Experience of the Gamma-Knife Center of Rabat. About 10 Cases

KINGDOM OF MOROCCO MOHAMMED V UNIVERSITY OF RABAT FACULTY OF MEDICINE AND PHARMACY RABAT

Year : 2019 Thesis N°: 512

Gamma-knife radiosurgical treatment of epilepsy : Experience of the gamma-knife center of rabat. About 10 cases

THESIS Publicly submitted and defended on the : / /2019

BY Mrs. Hajar EL OUARTASSI Born on November 28th, 1992 in Rabat Intern at University Hospital Center IBN SINA, Rabat

FOR THE DEGREE OF

Doctor of Medicine

Key Words : Epilepsy; Functional Radiosurgery; Leksell Gamma-Knife Surgery

Jury:

Mr. Yasser ARKHA President Professor of Neurosurgery Mr. Adyl MELHAOUI Director Professor of Neurosurgery Mrs. Mahjouba BOUTARBOUCH Member Professor of Neurosurgery Mrs. Yamna KRIOUILE Member Professor of Pediatrics Mrs. Wafa REGRAGUI Member Professor of Neurology

سبحانك ال علم لنا إال ما علمتنا إنك أنت العليم الحكيم

MOHAMMED V DE RABAT FACULTE DE MEDECINE ET DE PHARMACIE - RABAT

DOYENS HONORAIRES :

1962 – 1969 : Professeur Abdelmalek FARAJ 1969 – 1974 : Professeur Abdellatif BERBICH 1974 – 1981 : Professeur Bachir LAZRAK 1981 – 1989 : Professeur Taieb CHKILI 1989 – 1997 : Professeur Mohamed Tahar ALAOUI 1997 – 2003 : Professeur Abdelmajid BELMAHI 2003 - 2013 : Professeur Najia HAJJAJ – HASSOUNI

ADMINISTRATION : Doyen Professeur Mohamed ADNAOUI Vice-Doyen chargé des Affaires Académiques et estudiantines Professeur Brahim LEKEHAL Vice-Doyen chargé de la Recherche et de la Coopération Professeur Toufiq DAKKA Vice-Doyen chargé des Affaires Spécifiques à la Pharmacie Professeur Jamal TAOUFIK Secrétaire Général Mr. Mohamed KARRA

1 - ENSEIGNANTS-CHERCHEURS MEDECINS ET PHARMACIENS

PROFESSEURS : DECEMBRE 1984 Pr. MAAOUNI Abdelaziz Médecine Interne – Clinique Royale Pr. MAAZOUZI Ahmed Wajdi Anesthésie -Réanimation Pr. SETTAF Abdellatif Pathologie Chirurgicale

NOVEMBRE ET DECEMBRE 1985 Pr. BENSAID Younes Pathologie Chirurgicale

JANVIER, FEVRIER ET DECEMBRE 1987

Pr. LACHKAR Hassan Médecine Interne Pr. YAHYAOUI Mohamed Neurologie

DECEMBRE 1989 Pr. ADNAOUI Mohamed Médecine Interne –Doyen de la FMPR Pr. OUAZZANI Taïbi Mohamed Réda Neurologie

JANVIER ET NOVEMBRE 1990 Pr. HACHIM Mohammed* Médecine-Interne Pr. KHARBACH Aîcha Gynécologie -Obstétrique Pr. TAZI Saoud Anas Anesthésie Réanimation

FEVRIER AVRIL JUILLET ET DECEMBRE 1991

Pr. AZZOUZI Abderrahim Anesthésie Réanimation- Doyen de FMPO Pr. BAYAHIA Rabéa Néphrologie Pr. BELKOUCHI Abdelkader Chirurgie Générale Pr. BENCHEKROUN Belabbes Abdellatif Chirurgie Générale Pr. BENSOUDA Yahia Pharmacie galénique Pr. BERRAHO Amina Ophtalmologie Gynécologie Obstétrique Méd. Chef Maternité des Pr. BEZAD Rachid Orangers Pr. CHERRAH Yahia Pharmacologie Pr. CHOKAIRI Omar Histologie Embryologie Pr. KHATTAB Mohamed Pédiatrie Pr. SOULAYMANI Rachida Pharmacologie- Dir. du Centre National PV Rabat Pr. TAOUFIK Jamal Chimie thérapeutique V.D à la pharmacie+Dir. du CEDOC + Directeur du Médicament DECEMBRE 1992 Pr. AHALLAT Mohamed Chirurgie Générale Doyen de FMPT Pr. BENSOUDA Adil Anesthésie Réanimation Pr. CHAHED OUAZZANI Laaziza Gastro-Entérologie Pr. CHRAIBI Chafiq Gynécologie Obstétrique Pr. EL OUAHABI Abdessamad Neurochirurgie Pr. FELLAT Rokaya Cardiologie

Pr. GHAFIR Driss* Médecine Interne Pr. JIDDANE Mohamed Anatomie Pr. TAGHY Ahmed Chirurgie Générale Pr. ZOUHDI Mimoun Microbiologie MARS 1994 Pr. BENJAAFAR Noureddine Radiothérapie Pr. BEN RAIS Nozha Biophysique Pr. CAOUI Malika Biophysique Endocrinologie et Maladies Métaboliques Doyen de la Pr. CHRAIBI Abdelmjid FMPA Pr. EL AMRANI Sabah Gynécologie Obstétrique Pr. EL BARDOUNI Ahmed Traumato-Orthopédie Pr. EL HASSANI My Rachid Radiologie Pr. ERROUGANI Abdelkader Chirurgie Générale – Directeur du CHIS-Rabat Pr. ESSAKALI Malika Immunologie Pr. ETTAYEBI Fouad Chirurgie Pédiatrique Pr. HASSAM Badredine Dermatologie Pr. IFRINE Lahssan Chirurgie Générale Pr. MAHFOUD Mustapha Traumatologie – Orthopédie Pr. RHRAB Brahim Gynécologie –Obstétrique Pr. SENOUCI Karima Dermatologie MARS 1994 Pr. ABBAR Mohamed* Urologie Directeur Hôpital My Ismail Meknès Pr. ABDELHAK M’barek Chirurgie – Pédiatrique Pr. BENTAHILA Abdelali Pédiatrie Pr. BENYAHIA Mohammed Ali Gynécologie – Obstétrique Pr. BERRADA Mohamed Saleh Traumatologie – Orthopédie Pr. CHERKAOUI Lalla Ouafae Ophtalmologie Pr. LAKHDAR Amina Gynécologie Obstétrique Pr. MOUANE Nezha Pédiatrie MARS 1995 Pr. ABOUQUAL Redouane Réanimation Médicale Pr. AMRAOUI Mohamed Chirurgie Générale Pr. BAIDADA Abdelaziz Gynécologie Obstétrique Pr. BARGACH Samir Gynécologie Obstétrique Pr. DRISSI KAMILI Med Nordine* Anesthésie Réanimation Pr. EL MESNAOUI Abbes Chirurgie Générale Pr. ESSAKALI HOUSSYNI Leila Oto-Rhino-Laryngologie Pr. HDA Abdelhamid* Cardiologie Inspecteur du Service de Santé des FAR Pr. IBEN ATTYA ANDALOUSSI Ahmed Urologie Pr. OUAZZANI CHAHDI Bahia Ophtalmologie Pr. SEFIANI Abdelaziz Génétique

Pr. ZEGGWAGH Amine Ali Réanimation Médicale DECEMBRE 1996 Pr. AMIL Touriya* Radiologie Pr. BELKACEM Rachid Chirurgie Pédiatrie Pr. BOULANOUAR Abdelkrim Ophtalmologie Pr. EL ALAMI EL FARICHA EL Hassan Chirurgie Générale Pr. GAOUZI Ahmed Pédiatrie Pr. MAHFOUDI M’barek* Radiologie Pr. OUZEDDOUN Naima Néphrologie Pr. ZBIR EL Mehdi* Cardiologie DirecteurHôp.Mil. d’Instruction Med V Rabat NOVEMBRE 1997 Pr. ALAMI Mohamed Hassan Gynécologie-Obstétrique Pr. BEN SLIMANE Lounis Urologie

