et al., 2008; Kaido et al., 2006; Proserpio et al., 2011)

SOMATOSENSORY

PLE

Isnard et al., 2004; Montavont et al., 2015; Nguyen et al. 2009

Other: olfactory, gustatory, auditory, psychic, autonomic Obaid S., Zerouali Y., Nguyen DK. Insular epilepsy: semiology and non‐invasive investigations. JCNP 2017 (in press)

Insular spikes can only be seen when they project to the surface

Levy A., Tran TPY, Boucher O., Bouthillier A., Nguyen DK. OIE: scalp and icEEG findings. JCNP 2017 (in press)

Insular spikes propagation patterns

Zerouali Y., Pouliot P., Robert M., Mohamed I., Bouthillier A., Lesage F., Nguyen DK. MEG signatures of insular epileptic spikes based on functional connectivity. Hum Brain Mapp. 2016; 37(9): 3250‐61.

Scalp interictal EEG in OICE: • Anterior OICE: – Abundant to frequent – FP1/FP2 – F7/F8

• Posterior OICE: – Rare to abundant – T3/T4 ± F7/F8 or T5/T6 or C3/C4 Levy A., Tran TPY, Boucher O, Bouthillier A, Nguyen DK. OIE: scalp and icEEG findings JCNP 2017 (in press)

Non‐invasive investigation of ICE • MRI is the most useful test

Chevrier MC, Bard C, Guilbert F, Nguyen DK. Structural abnormalities in patients with insular/periinsular epilepsy: spectrum, frequency and pharmacoresistance. AJNR 2013; 34(11): 2152‐6

Quantitative MRI

Jamali S., Tucholka A., Leroux JM., Bouthillier A., Nguyen DK. Value of automated cortical thickness analysis in the detection of occult epileptogenic lesions in patients with nonlesional refractory insular cortex epilepsy [abstract]. Epilepsia. 2013;54(Suppl. 3):69.

MRS

Aitouche Y., Gibbs SA, Gilbert G., Boucher O., Bouthillier A., Nguyen DK. 1H‐MRS in patients with nonlesional IE confirmed by icEEG. J Neuroimaging 2017 (in press)

MEG • 2nd most useful test

R Mohamed IS, Gibbs SA, Robert M, Bouthillier A., Leroux JM, Nguyen DK. The utility of MEG in the presurgical evaluation of refractory insular epilepsy. Epilepsia 2013; 54(11): 1950‐9.

Ictal SPECT • 3rd best test – Correctly identified OI focus in 11/17 (65%) – Misleading in 3/17 (18%) – Secondary activation in areas known to be connected to the insula

Fei P., Soucy JP, Obaid S, Boucher O, Bouthillier A, Nguyen DK. The value of SPECT and PET in OIE (submitted)

Interictal SPECT – Concordant with OI focus in 8/17 (47%) – Misleading in 4/17 (24%)

Fei P., Soucy JP, Obaid S, Boucher O, Bouthillier A, Nguyen DK. The value of SPECT and PET in OIE (submitted)

IcEEG/SEEG • Non‐invasive tools can provide additional clues supporting clinical suspicion • Confirmation of insular seizures still requires an icEEG study in many, especially in nonlesional cases

Surbeck W, Bouthillier A, Weil AG, Crevier L, Carmant L, Lortie A, Major P, Nguyen DK. The combination of subdural and depth electrodes for intracranial EEG investigation of suspected insular epilepsy. Epilepsia 2011; 52(3): 458‐66

Invasive EEG recordings

Surbeck W, Bouthillier A, Weil AG, Crevier L, Carmant L, Lortie A, Major P, Nguyen DK. The combination of subdural and depth electrodes for intracranial EEG investigation of suspected insular epilepsy. Epilepsia 2011; 52(3): 458‐66

Case 2 • • • • • •

F, 34A, R‐H Brother with seizures ad 20yo Onset of seizures: 4yo (1yo?) Nocturnal predominance Semiology of nocturnal sz: arousal, howl, agitation Semiology of diurnal sz: anxiety, difficulty breathing, muffled sounds, grips • F = 1‐3/night (peak 40/night) • Failed 10 AED trials

Prior Investigations • MRI: N • EEG: L F‐T spikes

Video‐EEG: L T spikes

R T spikes

Seizure

L T electrical seizure

Diffuse/R T electrical seizures

PET scan

MEG

Genetic testing

Treatment • No surgery • Nicotine patch 7mg 2‐3h before bedtime – No seizures for 3 weeks than recurrence