Pr. BIROUK Nazha Neurologie

Pr. ERREIMI Naima Pédiatrie Pr. FELLAT Nadia Cardiologie Pr. KADDOURI Noureddine Chirurgie Pédiatrique Pr. KOUTANI Abdellatif Urologie Pr. LAHLOU Mohamed Khalid Chirurgie Générale Pr. MAHRAOUI CHAFIQ Pédiatrie Pr. TOUFIQ Jallal Psychiatrie Directeur Hôp.Ar-razi Salé Pr. YOUSFI MALKI Mounia Gynécologie Obstétrique NOVEMBRE 1998 Pr. BENOMAR ALI Neurologie Doyen de la FMP Abulcassis Pr. BOUGTAB Abdesslam Chirurgie Générale Pr. ER RIHANI Hassan Oncologie Médicale Pr. BENKIRANE Majid* Hématologie JANVIER 2000 Pr. ABID Ahmed* Pneumo-phtisiologie Pr. AIT OUAMAR Hassan Pédiatrie Pr. BENJELLOUN Dakhama Badr.Sououd Pédiatrie Pr. BOURKADI Jamal-Eddine Pneumo-phtisiologie Directeur Hôp. My Youssef Pr. CHARIF CHEFCHAOUNI Al Montacer Chirurgie Générale Pr. ECHARRAB El Mahjoub Chirurgie Générale Pr. EL FTOUH Mustapha Pneumo-phtisiologie Pr. EL MOSTARCHID Brahim* Neurochirurgie Pr. MAHMOUDI Abdelkrim* Anesthésie-Réanimation Pr. TACHINANTE Rajae Anesthésie-Réanimation

Pr. TAZI MEZALEK Zoubida Médecine Interne

NOVEMBRE 2000 Pr. AIDI Saadia Neurologie Pr. AJANA Fatima Zohra Gastro-Entérologie

Pr. BENAMR Said Chirurgie Générale Pr. CHERTI Mohammed Cardiologie Pr. ECH-CHERIF EL KETTANI Selma Anesthésie-Réanimation Pr. EL HASSANI Amine Pédiatrie - Directeur Hôp.Cheikh Zaid Pr. EL KHADER Khalid Urologie Pr. EL MAGHRAOUI Abdellah* Rhumatologie Pr. GHARBI Mohamed El Hassan Endocrinologie et Maladies Métaboliques Pr. MDAGHRI ALAOUI Asmae Pédiatrie Pr. ROUIMI Abdelhadi* Neurologie DECEMBRE 2000 Pr.ZOHAIR ABDELLAH * ORL Pr. BALKHI Hicham* Anesthésie-Réanimation Pr. BENABDELJLIL Maria Neurologie Pr. BENAMAR Loubna Néphrologie Pr. BENAMOR Jouda Pneumo-phtisiologie Pr. BENELBARHDADI Imane Gastro-Entérologie Pr. BENNANI Rajae Cardiologie Pr. BENOUACHANE Thami Pédiatrie Pr. BEZZA Ahmed* Rhumatologie Pr. BOUCHIKHI IDRISSI Med Larbi Anatomie Pr. BOUMDIN El Hassane* Radiologie Pr. CHAT Latifa Radiologie Pr. DAALI Mustapha* Chirurgie Générale Pr. DRISSI Sidi Mourad* Radiologie Pr. EL HIJRI Ahmed Anesthésie-Réanimation Pr. EL MAAQILI Moulay Rachid Neuro-Chirurgie Pr. EL MADHI Tarik Chirurgie-Pédiatrique Pr. EL OUNANI Mohamed Chirurgie Générale Pr. ETTAIR Said Pédiatrie - Directeur Hôp. d’EnfantsRabat Pr. GAZZAZ Miloudi* Neuro-Chirurgie Pr. HRORA Abdelmalek Chirurgie Générale Pr. KABBAJ Saad Anesthésie-Réanimation Pr. KABIRI EL Hassane* Chirurgie Thoracique Pr. LAMRANI Moulay Omar Traumatologie Orthopédie Pr. LEKEHAL Brahim Chirurgie Vasculaire Périphérique Pr. MAHASSIN Fattouma* Médecine Interne Pr. MEDARHRI Jalil Chirurgie Générale Pr. MIKDAME Mohammed* Hématologie Clinique Pr. MOHSINE Raouf Chirurgie Générale Pr. NOUINI Yassine Urologie - Directeur Hôpital Ibn Sina Pr. SABBAH Farid Chirurgie Générale Pr. SEFIANI Yasser Chirurgie Vasculaire Périphérique

Pr. TAOUFIQ BENCHEKROUN Soumia Pédiatrie

DECEMBRE 2002 Pr. AL BOUZIDI Abderrahmane* Anatomie Pathologique Pr. AMEUR Ahmed * Urologie Pr. AMRI Rachida Cardiologie Pr. AOURARH Aziz* Gastro-Entérologie Pr. BAMOU Youssef * Biochimie-Chimie Pr. BELMEJDOUB Ghizlene* Endocrinologie et Maladies Métaboliques Pr. BENZEKRI Laila Dermatologie Pr. BENZZOUBEIR Nadia Gastro-Entérologie Pr. BERNOUSSI Zakiya Anatomie Pathologique Pr. BICHRA Mohamed Zakariya* Psychiatrie Pr. CHOHO Abdelkrim * Chirurgie Générale Pr. CHKIRATE Bouchra Pédiatrie Pr. EL ALAMI EL Fellous Sidi Zouhair Chirurgie Pédiatrique Pr. EL HAOURI Mohamed * Dermatologie Pr. FILALI ADIB Abdelhai Gynécologie Obstétrique Pr. HAJJI Zakia Ophtalmologie Pr. IKEN Ali Urologie Pr. JAAFAR Abdeloihab* Traumatologie Orthopédie Pr. KRIOUILE Yamina Pédiatrie Pr. MABROUK Hfid* Traumatologie Orthopédie Pr. MOUSSAOUI RAHALI Driss* Gynécologie Obstétrique Pr. OUJILAL Abdelilah Oto-Rhino-Laryngologie Pr. RACHID Khalid * Traumatologie Orthopédie Pr. RAISS Mohamed Chirurgie Générale Pr. RGUIBI IDRISSI Sidi Mustapha* Pneumo-phtisiologie Pr. RHOU Hakima Néphrologie Pr. SIAH Samir * Anesthésie Réanimation Pr. THIMOU Amal Pédiatrie Pr. ZENTAR Aziz* Chirurgie Générale

JANVIER 2004 Pr. ABDELLAH El Hassan Ophtalmologie Pr. AMRANI Mariam Anatomie Pathologique Pr. BENBOUZID Mohammed Anas Oto-Rhino-Laryngologie Pr. BENKIRANE Ahmed* Gastro-Entérologie Pr. BOULAADAS Malik Stomatologie et Chirurgie Maxillo-faciale Pr. BOURAZZA Ahmed* Neurologie Pr. CHAGAR Belkacem* Traumatologie Orthopédie Pr. CHERRADI Nadia Anatomie Pathologique Pr. EL FENNI Jamal* Radiologie

Pr. EL HANCHI ZAKI Gynécologie Obstétrique Pr. EL KHORASSANI Mohamed Pédiatrie Pr. EL YOUNASSI Badreddine* Cardiologie Pr. HACHI Hafid Chirurgie Générale Pr. JABOUIRIK Fatima Pédiatrie Pr. KHARMAZ Mohamed Traumatologie Orthopédie Pr. MOUGHIL Said Chirurgie Cardio-Vasculaire Pr. OUBAAZ Abdelbarre * Ophtalmologie Pr. TARIB Abdelilah* Pharmacie Clinique