• Eslicarbazepine

Conclusion • How to suspect/recognize OIE: – Semiology: great mimicker? • Not if you know the role, function and connectivity of the insula

– Non‐invasive tests: • MRI  MEG  SPECT  PET • Scalp EEG: F, T > C, P

– icEEG/SEEG

Acknowledgments • • • • • • • • • • • • • • • •

Alain Bouthillier Ramez Malak Alex Weil Werner Surbeck Daniel Denis Patrice Finet Steve Gibbs Dong Bach Nguyen Olivier Boucher Myriam Irislimane François Lemieux David Mathieu Zorina Ziebenthal David‐Dan Nguyen Mélanie Nguyen Sami Obaid

• • • • • • • • • • • • • • •

Jean‐Maxime Leroux Alan Tucholka Jimmy Ghaziri Sara Jamali Marie‐Claude Chevrier Ismail Mohamed Philippe Pouliot Céline Bard François Guilbert Guillaume Gilbert Isabelle Rouleau Patrick Cossette Pierre Rainville Maxime Descoteaux Younes Zerouali

Recognizing Posterior Cingulate Epilepsy – Case Discussion

Philippe Kahane, MD, PhD

Surgery of the Insulo‐Opercular Complex – Yes We Can

Stephan Chabardes, MD, PhD

6/5/2017

Surgery of the posterior cortex: Does it work and it is safe?

Stefano Francione “Claudio Munari” Epilepsy Surgery Centre Milano – Italy

1

6/5/2017

The “C.Munari Epilepsy Surgery Centre” Clinical Neurophysiology Laura Tassi Stefano Francione Roberto Mai Lino Nobili Ivana Sartori Francesca Gozzo Veronica Pelliccia

Functional Neurosurgery Giorgio Lo Russo Massimo Cossu Francesco Cardinale Laura Castana Giuseppe Casaceli

LT Monitoring Unit Maurizio Rossi Antonio Menna Claudia Vilasi Katrina Sambusida Fabrizio Sandrin

Conflict of Interest Neuroradiology Physicsfrom Dr. FrancioneNeuropathology is consultantNeuropsychology for EISAI Italy Nadia Colombo Carlo Galli Gabriella Bottini Alberto Torresin 2016 to now.Manuela Bramerio Pina Scarpa Alberto Citterio Marco Minella Federica Pelle

Alessio Moscato

2

6/5/2017

Why “posterior cortex”…

42 pts

3

6/5/2017

4

6/5/2017

52 pts (29 “only occipital”)

5

6/5/2017

6

6/5/2017

7

6/5/2017

8

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Theoretical basis “discharge which occurs in the cerebral cortex may produce a wide variety of symptoms or signs, depending on the function of the area in question” “ crise comme un ensemble de signes déterminés essentiellement par une activité paroxystique dynamique à trajectoire le plus souvent multidirectionnelle” ("structure spatiotemporelle de la décharge").

9

6/5/2017

Eye movement control by the cerebral cortex. Pierrot-Deseilligny et al. 2004

10

6/5/2017

Study Population

o

1356 pts operated on from May ’96 to May 13 208 (15.3%) with a resection including an occipital and/or parietal structure (+/- temporal). Adults / Children 125 (60%) / 83 (40%) Males / Females 128 (61.5%) / 80 (38.5%) Age at onset 6.8 yrs (0-33 yrs) Onset < 14 years 190 (91.4%) Onset ≥ 14 years 18 (8.6%) Age at surgery 22.4 yrs (1-60 yrs) Duration of epilepsy 15.5 yrs (0-53 yrs)

o

Seizure frequency :

o

High (≥ 25 seizures/m) Moderate (8-24 seizures/m) Low (≤ 7 seizures/m) Status19 (9%)

o o o o o o o o

o o o

106 (51%) 54 (26%) 48 (23%)

11

6/5/2017

General characteristics o

Family history (epilepsy or FC): + in 28%

o

Personal history: ► Pregnancy: ► Delivery

(peri-natal): ► CNS infections: ► Head trauma: ► Febrile Convulsions:

o

+ in 44.8% 28 pts 37 pts 6 pts 4 pt 8 pts

Neurological examination: ► Lat

somato-sensory: ► Visual Field: ► Ocular motility: ► Other:

+ in 37 (29.6%) 20 14 9 12

pts (+oc mot 6; + vf 2) pts pts pts

12

6/5/2017

Pre-surgical Diagnostic work-up SEEG in F: 50.1% SEEG in T: 14.6%

VEEG monitoring

Detailed anamnesis; o Inter-ictal EEG (+/ictal EEG); o Neuroimaging (CTscan; MRI) o Neuropsychological evaluation; o

74 pts

Stereo-EEG exploration 113 pts

54.3%

Surgery: lesionectomy, Corticectomy +/- lesionectomy 21 pts

13

6/5/2017

MRI MRI Positive -sublobar/lobar -multilobar -multiple Suspicious Negative

179 (86%) 90 82 7 10 (5%) 19 (9%)

14

6/5/2017

Stereo-EEG in 113 pts Ad / Chil

84 (74%) / 29 (26%) SEEG+

41 (43%) / 54 (57%) SEEG-

0.0001

Unilateral in 96 pts; bilateral asymmetric in 17 cases; o 6-19 electrodes per pt (with a mean of 13): o

►9

o

pts with less than 10 electrodes, 29 with more than 15.

Implanted lobes:  2 in 19 pt:  3 in 41 pts:  4 in 33 pts ► POT+C

CP POT

in 20 pts; POT+F in 2pts; PO+FC in 2 pts; PT+FC in

1pt.

 5 in 17 pts

15

6/5/2017

16

6/5/2017

Parietal (+/- PoCG) 59 pts (23.5%)

Temporo-occipital 69 pts (34.2%)

Parieto-occipital 19 pts (9 %)

Resection Topography Occipital 13 pts (6.5%)

Temporo-parietal 13 pts (6.5%)

Temp-par-occipital 45 pts (17.2%)

17

6/5/2017

Adults (107 p)

Children (83 p)

p≤0.05

Seizure frequency High

47

53

Moderate

38

13

Low

22

17

8

10

14

10

40 (37.4%)

19 (22.9%)

Status Morpheic seiz SGS

0.0399

18

6/5/2017

Adults (107 p)

Children (83 p)

p≤0.05

Aura

82

42

Visual

32

27

Somatosensitive

31

5

Psychic

12

8

Viscerosensitive

9

5

Vertiginous

7

2

Cephalic

8

0

Auditive

7

3

29

8

Multiple auras

19

6/5/2017

Adults (107 p)

Children (83 p)

p≤0.05

Seiz pattern Frontal

53

41

Temporal

54

32

0

10

Spasm

0.0002

20

6/5/2017

Conclusions Semeiology: subjective manifestations o

o o o o o

Visual symptoms very important, often lateralised but not always, hall mainly in occipito-temporal, illus mainly in parieto-occipital. Frequent “temporal” symptoms: nausea & vomit. Peculiar, but rare, sensation of ocular movement, sometimes monocular. Possible auditory, vertiginous and somato-sensory hall in case of posterior temporal and inferior parietal. Relatively Frequent: multiple auras, mainly in Parietal Relatively Frequent: absence of subjective manifestations, mainly in Children.

21

6/5/2017

Conclusions Semeiology: objective manifestations o

Ocular movements (+/- head): Really Impressive  Patognomonic, but rare, monocular deviation  Tipical saccadic (oculoclonias)  Controlat dev more frequent in occipital, ipsilateral in parietal, 50/50 in temporal  Possible head/eyes dissociation in parietal

Possible “temporal pattern” o Possible “frontal pattern” o Frequent “spasms” in little children, often with intial ocular component o

22

6/5/2017

57 pts: mean follow-up of 3.3 years. Estimated chance of seizure freedom: -73.1% at 6 postoperative months, - 68.5% at 1 year, - 65.8% at between 2 and 5 years, - 54.8% at 6 years and beyond.

Most recurrences (75%) within first 6 months. Parietal resections worse outcome than occipital or parietooccipital at 5 years): (52% SF vs. 89% and 93%, respectively,

Longitudinal study on seizure outcome following PCE surgery. Well-characterized patients: (1) long-term chances of SF promising, surgical failures can be identified early postop; (2) More aggressive resections optimize chances of SF; (3) Epileptogenicity of the ipsilateral temporal lobe and need for resection; (4) Routine 6 month postoperative EEG may provide useful prognostic information; (5) Language deficits may occur with resections involving the dominant IPL; (6) Further research to evaluate the issue of AED discontinuation following surgery.