Pr. TIJAMI Fouad Chirurgie Générale Pr. ZARZUR Jamila Cardiologie JANVIER 2005 Pr. ABBASSI Abdellah Chirurgie Réparatrice et Plastique Pr. AL KANDRY Sif Eddine* Chirurgie Générale Pr. ALLALI Fadoua Rhumatologie Pr. AMAZOUZI Abdellah Ophtalmologie Pr. AZIZ Noureddine* Radiologie Pr. BAHIRI Rachid Rhumatologie Directeur Hôp. Al Ayachi Salé Pr. BARKAT Amina Pédiatrie Pr. BENYASS Aatif Cardiologie Pr. DOUDOUH Abderrahim* Biophysique Pr. EL HAMZAOUI Sakina * Microbiologie Pr. HAJJI Leila Cardiologie (mise en disponibilité Pr. HESSISSEN Leila Pédiatrie Pr. JIDAL Mohamed* Radiologie Pr. LAAROUSSI Mohamed Chirurgie Cardio-vasculaire Pr. LYAGOUBI Mohammed Parasitologie Pr. RAGALA Abdelhak Gynécologie Obstétrique Pr. SBIHI Souad Histo-Embryologie Cytogénétique Pr. ZERAIDI Najia Gynécologie Obstétrique

AVRIL 2006 Pr. ACHEMLAL Lahsen* Rhumatologie Pr. AKJOUJ Said* Radiologie Pr. BELMEKKI Abdelkader* Hématologie Pr. BENCHEIKH Razika O.R.L Pr. BIYI Abdelhamid* Biophysique Pr. BOUHAFS Mohamed El Amine Chirurgie - Pédiatrique Pr. BOULAHYA Abdellatif* Chirurgie Cardio – Vasculaire. Pr. CHENGUETI ANSARI Anas Gynécologie Obstétrique Pr. DOGHMI Nawal Cardiologie Pr. FELLAT Ibtissam Cardiologie Pr. FAROUDY Mamoun Anesthésie Réanimation Pr. HARMOUCHE Hicham Médecine Interne

Pr. HANAFI Sidi Mohamed* Anesthésie Réanimation Pr. IDRISS LAHLOU Amine* Microbiologie Pr. JROUNDI Laila Radiologie Pr. KARMOUNI Tariq Urologie Pr. KILI Amina Pédiatrie Pr. KISRA Hassan Psychiatrie Pr. KISRA Mounir Chirurgie – Pédiatrique Pr. LAATIRIS Abdelkader* Pharmacie Galénique Pr. LMIMOUNI Badreddine* Parasitologie Pr. MANSOURI Hamid* Radiothérapie Pr. OUANASS Abderrazzak Psychiatrie Pr. SAFI Soumaya* Endocrinologie Pr. SEKKAT Fatima Zahra Psychiatrie Pr. SOUALHI Mouna Pneumo – Phtisiologie Pr. TELLAL Saida* Biochimie Pr. ZAHRAOUI Rachida Pneumo – Phtisiologie DECEMBRE 2006 Pr SAIR Khalid Chirurgie générale Dir. Hôp.Av.Marrakech OCTOBRE 2007 Pr. ABIDI Khalid Réanimation médicale Pr. ACHACHI Leila Pneumo phtisiologie Pr. ACHOUR Abdessamad* Chirurgie générale Pr. AIT HOUSSA Mahdi * Chirurgie cardio vasculaire Pr. AMHAJJI Larbi * Traumatologie orthopédie Pr. AOUFI Sarra Parasitologie Pr. BAITE Abdelouahed * Anesthésie réanimation Directeur ERSSM Pr. BALOUCH Lhousaine * Biochimie-chimie Pr. BENZIANE Hamid * Pharmacie clinique Pr. BOUTIMZINE Nourdine Ophtalmologie Pr. CHERKAOUI Naoual * Pharmacie galénique Pr. EHIRCHIOU Abdelkader * Chirurgie générale Pr. EL BEKKALI Youssef * Chirurgie cardio-vasculaire Pr. EL ABSI Mohamed Chirurgie générale Pr. EL MOUSSAOUI Rachid Anesthésie réanimation Pr. EL OMARI Fatima Psychiatrie Pr. GHARIB Noureddine Chirurgie plastique et réparatrice Pr. HADADI Khalid * Radiothérapie Pr. ICHOU Mohamed * Oncologie médicale Pr. ISMAILI Nadia Dermatologie Pr. KEBDANI Tayeb Radiothérapie Pr. LALAOUI SALIM Jaafar * Anesthésie réanimation Pr. LOUZI Lhoussain * Microbiologie

Pr. MADANI Naoufel Réanimation médicale Radiologie Pr. MAHI Mohamed * Pr. MARC Karima Pneumo phtisiologie Pr. MASRAR Azlarab Hématologie biologique Pr. MRANI Saad * Virologie Pr. OUZZIF Ez zohra * Biochimie-chimie Pr. RABHI Monsef * Médecine interne Pr. RADOUANE Bouchaib* Radiologie Pr. SEFFAR Myriame Microbiologie Pr. SEKHSOKH Yessine * Microbiologie Pr. SIFAT Hassan * Radiothérapie Pr. TABERKANET Mustafa * Chirurgie vasculaire périphérique Pr. TACHFOUTI Samira Ophtalmologie Pr. TAJDINE Mohammed Tariq* Chirurgie générale Pr. TANANE Mansour * Traumatologie-orthopédie Pr. TLIGUI Houssain Parasitologie Pr. TOUATI Zakia Cardiologie

DECEMBRE 2008 Pr TAHIRI My El Hassan* Chirurgie Générale MARS 2009 Pr. ABOUZAHIR Ali * Médecine interne Pr. AGADR Aomar * Pédiatrie Pr. AIT ALI Abdelmounaim * Chirurgie Générale Pr. AIT BENHADDOU El Hachmia Neurologie Pr. AKHADDAR Ali * Neuro-chirurgie Pr. ALLALI Nazik Radiologie Pr. AMINE Bouchra Rhumatologie Pr. ARKHA Yassir Neuro-chirurgie Directeur Hôp.des Spécialités Pr. BELYAMANI Lahcen* Anesthésie Réanimation Pr. BJIJOU Younes Anatomie Pr. BOUHSAIN Sanae * Biochimie-chimie Pr. BOUI Mohammed * Dermatologie Pr. BOUNAIM Ahmed * Chirurgie Générale Pr. BOUSSOUGA Mostapha * Traumatologie-orthopédie Pr. CHTATA Hassan Toufik * Chirurgie Vasculaire Périphérique Pr. DOGHMI Kamal * Hématologie clinique Pr. EL MALKI Hadj Omar Chirurgie Générale Pr. EL OUENNASS Mostapha* Microbiologie Pr. ENNIBI Khalid * Médecine interne Pr. FATHI Khalid Gynécologie obstétrique Pr. HASSIKOU Hasna * Rhumatologie Pr. KABBAJ Nawal Gastro-entérologie Pr. KABIRI Meryem Pédiatrie Pr. KARBOUBI Lamya Pédiatrie