23

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Surgical Outcome

9.6 years (2.4-19) follow-up Engel class I (Ia – Ib – Ic - Id) II (IIa - IIb) III IV

145 (69.7%) (119 – 8 - 9 - 9) 21 (10%) (15 - 6) 26 (12.5%) 16 (7.8%)

24

6/5/2017

Post-surgical Deficits Post-op permanent deficits

Visual field

88 (42.3%)

- de-novo HH

41

–de-novo HQ

39

- worsening HQ in HH Neurological

8 1 (0.5%)

25

6/5/2017

Histhology (+1 nd)

Histology FCD:

89 (43%)

-I

- 30

- II

– 50

- III

–9

Tumor:

44 (21%)

-glioneuronal /other

- 41/ 3

Ulegyria

6 (3%)

Scar

7 (3.5%)

Gliosis & non-spec cha 38 (18%) Other

24 (11.5%)

26

6/5/2017

Outcome Children Vs Adults Engel class

Adults (107 pts) Children (83 pts)

I

65 (60.7%)

69 (83%)

(Ia – Ib – Ic - Id)

(47- 4- 7- 7)

(65- 2- 0- 2)

II

17

2

III

17 (1 SUDEP) 7

IV

8

p≤0.05

0.0008

5

27

6/5/2017

Outcome Children Vs Adults AEDS

Adults (107 pts)

Children (83 pts)

p≤0.05

Stopped

19

41

0.0001

Tapered

61

28

24 (1 VNS)

13

3

1

Unchanged Recommenced

28

6/5/2017

Pr og no sti c fa ct or s

Age onset

(meanage in

Engel class I

Engel class not-I p

(145 pts)

(63 pts)

6.55 (0-33)

7.6 (0-27)

0.2754 (ns)

0.1678 (ns)

years) Age onset:

Yes

75

24

0-5 years

No

215

102

Age onset:

Yes

70

39

> 6 years

No

75

24

Age surgery

(mean age in yrs) 20.68 (1-60)

26.3 (3-53)

0.0055

Surgery child(≤

Yes

69

14

0.0007

16yrs)

No

76

49

Dur epilepsy

(mean dur in yrs)

14.17 (0-53)

18.69 (2-44)

0.0084

Dur epilepsy

Yes

80

49

0.0019

> 10 years

No

65

14

Dur epilepsy

Yes

27

10

5-10 years

No

118

53

Dur epilepsy

Yes

38

4

< 5 yrs

No

107

59

0.0962 (ns)

0.6972 (ns)

0.0007

29

6/5/2017

Conclusions……. o

Not episodical kind of surgery: 15.3 %.

o

Often requiring invasive recordings: 55%, lowering year by year.

o

Frequently multilobar: 70 %.

o

Possible good post-operative results, mainly in temporo-occipital and occipital localization.

o

Seizure outcome and “drug-outcome” significantly better in children than adults

o

Duration of Epilepsy: really

important

30

Louis Maillard, PhD SEEG in Polymicrogyria‐related‐epilepsy: should we? When and how? Polymicrogyria (PMG) is a common cortical malformation. Although the majority of PMG patients present with epilepsy, two-thirds of them with a refractory course, epilepsy surgery and SEEG exploration are rarely considered and their clinical relevance remain unclear. To address this question, we report here the preliminary results of a retrospective multicentric study that aimed to 1) assess the concordance between a variety of PMG types and their epileptogenic zone, as defined by stereo-encephalography (SEEG), and 2) to determine the postsurgical seizure outcome in patients with PMG-related refractory epilepsy, in order to identify optimal surgical candidates. We retrospectively analysed 58 patients with PMG-related refractory epilepsy from 11 tertiary epilepsy centres: 49 had SEEG evaluation and 39 underwent curative epilepsy surgery. Mean age at seizure onset was 11 years (range 0.1-36) and mean age at SEEG or surgery was 28.3 years (range 2-50). PMG was bilateral in 8 patients and unilateral in 50: 19 (33%) unilobar, 19 (33%) perisylvian, 15 (26%) multilobar, and only 5 (9%) hemispheric. Twenty-two (38%) patients additionally had a schizencephaly, heterotopia or focal cortical dysplasia. The SEEG-delineated epileptogenic zone was fully concordant with the PMG in only 8 (16%) cases. The epileptogenic zone was partially concordant in 74% and discordant in 10%. The epileptogenic zone included remote cortical areas in 21 (43%) and localized predominantly in those in 5 (10%) cases, all related to the mesial temporal structures. Only unilateral PMG patients underwent resective surgery. At last follow-up (mean 4.6 years, range 1-16), 28 (72%) patients remained seizure free; 9 were off antiepileptic drugs. Shorter epilepsy duration to surgery was identified as an independent predictor of seizure freedom. Our study demonstrates that PMG-associated refractory epilepsy warrants a comprehensive presurgical evaluation, including SEEG investigations in the majority of cases, in order to accurately delineate the EZ. SEEG is indeed essential for guiding tailored resections, since the EZ may only partly overlap with the PMG or include only remote cortical areas. Favourable results in terms of seizure freedom and antiepileptic drug cessation are feasible in a large proportion of patients and PMG extent should not deter from exploring the possibility of epilepsy surgery. Finally, our data supports the early consideration of epilepsy surgery in patients with PMG-related refractory epilepsy.