Pr. LAMSAOURI Jamal * Chimie Thérapeutique Pr. MARMADE Lahcen Chirurgie Cardio-vasculaire Pr. MESKINI Toufik Pédiatrie Pr. MESSAOUDI Nezha * Hématologie biologique Pr. MSSROURI Rahal Chirurgie Générale Pr. NASSAR Ittimade Radiologie Pr. OUKERRAJ Latifa Cardiologie Pr. RHORFI Ismail Abderrahmani * Pneumo-Phtisiologie OCTOBRE 2010 Pr. ALILOU Mustapha Anesthésie réanimation Pr. AMEZIANE Taoufiq* Médecine Interne Pr. BELAGUID Abdelaziz Physiologie Pr. CHADLI Mariama* Microbiologie Pr. CHEMSI Mohamed* Médecine Aéronautique Pr. DAMI Abdellah* Biochimie- Chimie Pr. DARBI Abdellatif* Radiologie Pr. DENDANE Mohammed Anouar Chirurgie Pédiatrique Pr. EL HAFIDI Naima Pédiatrie Pr. EL KHARRAS Abdennasser* Radiologie Pr. EL MAZOUZ Samir Chirurgie Plastique et Réparatrice Pr. EL SAYEGH Hachem Urologie Pr. ERRABIH Ikram Gastro-Entérologie Pr. LAMALMI Najat Anatomie Pathologique Pr. MOSADIK Ahlam Anesthésie Réanimation Pr. MOUJAHID Mountassir* Chirurgie Générale Pr. NAZIH Mouna* Hématologie Pr. ZOUAIDIA Fouad Anatomie Pathologique DECEMBRE 2010 Pr.ZNATI Kaoutar Anatomie Pathologique

MAI 2012 Pr. AMRANI Abdelouahed Chirurgie pédiatrique Pr. ABOUELALAA Khalil * Anesthésie Réanimation Pr. BENCHEBBA Driss * Traumatologie-orthopédie Pr. DRISSI Mohamed * Anesthésie Réanimation Pr. EL ALAOUI MHAMDI Mouna Chirurgie Générale Pr. EL KHATTABI Abdessadek * Médecine Interne Pr. EL OUAZZANI Hanane * Pneumophtisiologie Pr. ER-RAJI Mounir Chirurgie Pédiatrique Pr. JAHID Ahmed Anatomie Pathologique Pr. MEHSSANI Jamal * Psychiatrie Pr. RAISSOUNI Maha * Cardiologie

* Enseignants Militaires FEVRIER 2013

Pr.AHID Samir Pharmacologie Pr.AIT EL CADI Mina Toxicologie Pr.AMRANI HANCHI Laila Gastro-Entérologie Pr.AMOR Mourad Anesthésie Réanimation Pr.AWAB Almahdi Anesthésie Réanimation Pr.BELAYACHI Jihane Réanimation Médicale Pr.BELKHADIR Zakaria Houssain Anesthésie Réanimation Pr.BENCHEKROUN Laila Biochimie-Chimie Pr.BENKIRANE Souad Hématologie Pr.BENNANA Ahmed* Informatique Pharmaceutique Pr.BENSGHIR Mustapha * Anesthésie Réanimation Pr.BENYAHIA Mohammed * Néphrologie Pr.BOUATIA Mustapha Chimie Analytique et Bromatologie Pr.BOUABID Ahmed Salim* Traumatologie orthopédie Pr BOUTARBOUCH Mahjouba Anatomie Pr.CHAIB Ali * Cardiologie Pr.DENDANE Tarek Réanimation Médicale Pr.DINI Nouzha * Pédiatrie Pr.ECH-CHERIF EL KETTANI Mohamed Ali Anesthésie Réanimation Pr.ECH-CHERIF EL KETTANI Najwa Radiologie Pr.EL FATEMI NIZARE Neuro-chirurgie Pr.EL GUERROUJ Hasnae Médecine Nucléaire Pr.EL HARTI Jaouad Chimie Thérapeutique Pr.EL JAOUDI Rachid * Toxicologie Pr.EL KABABRI Maria Pédiatrie Pr.EL KHANNOUSSI Basma Anatomie Pathologique Pr.EL KHLOUFI Samir Anatomie Pr.EL KORAICHI Alae Anesthésie Réanimation Pr.EN-NOUALI Hassane * Radiologie Pr.ERRGUIG Laila Physiologie Pr.FIKRI Meryem Radiologie Pr.GHFIR Imade Médecine Nucléaire Pr.IMANE Zineb Pédiatrie Pr.IRAQI Hind Endocrinologie et maladies métaboliques Pr.KABBAJ Hakima Microbiologie Pr.KADIRI Mohamed * Psychiatrie Pr.MAAMAR Mouna Fatima Zahra Médecine Interne

Pr.MEDDAH Bouchra Pharmacologie Pr.MELHAOUI Adyl Neuro-chirurgie Pr.MRABTI Hind Oncologie Médicale Pr.NEJJARI Rachid Pharmacognosie Pr.OUBEJJA Houda Chirugie Pédiatrique Pr.OUKABLI Mohamed * Anatomie Pathologique

Pr.RAHALI Younes Pharmacie Galénique Pr.RATBI Ilham Génétique Pr.RAHMANI Mounia Neurologie Pr.REDA Karim * Ophtalmologie Pr.REGRAGUI Wafa Neurologie Pr.RKAIN Hanan Physiologie Pr.ROSTOM Samira Rhumatologie Pr.ROUAS Lamiaa Anatomie Pathologique Pr.ROUIBAA Fedoua * Gastro-Entérologie Pr SALIHOUN Mouna Gastro-Entérologie Pr.SAYAH Rochde Chirurgie Cardio-Vasculaire Pr.SEDDIK Hassan * Gastro-Entérologie Pr.ZERHOUNI Hicham Chirurgie Pédiatrique Pr.ZINE Ali* Traumatologie Orthopédie

AVRIL 2013 Pr.EL KHATIB MOHAMED KARIM * Stomatologie et Chirurgie Maxillo-faciale MAI 2013 Pr.BOUSLIMAN Yassir Toxicologie

MARS 2014 Pr. ACHIR Abdellah Chirurgie Thoracique Pr.BENCHAKROUN Mohammed * Traumatologie- Orthopédie Pr.BOUCHIKH Mohammed Chirurgie Thoracique Pr. EL KABBAJ Driss * Néphrologie Pr. EL MACHTANI IDRISSI Samira * Biochimie-Chimie Pr. HARDIZI Houyam Histologie- Embryologie-Cytogénétique Pr. HASSANI Amale * Pédiatrie Pr. HERRAK Laila Pneumologie Pr. JANANE Abdellah * Urologie Pr. JEAIDI Anass * Hématologie Biologique Pr. KOUACH Jaouad* Gynécologie-Obstétrique Pr. LEMNOUER Abdelhay* Microbiologie Pr. MAKRAM Sanaa * Pharmacologie Pr. OULAHYANE Rachid* Chirurgie Pédiatrique Pr. RHISSASSI Mohamed Jaafar CCV Pr. SABRY Mohamed* Cardiologie Pr. SEKKACH Youssef* Médecine Interne Pr. TAZI MOUKHA Zakia Gynécologie-Obstétrique

AVRIL 2014 Pr.ZALAGH Mohammed ORL PROFESSEURS AGREGES : DECEMBRE 2014 Pr. ABILKASSEM Rachid* Pédiatrie

Pr. AIT BOUGHIMA Fadila Médecine Légale Pr. BEKKALI Hicham * Anesthésie-Réanimation Pr. BENAZZOU Salma Chirurgie Maxillo-Faciale Pr. BOUABDELLAH Mounya Biochimie-Chimie Pr. BOUCHRIK Mourad* Parasitologie Pr. DERRAJI Soufiane* Pharmacie Clinique Pr. DOBLALI Taoufik* Microbiologie Pr. EL AYOUBI EL IDRISSI Ali Anatomie Pr. EL GHADBANE Abdedaim Hatim* Anesthésie-Réanimation Pr. EL MARJANY Mohammed* Radiothérapie Pr. FEJJAL Nawfal Chirurgie Réparatrice et Plastique Pr. JAHIDI Mohamed* O.R.L Pr. LAKHAL Zouhair* Cardiologie Pr. OUDGHIRI NEZHA Anesthésie-Réanimation Pr. RAMI Mohamed Chirurgie Pédiatrique Pr. SABIR Maria Psychiatrie Pr. SBAI IDRISSI Karim* Médecine préventive, santé publique et Hyg. AOUT 2015 Pr. MEZIANE Meryem Dermatologie Pr. TAHRI Latifa Rhumatologie JANVIER 2016 Pr. BENKABBOU Amine Chirurgie Générale Pr. EL ASRI Fouad* Ophtalmologie Pr. ERRAMI Noureddine* O.R.L

Pr. NITASSI Sophia O.R.L

JUIN 2017 Pr. ABI Rachid* Microbiologie Pr. ASFALOU Ilyasse* Cardiologie Pr. BOUAYTI El Arbi* Médecine préventive, santé publique et Hyg. Pr. BOUTAYEB Saber Oncologie Médicale Pr. EL GHISSASSI Ibrahim Oncologie Médicale Pr. OURAINI Saloua* O.R.L Pr. RAZINE Rachid Médecine préventive, santé publique et Hyg. Pr. ZRARA Abdelhamid* Immunologie Enseignants Militaires 2 - ENSEIGNANTS-CHERCHEURS SCIENTIFIQUES

PROFESSEURS/Prs. HABILITES

Pr. ABOUDRAR Saadia Physiologie Pr. ALAMI OUHABI Naima Biochimie-chimie Pr. ALAOUI KATIM Pharmacologie

Pr. ALAOUI SLIMANI Lalla Naïma Histologie-Embryologie Pr. ANSAR M’hammed Chimie Organique et Pharmacie Chimique Pr .BARKIYOU Malika Histologie-Embryologie Pr. BOUHOUCHE Ahmed Génétique Humaine Pr. BOUKLOUZE Abdelaziz Applications Pharmaceutiques Pr. CHAHED OUAZZANI Lalla Chadia Biochimie-chimie Pr. DAKKA Taoufiq Physiologie Pr. FAOUZI Moulay El Abbes Pharmacologie Pr. IBRAHIMI Azeddine Biologie moléculaire/Biotechnologie Pr. KHANFRI Jamal Eddine Biologie Pr. OULAD BOUYAHYA IDRISSI Med Chimie Organique Pr. REDHA Ahlam Chimie Pr. TOUATI Driss Pharmacognosie Pr. ZAHIDI Ahmed Pharmacologie

Mise à jour le 10/10/2018 Khaled Abdellah Chef du Service des Ressources Humaines

Dedications

To my beloved parents

This work is dedicated to you. I am forever grateful for the unconditional love, unshakable support and kindness you have showered upon me from birth. Thank you both for giving me strength to reach for the stars and chase my dreams. I hope that you will find in this modest work the fruit of your efforts, prayers and dedication. I owe my success to you. Thank you for the education you have provided me with. Thanks to you, I am becoming a doctor today, but I am always your little girl before all.

To my dearest mom

Mother and friend, confidante and counselor, my constant ally. Your support, prayers and constant presence carried me through difficult times, and your smile rewarded each success. I am forever grateful for your wisdom, patience and unconditional love that have forged the person I am today.

To the most wonderful of mothers, my dearest wish is to always make you proud. To my dearest dad

The best, sweetest and most loving of fathers, the education you gave me was filled with affection, trust and patience. Thank you for teaching me the sense of responsibility and independence. You have always been my role model and source of inspiration. Ever since I was a child you had this dream for me to become a doctor, I can only hope that I made you proud. May God bless you both, keep you from all harm and grant you prosperity, longevity and lasting happiness. I love you.

To my sweetest sister Sarah and brother Mohammed

I’m grateful to have you in my life and couldn’t possibly ask for better siblings. I wish you both a life full of happiness, prosperity, and success for all your projects. I wish all your dreams come true. May God, the almighty, protect you and keep you safe. You are the sunshine of my life. I love you.

To my beloved husband, Zakarya

My soulmate. This thesis would not have been possible if it weren’t for you. There’s not a day that goes by that I don’t thank God for putting you in my path. I am forever grateful for your constant presence and all the attention and support you’ve shown me. I wish you a successful career and a long happy life. I am permanently in love with you, always and forever.

To my beloved in-laws

You are my second family, my second home. My heart felt regards go to all of you for your love and endless support. To my grandmother, aunts, uncles and cousins This work is dedicated to you with the expression of my deepest respect and my most sincere affection. In memory of my late grandmother, grandfathers and aunts

May your souls rest in peace. May God the Almighty grant you his grace and infinite mercy.

To my closest friends Abir, Safaa, Hind, Salma

Life is so much better in your company. This thesis is an opportunity to express my love to you. Long and happy lives to you and to those who are dear to you. To my colleagues at the Cardiology Department

Thank you for showing me support throughout this work. This thesis is dedicated to you. To interns and residents, members of AMIR

Becoming an intern and part of this family is one of my proudest achievements. You have made me a better doctor and boosted my self-confidence. This work is dedicated to you. To my friends at Cervantes

Learning a new language alongside you has been the joy of my life, and a breath of fresh air every Saturday.

Acknowledgments

Professor Arkha Yasser

Professor Melhaoui Adyl

Professor Boutarbouch Mahjouba

To Professor Yamna Kriouile

To Professor Wafaa Regragui

To professor Jean Regis

To all staff workers at the NCRNS

List of abbreviations

 AANS : American Association of Neurological Surgeons  AED : Anti-Epileptic Drugs  AVM : Arterio-Veinous Malformations  CTScan : Computed Tomography Scan  DRE : Drug-Resistant Epilepsy  EEG : Electro-encephalogram

 GABA : Gamma-Aminobutyric Acid  GK : Gamma-Knife  GTCS : Generalized Tonic-Clonic Seizure  GY : Gray  HH : Hypothalamic Hamartoma  ILAE : International League Against Epilepsy  KD : Ketogenic Diet  MRI : Magnetic Resonance Imaging  MRM : Magnetic Resonance Microscopy  NA : Not available  NCRNS : National Center for Rehabilitation and Neuroscience  RS : Radiosurgery  SRS : Stereotactic Radiosurgery  TS : Tuberous Sclerosis