Invasive evaluation of hemispheric malformations – Can we? Pr Sylvain Rheims Department of Functional Neurology and Epileptology, Hospices Civils de Lyon and Lyon’s University, Lyon, France Lyon’s Neuroscience Research Center, INSERM 1028, CNRS UMR5292

Among the novel epilepsy surgery indications and/or approaches that have emerged during the past 10 years, one growing concept is that successful epilepsy surgery outcome can be achieved in some patients with MRI abnormalities that are more widespread than the region that can be safely resected, including patients with hemispheric malformations (1). This concept has primarily been demonstrated in early-onset catastrophic epilepsies which can be successfully treated by surgery in the presence of a definitive localized or lateralized brain lesion despite generalized semiology and EEG abnormalities (2). Similarly, in tuberous sclerosis with many lesions or multifocal cortical dysplasia investigation with invasive recordings in order to determine and eventually resect the most epileptogenic lesion can lead to seizure control (3). One important aspect in these patients with large cortical malformation is that the extension of the epileptogenic zone is not necessarily as large as anatomical abnormalities. In these patients, a partial resection of the malformation can result in a complete resection of the epileptogenic zone. This situation has been reported in patients with unilateral or bilateral polymicrogyria in whom a limited resection guided intracerebral EEG may lead to a significant improvement or recovery (4). Furthermore, it has been that, even in the absence of hippocampal MRI abnormality, ictal symptoms compatible with a temporal origin of seizures should be considered as a reliable indicator for surgery eligibility regardless of MRI lesion size. These patients should not be excluded a priori from invasive exploration and surgical treatment, even if a large portion of their lesion is likely to be left in place after surgery (5).

1. 2. 3. 4. 5.

Ryvlin P, Cross JH, and Rheims S. Epilepsy surgery in children and adults. Lancet Neurol 2014;13:1114-26. Wyllie E, Lachhwani DK, Gupta A, et al. Successful surgery for epilepsy due to early brain lesions despite generalized EEG findings. Neurology 2007;69:389-97. Fauser S, Sisodiya SM, Martinian L, et al. Multi-focal occurrence of cortical dysplasia in epilepsy patients. Brain 2009;132:2079-90. Ramantani G, Koessler L, Colnat-Coulbois S, et al. Intracranial evaluation of the epileptogenic zone in regional infrasylvian polymicrogyria. Epilepsia 2013;54:296-304. Catenoix H, Montavont A, Isnard J, et al. Mesio-temporal ictal semiology as an indicator for surgical treatment of epilepsies with large multilobar cerebral lesions. Seizure 2013;22:37883.

Combining SEEG and Grids – Can We Do This?

Nitin Tandon, MD

Case Discussions

Susan Arnold, MD

Impact of genetic findings in epilepsy surgery Karl Martin Klein EPILEPSY CENTER FRANKFURT RHINE-MAIN Goethe University Frankfurt

Impact of genetic findings in epilepsy surgery ■ ■

■

Overview epilepsy genetics Epilepsy surgery ■

Genetic structural epilepsy

■

Epileptic encephalopathy

■

Focal epilepsy

Pitfalls

Genetics of Epilepsy Monogenic Epilepsy

Helbig and Tayoun Mol Syndromol 2016

Epilepsy surgery in genetic epilepsies ■

■

Presurgical evaluation may not suggest surgical approach ■

Gene mutation does not influence decision for surgery

■

May prevent invasive investigations

Presurgical evaluation may suggest surgical approach ■

Outcome with known gene mutation?

How much does the genetic information add?

Genetic structural epilepsy

Genetic structural epilepsy ■

Example: Tuberous sclerosis TSC1/TSC2

■

Often multiple lesions Video EEG monitoring to identify epileptogenic lesion Epilepsy surgery may be possible depending on results

■ ■

Kivelev et al. Neurosurgery 2009, Arya et al. J Neurosurg Pediatr 2015

Epilepitic encephalopathy

Epileptic encephalopathy ■

Definition: “Epileptic activity itself contributes to severe cognitive and behavioral impairments above and beyond what might be expected from the underlying pathology alone”

■

De novo mutations in 10-50% ■

Particularly in severe non-lesional cases with early onset

Berg et al. Epilepsia 2010, McTague et al. Lancet Neurology 2016, Helbig et al. Genetics in Medicine 2016

Dravet syndrome ■

Onset T; p.Ala1255Val (het.)