Summary

Introduction ...... 6

Reviews ...... 9

I. Reviews on epilepsy ...... 10

1) Definition ...... 10

2) Pathophysiology ...... 10

3) Classifications: ...... 11

i. The 1981 ILAE Classification of Epilepsy ...... 11

ii. The 2017 ILAE Classification of the Epilepsies: ...... 16

4) Diagnosis ...... 20

i. Testing ...... 20

ii. Imaging studies ...... 21

5) Treatment Options ...... 21

i. Dietary / lifestyle measures ...... 21

ii. Medical treatments: ...... 24

iii. Surgical treatments: ...... 28

II. Stereotactic Radiosurgery: ...... 30

1) Definition of Stereotactic Radiosurgery ...... 30

i. Leksell’s deﬁnition ...... 30

ii. Borje Larsson’s deﬁnition ...... 30

iii. The Ofﬁcial Current USA deﬁnition / AANS: ...... 30

2) Historical Review: The creation of Gamma Knife radiosurgery ...... 31

3) General mechanism of action:...... 33

4) Description of the device: ...... 34

5) Specificities of the intervention: ...... 36

i. Dynamic shaping: ...... 36

ii. Automatic positioning ...... 39

6) General indications of Stereotactic Radiosurgery : ...... 40

i. Tumoral Pathology: ...... 40

ii. Vascular Pathology ...... 40

iii. Functional neurosurgery: ...... 41

7) Contraindications of Stereotactic Radiosurgery: ...... 41

8) Complications ...... 42

i. Head frame placement ...... 42

ii. Early effects ...... 42

iii. Late effects ...... 43

Material and methods ...... 45

I. Type of study: ...... 46

II. Inclusion / exclusion criteria: ...... 46

III. Objectives: ...... 46

IV. Sources and data collection ...... 46

V. Pre and post-surgical assessment methodology of epilepsy ...... 47

Results ...... 48

I. The radiosurgery procedure: ...... 49

1) Phase 1: The preoperative consultation ...... 49

2) Phase 2: The surgical procedure ...... 50

i. Attaching the stereotactic frame ...... 50

ii. Imaging: ...... 52

iii. Treatment planning: ...... 54

iv. Treatment application ...... 56

3) Phase 3: The postoperative follow-up ...... 57

II. Statistics of Radiosurgical interventions at the NCRNS: ...... 58

III. Statistics of the radiosurgical treatment of epilepsy at the NCRNS:... 61

IV. Descriptive study of patients ...... 62

1) Distribution of patients by age ...... 62

2) Distribution of patients by Gender: ...... 62

3) Medical History: ...... 63

i. Personal history ...... 63

ii. Family history ...... 63

4) Etiology of epilepsy: ...... 63

5) Duration of evolution of epilepsy before radiosurgery ...... 64

6) Seizure Frequency for each case: ...... 65

7) Use of ketogenic diet, ACTH and steroids: ...... 66

8) Number and nature of antiepileptic drugs used before radiosurgery ...... 66

9) Illustrative case of each pathology: ...... 67

i. Hypothalamic Hamartoma ...... 67

ii. Frontal Cavernoma: ...... 69

iii. Lennox Gastaut Syndrome: ...... 72

iv. Mesial Temporal Glioma: ...... 73

v. Periventricular Nodular Heterotopia (PVNH): ...... 74

V. Surgical characteristics: ...... 75

1) Number of shots delivered in each case: ...... 75

2) Treatment duration ...... 76

3) Irradiated target volume ...... 77

4) Post-surgical evaluation of patients ...... 78

i. Follow-up duration ...... 78

ii. Success/ failure rates: ...... 78

iii. Appearance of the first therapeutic effects of radiosurgery ...... 82

iv. Personal appreciation of the patient's improvement ...... 82

v. Engel Epilepsy Surgery Outcome Scale: ...... 82

vi. Complications: ...... 83

Discussion ...... 88

I. Defining medically intractable epilepsy: ...... 89

II. Historical review: The beginnings of Stereotactic Radiosurgery in epilepsy: ...... 89

III. Mechanism of action: Effects of radiosurgery on epileptic lesions: .. 90

IV. Specific Indications of Stereotactic Radiosurgery in epilepsy: ...... 92

1) Treatment of lesional epilepsy...... 92

i. Supratentorial Tumors...... 92

ii. Arteriovenous Malformations ...... 93

iii. Cavernous Malformations ...... 94

iv. Hypothalamic Hamartomas ...... 95

v. The particular case of Tuberous Sclerosis ...... 99

2) Treatment of physiologic epilepsies ...... 99

i. Mesial Temporal Lobe Epilepsy...... 99

ii. Other Non-lesional Epilepsies ...... 105

V. Limits of our study: ...... 107

Abstracts ...... 111

List of figures ...... 114

List of tables...... 117

Appendixes ...... 118

References ...... 122

The Hippocratic Oath ...... 138

Introduction

Epilepsy is not a single disease, but a broad group of conditions characterized by recurrent seizures resulting from the abnormal firing of cerebral neurons (1). In addition to its medical and surgical treatments that have been around for over a century, Gamma Knife Radiosurgery comes as an interesting alternative, particularly in cases of medically intractable epilepsy, for it succeeds in some cases to replace open surgery.

Indeed, Gamma Knife Radiosurgery is a neurosurgical approach having now demonstrated well its efficiency, its low morbidity and its comfort in the treatment of numerous neurosurgical disorders. All these advantages make it a method of great interest in functional neurosurgery and quite particularly in surgery of epilepsy.

If for several years the positive evolution of epilepsy associated to brain lesions had been noticed after the Gamma Knife radiosurgical treatment, the use of this approach in surgery of epilepsy has only been systematically evaluated since 1993.

Data are today available concerning the surgical treatment of epilepsies originating in temporo-mesial area without an occupying process, epilepsies associated to hypothalamic hamartomas and epilepsies associated to cavernous angiomas or to low grade gliomas. The quality of the epileptological result obtained in these various indications associated to a very reduced morbidity let suppose that Gamma Knife radiosurgery could indeed have in the future a place within the panel of surgical approaches dedicated to the treatment of severe epilepsies. However, a treatment of a larger number of patients and a more prolonged follow-up remain necessary to estimate in a more definitive way this approach.

In Morocco, since 2008, the National Center for Rehabilitation and Neuroscience (NCRNS) is equipped with Gamma Knife® Perfexion ™ - the result of a continuous evolution of Gamma Knife. It presented with a complete automation of the treatment procedure that seemed to bring in daily practice an adequate therapeutic response to a variety of clinical situations (2).This device was upgraded by an improved version, Gamma Knife Icon, in February 2017.

Some studies carried out in this center have demonstrated the effectiveness of this technique in the management of multiple brain conditions including arteriovenous malformations (AVM), meningiomas, brain metastases, tremors. But what about medically intractable epilepsy?

The following thesis work will be discussing 10 cases of patients with medically intractable epilepsy treated with Radiosurgery in the Gamma Knife Center of Rabat between 2008 and 2019, in order to address in greater detail the indications, results, and consequences of this approach, hopefully improving decision making when it comes to choosing the ideal treatment for patients to come.

Reviews

I. Reviews on epilepsy 1) Definition

Epilepsy is a disease characterized by an enduring predisposition to generate epileptic seizures and by the neurobiological, cognitive, psychological, and social consequences of this condition. An epileptic seizure, on the other hand, is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.

In December of 2013, the ILAE Executive Committee adopted a new operational clinical definition of epilepsy:

Epilepsy is a disease of the brain defined by any of the following conditions

 At least two unprovoked (or reflex) seizures occurring >24 h apart

 One unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years

 Diagnosis of an epilepsy syndrome

Epilepsy is considered to be resolved for individuals who had an age-dependent epilepsy syndrome but are now past the applicable age or those who have remained seizure-free for the last 10 years, with no seizure medicines for the last 5 years (3). 2) Pathophysiology

Seizures are paroxysmal manifestations of the electrical properties of the cerebral cortex. A seizure results when a sudden imbalance occurs between the excitatory and inhibitory forces within the network of cortical neurons in favor of a sudden-onset net excitation.

The brain is involved in nearly every bodily function, including the higher cortical functions. If the affected cortical network is in the visual cortex, the clinical manifestations are visual phenomena. Other affected areas of primary cortex give rise to sensory, gustatory, or motor

manifestations. The psychic phenomenon of ―déjà-vu‖ occurs when the temporal lobe is involved.

The pathophysiology of focal-onset seizures differs from the mechanisms underlying generalized-onset seizures. Overall, cellular excitability is increased, but the mechanisms of synchronization appear to substantially differ between these 2 types of seizure. (4) 3) Classifications: i. The 1981 ILAE Classification of Epilepsy A. Classification of epileptic seizures ILAE clinical and electroencephalographic classification of epileptic seizures (1981)

This revised 1981 clinical and electroencephalographic classification of epileptic seizures was approved by the ILAE General Assembly in Kyoto in 1981, and remains the classification that is still the most widely accepted today. (5) a) Partial (focal, local) seizures:

Table 1 : ILAE clinical and electroencephalographic classification of partial seizures Clinical seizure type EEG seizure type EEG interictal expression A. Simple partial seizures (consciousness not impaired) 1. With motor signs: Local contralateral discharge Local contralateral discharge (a) focal motor without march starting over the corresponding (b) focal motor with march area of cortical representation (c) versive (not always recorded on scalp) (d) postural (e) phonatory 2. With somatosensory or special sensory symptoms (simple hallucinations): (a) somatosensory (d) olfactory (b) visual (e) gustatory (c) auditory (f) vertiginous 3. With autonomic symptoms or signs  epigastric  sweating, sensation,  flushing,  pallor,  piloerection and pupillary dilatation 4. With psychic symptoms: (a) dysphasic (b) dysmnesic (e.g. deja vu) (c) cognitive (e.g. dreamy state, distortions of time sense) (d) affective (e.g. fear, anger) (e) Illusions (e.g. macrospsia) (f) structured hallucinations B. Complex partial seizures 1. Simple partial onset followed by Unilateral or, frequently bilateral Unilateral or bilateral generally impairment of consciousness discharge, asynchronous focus, usually in (a) simple partial onset followed by diffuse or focal in temporal or the temporal or frontal regions impairment of consciousness frontotemporal (b) with automatism regions 2. With impairment of consciousness at onset (a) with impairment of consciousness only (b) with automatism C. Partial seizures evolving to secondarily generalized seizures (tonic–clonic, tonic or clonic) 1. Simple partial seizures evolving to Above discharges become generalized seizures secondarily and 2. Complex partial seizures evolving to rapidly generalized generalized seizures 3. Simple partial seizures evolving to complex partial seizures evolving to generalized seizures

b) Generalized seizures (convulsive and non- convulsive) Table 2: ILAE clinical and electroencephalographic classification of generalized seizures

Clinical seizure type EEG seizure type EEG interictal expression A. Absence seizures 1. Absence seizures Usually regular and symmetrical 3 Background activity usually normal (a) impairment of consciousness Hz but may be 2-4 Hz spike and although paroxysmal activity (such only slow wave complexes and may as spikes or spike and slow wave (b) with mild clonic components have multiple spike and slow wave complexes) may occur. This complexes. Abnormalities are activity is usually regular and (c) with atonic components bilateral symmetrical. (d) with tonic components

(e) with automatisms (f) with autonomic components) EEG more heterogeneous; may Background activity abnormal; 2. Atypical absence seizures include irregular spike and slow paroxysmal activity (such as spikes may have wave complexes, or spike and slow wave complexes) (a) changes in tone that are more fast activity or other paroxysmal frequently irregular and (b) onset and/or offset that is not activity. pronounced than in absence and abrupt) Abnormalities are bilateral but asymmetrical. often irregular asymmetrical Polyspike and wave, or sometimes Same as ictal B. Myoclonic seizures (single or spike and wave or sharp and slow multiple) waves Fast activity (10 c/s or more) and Spike or wave or polyspike and C. Clonic seizures slow waves; occasional spike and wave wave patterns discharges Low voltage, fast activity or a fast More or less rhythmic discharges rhythm of 9-10 c/s, or more of sharp and slow waves, D. Tonic seizures decreasing in frequency and sometimes asymmetrical. increasing in amplitude Background is often abnormal for age Rhythm at 10 c/s or more Polyspike and waves or spike and decreasing in frequency and wave, or, sometimes, sharp and E. Tonico–clonic seizures increasing in amplitude during slow wave discharges tonic phase, clonic phase interrupted by slow waves F. Atonic seizures (astatic Polyspikes and wave or flattering Polyspikes and slow wave seizures) or low-voltage fast activity c) Unclassified epileptic seizures

B. Classification of epilepsies and epileptic syndromes The 1989 ILAE international classification of epilepsies and epileptic syndromes is still currently accepted. (6) a) Localization related  Idiopathic (with age-related onset)

o Benign childhood epilepsy with centrotemporal spike

o Childhood epilepsy with occipital paroxysms

o Primary reading epilepsy

 Symptomatic epilepsy (Table 3)

o Chronic epilepsia partialis continua of childhood (Kojewnikow syndrome)

o Syndromes characterized by seizures with specific modes of precipitation.

o Syndromes based on anatomic localization:

Table 3 Syndromes based on anatomic localization

Temporal lobe •Mesiobasal limbic •Lateral temporal Frontal lobe •Supplementary motor •Cingulate •Anterior frontopolar •Orbitofrontal •Dorsolatreral •Opercular Parietal lobe

Occipital lobe

 Cryptogenic

b) Generalized epilepsies and syndromes  Idiopathic (with age-related onset – listed in order of age)

o Benign neonatal familial convulsions

o Benign neonatal convulsions

o Benign myoclonic epilepsy in infancy

o Childhood absence epilepsy (pyknolepsy)

o Juvenile absence epilepsy

o Juvenile myoclonic epilepsy (impulsive petit mal)

o Epilepsy with grand mal (GTCS) seizures on awakening

o Other generalized idiopathic epilepsies not defined above

o Epilepsies with seizures precipitated by specific modes of activation

 Cryptogenic or symptomatic (in order of age)

o West syndrome (infantile spasms, Blitz–Nick–Salaam–Krämpfe)

o Lennox–Gastaut syndrome

o Epilepsy with myoclonic–astatic seizures

o Epilepsy with myoclonic absence

 Symptomatic

o Non-specific aetiology:

. Early myoclonic encephalopathy

. Early infantile epileptic encephalopathy with suppression-burst

. Other symptomatic generalized epilepsies not defined above

o Specific syndromes: Epileptic seizure may complicate many disease states. Under this heading are diseases in which seizures are a presenting or predominant feature c) Epilepsies and syndromes undetermined whether focal or generalized  With both generalized and focal seizures

o Neonatal seizures

o Severe myoclonic epilepsy in infancy

o Epilepsy with continuous spike waves during slow-wave sleep

o Acquired epileptic aphasia (Landau–Kleffner)

o Other undetermined epilepsies not defined above

 Without unequivocal generalized or focal features: All cases with generalized tonic–clonic seizures in which clinical and EEG findings do not permit classification as clearly generalized or localization-related such as in many cases of sleep grand mal (GTCS) are considered not to have unequivocal generalized or focal features. d) Special syndromes Situation-related seizures (Gelegenheitsanfälle)

 Febrile convulsions

 Isolated seizures or isolated status epilepticus

 Seizures occurring only when there is an acute metabolic or toxic event due to factors such as alcohol, drugs, eclampsia, non-ketotic hyperglycaemia ii. The 2017 ILAE Classification of the Epilepsies:

In 2017, The ILAE presented a revised framework for the Classification of the Epilepsies (7), designed to work with the classification of seizure types. It presented three levels of diagnosis:

 Seizure type: where it assumes that the patient is having epileptic seizures as defined by the new 2017 ILAE Seizure Classification.

 Epilepsy type (focal, generalized, combined generalized and focal, unknown)

 Epilepsy syndrome where a specific syndromic diagnosis can be made.

The new classification incorporates etiology along each stage, emphasizing the need to consider etiology at each step of diagnosis, as it often carries significant treatment implications. Etiology is broken into six subgroups, selected because of their potential therapeutic consequences.

The term ―benign‖ is replaced by the terms self-limited and pharmacoresponsive to be used where appropriate. The term ―developmental and epileptic encephalopathy‖ can be applied in whole or in part where appropriate.

Figure 1: Framework for classification of the epilepsies. *Denotes onset of seizure. Epilepsia ILAE.

A. Seizure Types

Figure 2: The ILAE 2017 Classification of Seizure Types, expended vesrion (7) B. Epilepsy types

The Epilepsy Type level includes a new category of ―Combined Generalized and Focal Epilepsy‖ in addition to the well-established Generalized Epilepsy and Focal Epilepsies. It also includes an Unknown category. Many epilepsies will include multiple types of seizures.

The new group of Combined Generalized and Focal Epilepsies exists, as there are patients who have both generalized and focal seizures. The diagnosis is made on clinical grounds, supported by EEG findings. Ictal recordings are helpful but not essential. The interictal EEG may show both generalized spike-wave and focal epileptiform discharges, but epileptiform activity is not required for the diagnosis. Common examples in which both types of seizures occur are Dravet syndrome and Lennox-Gastaut syndrome.

The term ―Unknown‖ is used to denote where it is understood that the patient has Epilepsy but the clinician is unable to determine if the Epilepsy Type is focal or generalized because

there is insufficient information available. This may be for a variety of reasons. There may be no access to EEG, or the EEG studies may have been uninformative, for example, normal. If the Seizure Type(s) are unknown, then the Epilepsy Type may be unknown for similar reasons, although the two may not always be concordant. C. Epilepsy syndromes

An epilepsy syndrome refers to a cluster of features incorporating seizure types, EEG, and imaging features that tend to occur together. It often has age-dependent features such as age at onset and remission (where applicable), seizure triggers, diurnal variation, and sometimes prognosis. It may also have distinctive comorbidities such as intellectual and psychiatric dysfunction, together with specific findings on EEG and imaging studies. It may have associated etiologic, prognostic, and treatment implications. It is important to note that an epilepsy syndrome does not have a one-to-one correlation with an etiologic diagnosis and serves a different purpose such as guiding management.