Genetic epilepsy with febrile seizures plus (GEFS+)

■

■

Multiple phenotypes ■

Febrile seizures

■

Febrile seizures plus

■

Genetic (idiopathic) generalized epilepsy

■

Focal epilepsy (including TLE ± HS)

Mutations in SCN1A, SCN1B, SCN2A, GABRG2 Scheffer and Berkovic Brain 1997

Epilepsy surgery in GEFS+ R ATL (Engel IIa, ILAE 3) ■ ■

TLE+HS SCN1A

■

Seizure free for 2 yrs Then infrequent GTCS Seizures controlled after optimization of medication

TLE+HS SCN1B

R ATL (Engel Ib, ILAE 2)

lesion-negative TLE SCN1B

R ATL (Engel Ia, ILAE 1)

■

■

Infrequent psychic aura (follow-up 3 yrs)

Seizure free (follow-up 2 yrs)

Abou-Khalil et al. Neurology 2001, Scheffer et al. Brain 2007

Epilepsy surgery in GEFS+ ■

Patient mit febrile seizures and structural epilepsy after head trauma ■

SCN1A mutation

■

EEG ■ Interictal: no IED ■ Ictal: Left frontal seizure onset (1x), non-localized (1x)

■

MRI: left frontal posttraumatic lesion, HS

■

Left frontal lesionectomy ■ Outcome: Engel IVb, ILAE 5 (follow-up 18 mths) Skjei et al. J Neurosurg Pediatr 2015

Case – 37yo female patient ■

■ ■

Epilepsy surgery in GEFS+ ■

Evidence weak

■

No contraindication

Second resection (left ATL) Outcome: infrequent nocturnal seizures, no GTCS (Engel IId, ILAE 3)

Familial focal epilepsy with variable foci (FFEVF) ■ ■

■

Autosomal dominant Location of epileptogenic zone ■

Different between family members

■

Constant during life

Mutations in GATOR1 complex (mTOR pathway) ■

DEPDC5

■

NPRL2

■

NPRL3

Scheffer et al. Ann Neurol 1998, Klein et al. Epilepsia 2012, Dibbens et al. Nature Genetics 2013, Ricos et al. Ann Neurol 2016, Sim et al. Ann Neurol 2016, Korenke et al. Epilepsia 2016, Weckhuysen et al. Epilepsia 2016

Additional studies DEPDC5 DEPDC5-

Studie

Phänotyp

Dibbens et al. Nature Genetics 2013

Familial focal epilepsy with variable foci Familial focal epilepsy

7/8 10/82

Ishida et al. Nature Genetics 2013

Autosomal dominant focal epilepsy (FFEVF, ADNFLE, FTLE)

6/16

Martin et al. Clinical Genetics 2013

Focal epilepsy (mostly familial)

4/79

Mutationen

Lal et al. Annals of Neurology 2014

Rolandic epilepsy

3/207

Unclassified childhood focal epilepsy

3/82

Picard et al. Neurology 2014

Autosomal dominant nocturnal frontal lobe epilepsy

4/30

Carvill et al. Neurol Genet 2015

Epileptic spasms

3/130

Tsai et al. 2016

Sporadic non-lesional focal epilepsy

2/220

DEPDC5 most frequent gene in focal epilepsy

Function GATOR1 mTORC1 GATOR1 DEPDC5 NPRL2 NPRL3

modified from Shimobayashi et al. Nature Reviews 2014 Bar-Peled et al. Science 2013

Australian family: 3T-MRT

Cortical dysplasia results from disinhibition of mTOR pathway due to GATOR1 mutations Scheffer et al. Annals of Neurology 2014

Epilepsy surgery in FFEVF

Weckhuysen et al.

Baulac et al.

Study

Mutation

Localisation

Histology

DEPDC5

R frontal

FCD I (?)

DEPDC5

L insular

FCD IIa

DEPDC5

R frontal

FCD IIa

DEPDC5

R zentral

?

DEPDC5

L precentral

?

Complete resection

2nd

Outcome Engel

ILAE

Followup

Ia

1

13 yrs

Ia

1

4 yrs

Ia

1

7 yrs

-

IIIa

4

N/A

-

IVb

5

N/A

+ + surgery +

L frontal+insular, FCD IIa +(?) Epilepsy surgery is an optionId in 3 L temporal (+HS) 2 surgery medication-resistant focal epilepsies due to GATOR1 mutations NPRL2 R frontal+insular FCD I IIIa 4

NPRL3

nd

9 yrs

N/A

Baulac et al. Annals of Neurology 2015, Weckhuysen et al. Epilepsia 2016

Autosomal dominant epilepsy with auditory features

7

3

3

Epilepsy with auditory aura 4

3

2

Epilepsy with visual aura

5

Epilepsy with vertiginous aura

Epilepsy surgery?

Epilepsy without known focal features Unclassified

3

4

Israeli-Palestinian Epilepsy Family Consortium Klein et al. J Neurol 2016

LGI1 sequencing (chr 10)

7 m/-

-/-

3

3

m/-

m/-

m/-

5

4

m/-

-/-

m/-

-/-

m/-

3

3

-/-

m/-

Epilepsy with auditory aura Epilepsy with visual aura

2 m/-

m/-

Epilepsy with vertiginous aura

phenocopy

Epilepsy without known focal features Unclassified

-/-

4

■

Heterozygeous LGI1 mutation (exon 6, c.641T>C, p.L214P)

■

SIFT: deleterious (0)

■

PolyPhen2: probably damaging (0.953)

Autosomal dominant epilepsy with auditory features

7

3

3

Epilepsy with auditory aura 5

Epilepsy with visual aura

4

3

2

Epilepsy with vertiginous aura Epilepsy without known focal features Unclassified

4

Histology: focal cortical dysplasia (FCD) type IIA Outcome: seizure free

3

Summary – Impact of genetic findings in epilepsy surgery ■

Epileptic encephalopathy ■ Often no resective strategy possible ■

■

Poor outcome in Dravet syndrome

Genetic structural epilepsy (TSC1, TSC2, DEPDC5, NPRL2, NPRL3) ■

■

GEFS+ ■

■

Epilepsy surgery may be possible No contraindications in patients with SCN1A/1B mutations and TLE

Caveat: Phenocopies, variants of unknown significance

1

Psychiatric Comorbidities in Treatment-Resistant Focal Epilepsy: A complex relationship with significant clinical implications. Andres M. Kanner, MD, FANA, FAAN, FAES Professor of Clinical Neurology Director, Comprehensive Epilepsy Center and Chief, Epilepsy Division Department of Neurology, University of Miami, Miller School of Medicine.

Psychiatric comorbidities and treatment-resistant epilepsy have a complex relation, the magnitude and clinical implications of which are yet to be properly recognized by epileptologists. Given the theme of this colloquium, this presentation will focus on the relations between psychiatric comorbidities and treatment-resistant focal epilepsy (TRFE). We will review the impact that psychiatric comorbidities have on the pharmacologic and surgical treatments of TRFE, with special attention to the complex psychiatric aspects of epilepsy surgery and will highlight some of the clinical manifestations of psychiatric comorbidities that are unique to TRFE, which have a negative impact on the life of patients. A. Do psychiatric disorders predict the development of TRFE? Psychiatric comorbidities are frequent in patients with TRFE, with mood and anxiety disorders being the most frequently identified in adults, while Attention Deficit Hyperactivity Disorders is the comorbidity most often recognized in children with TRFE. Psychotic disorders are also significantly more frequent in patients with TRFE than in the general population. Typically, psychiatric comorbidities are considered to be a complication and /or consequence of the TRFE. Yet recent studies have actually suggested that a psychiatric history, particularly depression and anxiety disorders preceding the onset of the seizure disorder increases the risk of developing TRFE in patients with newly diagnosed epilepsy. Accordingly, there appears to be a “bidirectional” relation between TRFE and psychiatric comorbidities. B. Impact of psychiatric comorbidities on the management of TRFE: B. 1 Pharmacologic management Psychiatric comorbidities affect the pharmacologic management of TRFE at several levels, which include: 1) An increased risk of poor AED tolerance, presenting as medical, neurologic and psychiatric adverse events. The risk of iatrogenic psychiatric adverse events associated with a past and /or current psychiatric histories (and / or family psychiatric history) must play a pivotal role in the prescription and /or discontinuation of AEDs with positive and negative psychotropic properties. 2) Interference with AED compliance of AEDs, which can worsen the seizure frequency and severity. B.2 Surgical treatment of TRFE Psychiatric aspects of epilepsy surgery are complex and present in various forms which include:

2 1) 2) 3) 4)

A worsening and /or recurrence of presurgical psychiatric comorbidities. The development of de-novo psychiatric comorbidities. The remission of presurgical psychiatric comorbidities after epilepsy surgery. A lower probability of achieving complete seizure-freedom among patients with a presurgical history of psychiatric comorbidities.

Here is some of the evidence: 1) Worsening and /or recurrence of presurgical psychiatric comorbidities: - A presurgical history of mood and anxiety disorders is associated with an increased risk of post-surgical mood and anxiety episodes during the first three to 6 months after surgery. - Presurgical personality disorders are associated with an increased risk of post-surgical psychotic episodes. 2) The development of de-novo psychiatric comorbidities Between 15% to 20% of patients who undergo a temporal lobectomy can develop de-novo mood and anxiety disorders and approximately 5 to 10%, de-novo psychotic disorders. Furthermore, a family history of psychosis has been associated with the increased risk of post-surgical psychosis. 3) The remission of presurgical psychiatric comorbidities after epilepsy surgery Temporal lobectomies in adults with presurgical mood and anxiety disorders have resulted in their remission post-surgically in 30% to 50% of patients. 4) A lower probability of achieving complete seizure-freedom among patients with a presurgical history of psychiatric comorbidities Presurgical mood, psychotic and personality disorders have been associated with a worse post-surgical seizure outcome of antero-temporal lobectomies, and this effect is more obvious among patients with a personality disorder AND one of the Axis I psychiatric disorders. C. Clinical manifestations of psychiatric comorbidities unique to TRFE: These include postictal psychiatric symptoms, postictal psychiatric episodes and alternative psychopathology, which remain in a large part under-recognized by clinicians. C.1 Postictal psychiatric symptoms are relatively frequent in patients with TRFE, but rarely investigated in their evaluation. These symptoms typically appear following a symptom-free period ranging from a few hours to up to seven days after a seizure (cluster of seizures), making often the temporal relation between psychiatric and ictal phenomena challenging to recognize. Postictal symptoms of depression and anxiety are the most frequently reported symptoms, identified in more than 40% of patients with TRFE, suicidal ideation in close to 15% and psychotic symptoms in close to 10%. Their duration can range from a few hours to several weeks with median duration in most symptoms of about 24 hours. Of note, postictal symptoms of depression and anxiety do not remit with psychotropic medications.

3

When several postictal psychotic symptoms cluster, they present as postictal psychotic episodes, which have been found to have a yearly incidence of close to 8% in patients with TRFE evaluated for epilepsy surgery. In contrast to postictal symptoms of depression and anxiety, postictal psychotic symptoms and episodes respond to low doses of antipsychotic medications, which need to be used for a few days only. However, in close to 15% of these patients, interictal psychotic episodes can develop overtime. Of note, the presence of postictal psychotic episodes should serve as a redflag for the possibility of bilateral independent ictal foci and the presurgical evaluation should be planned to rule-in or rule-out this possibility. C.2 Alternative psychopathology is the other form of psychiatric phenomena that are unique to TRFE. They present as alternative psychotic and /or depressive episodes, but can also occur in other forms of treatment-resistant epilepsy. This phenomenon is also referred as “forced normalization” and has been identified in approximately 1% of patients with treatment resistant epilepsy after seizures stop following the introduction of certain AEDs (e.g., ethosuximide, clobazam, vigabatrin). Of note, the development of de-novo psychosis following epilepsy surgery has been proposed as a form of this phenomenon. D. Impact of psychiatric comorbidities on the life of patients with TRFE: In patients with TRFE, comorbid depression and /or anxiety disorders have been identified, together with AED toxicity as the two sets of variables that have the greatest impact on the poor quality of life of these patients, beyond that of the seizure frequency and / or severity. A comorbid mood and /or anxiety disorder have been associated with an increased risk of premature death from external causes and from suicide. E. Treatment of psychiatric comorbidities in TRFE Despite the relatively high prevalence and the very negative impact of psychiatric comorbidities in patients with TRFE, they remain under-recognized and under-treated. One of the fears has been the potential worsening of seizures by psychotropic drugs. Yet, with very few exceptions, psychotropic drugs are safe in patients with TRFE when used at therapeutic doses. On the other hand, psychotropic drugs may have pharmacokinetic and pharmacodynamic interactions with AEDs that clinicians need to factor-in to avoid drug toxicity

Neuropsychological Assessment – What’s Changed?

Philip Fastenau, PhD

Case Discussions

Naira Garcia, MD

Bring Your Own Cases

Panelists Prasanna Jayakar, MD, PhD; Felix Rosenow, MD; Nitin Tandon, MD; Louis Maillard, MD, PhD; Philippe Kahane, MD, PhD