There are many well-recognized syndromes, such as childhood absence epilepsy, West syndrome, and Dravet syndrome, although it should be noted that there has never been a formal classification of syndromes by the ILAE.

 Idiopathic Generalized Epilepsies (IGEs): The IGEs encompass four well- established epilepsy syndromes: Childhood Absence Epilepsy, Juvenile Absence Epilepsy, Juvenile Myoclonic Epilepsy and Generalized Tonic–Clonic Seizures Alone.

 Self-limited focal epilepsies: Typically beginning in childhood. The most common is self-limited epilepsy with centrotemporal spikes, formerly called ―benign epilepsy with centrotemporal spikes.‖ Self-limited occipital epilepsies of childhood, with the early-onset form described by Panayiotopoulos and the late-onset form by Gastaut. Other self-limited frontal lobe, temporal, and parietal lobe epilepsies have been described with some beginning in adolescence and even adult life. D. Etiology:

Often the first investigation carried out involves neuroimaging, ideally MRI where available. This enables the clinician to decide if there is a structural etiology for the patient’s epilepsy.

The five additional etiologic groups are genetic, infectious, metabolic, and immune, as well as an unknown group. A patient’s epilepsy may be classified into more than one etiologic category. E. Comorbidities:

Many of the epilepsies are associated with comorbidities such as learning, psychological, and behavioral problems. These range in type and severity, from subtle learning difficulties to intellectual disability, to psychiatric features such as autism spectrum disorders and depression, to psychosocial concerns. In the more severe epilepsies, a complex range of comorbidities may be seen, including motor deficits such as cerebral palsy or deterioration in gait, movement disorders, scoliosis, sleep, and gastrointestinal disorders. Like etiology, it is important that the presence of comorbidities be considered for every patient with epilepsy at each stage of classification, enabling early identification, diagnosis, and appropriate management. 4) Diagnosis

The diagnosis of epileptic seizures is made by analyzing the patient's detailed clinical history and by performing ancillary tests for confirmation. Physical examination helps in the diagnosis of specific epileptic syndromes that cause abnormal findings, such as dermatologic abnormalities etc. i. Testing

Potentially useful laboratory tests for patients with suspected epileptic seizures include the following:

 Prolactin levels obtained shortly after a seizure to assess the etiology (epileptic vs nonepileptic) of a spell; levels are typically elevated 3- or 4-fold and more likely to occur with generalized tonic-clonic seizures than with other seizure types; however, the considerable variability of prolactin levels has precluded their routine clinical use

 Serum levels of anticonvulsant agents to determine baseline levels, potential toxicity, lack of efficacy, treatment noncompliance, and/or autoinduction or pharmacokinetic change

 Cerebrospinal fluid examination in patients with obtundation or in patients in whom meningitis or encephalitis is suspected ii. Imaging studies

The following 2 imaging studies must be performed after a seizure:

 Neuroimaging evaluation (eg, MRI, CT scanning)

 EEG

The clinical diagnosis can be confirmed by abnormalities on the interictal EEG, but these abnormalities could be present in otherwise healthy individuals, and their absence does not exclude the diagnosis of epilepsy.

Video-EEG monitoring is the standard test for classifying the type of seizure or syndrome or to diagnose pseudoseizures (ie, to establish a definitive diagnosis of spells with impairment of consciousness). This technique is also used to characterize the type of seizure and epileptic syndrome to optimize pharmacologic treatment and for presurgical workup. (8) 5) Treatment Options

i. Dietary / lifestyle measures

In July 1921, the ketogenic diet (KD) was first reported as beneficial by Dr. Wilder and colleagues at the Mayo Clinic in Rochester, Minnesota (9). This treatment restricted carbohydrates, protein, calories, and fluids while significantly increasing fat intake to comprise approximately 90% of calories.

There are now four different KDs available to choose from: the traditional ―classic‖ KD, the medium-chain triglyceride (MCT) diet, the modified Atkins diet (MAD), and the low

glycemic index treatment (LGIT) (10) (11). Despite this recent progress, the KD is still vastly underutilized. A. Mechanisms of action

There are multiple likely reasons for the benefits of KD: The KD produces metabolic changes often associated with the starvation state. Fasting appears to have an independent effect on seizure control, however, even before actual KD food is provided. Similarly, added benefits of fasting can be seen in children treated with the KD (12).

The name of the KD derives from the theory that ketone bodies (acetoacetate, acetone, and beta- hydroxybutyrate), created in the liver from long- and medium-chain fatty acids, are directly anticonvulsant when crossing the blood–brain barrier. Urine and occasionally serum ketone levels are generally checked in patients on the KD to ensure that the diet is being managed correctly, in a manner analogous to anticonvulsant levels. However, it is unclear if ketosis is truly a mechanism of action or solely a marker that the body has made the metabolic shift to burn fat.

Increased mitochondrial biogenesis, oxidative phosphorylation, enhanced gamma aminobutyric acid levels, reduced neuronal excitability and firing, and stabilized synaptic function have been shown to occur in patients on the KD (13). While these may be induced by ketosis, alternative mechanisms proposed include elevated plasma free fatty acids (including polyunsaturated fatty acids), reduced glucose fluctuations, increased activation of ATP- sensitive potassium channels and adenosine, caloric restriction, and elevated brain amino acids (13). B. Indications / Contraindications:

The use of the ketogenic diet is restricted mainly to the treatment of refractory paediatric epilepsies.

KD treatment in adults with intractable epilepsy has rarely been utilized and infrequently studied (14).

The 2009 Consensus Statement focused on indications and provided a list of ―indications‖ for the KD that is available (Figure 3) (15).

Probable benefit (at least two Suggestion of benefit (one Contraindications (relative) publications) case report or series)

•Glucose transporter protein •Landau-Kleffner syndrome •Pyruvate carboxylase 1 GLUT-1 deficiency •Lafora body disease deficiency •Pyruvate dehydrogenase •Juvenile myoclonic epilepsy •Porphyria dficiency •Absence epilepsy •Fatty acid oxidation defects •Infantile spasms •Hypothalamic hamartoma •Primary carnitine deficiency •Myoclonic astatic epilepsy •Angelman syndrome •Pancreatitis (doose syndrome) •Combined use with vagus •Cardiomyopathy •tuberous sclerosis complex nerve stimulation •Inadequate ability to •Rett syndrome •combined use with maintain nutrition, or •Lennox-gastraut syndrome zonisamide at KD onset comply with the KD •Severe myoclonic epilepsy of •Children with recently restrictions infancy worsened seizures in the •combined use with •mitochondrial disorders past month phenobarbital at KD onset •children receiving only •Children with a clear focal formula and potentially resectable •Refractory status epilepticus lesion •Severe gastroeosophageal reflux •Concurrent propofol use

Figure 3: Indications and contraindications of KD (15)

C. Side effects:

Common: Occasional: Rare (case reports):

•- lack of significant weight •- gastrointestinal upset or • - kidney stones (with use gain, gastrooesophageal reflux, • of oral citrates, • • - constipation, - dehydration or acidosis • otherwise occasional), •- hypoglycemia (mostly (more frequent with with fasting) illness), • - pancreatitis, •- dyslipidemia, • - cardiomyopathy, •- growth slowing (especially • - bruising, in infants), • - prolonged QT •- skeletal fractures (more syndrome, common with long-term • - basal ganglia changes, use) • - selenium and zinc deficiencies (if unsupplemented), • - carnitine deficiency (symptomatic)

Figure 4: Side effects of KD ii. Medical treatments:

A. Anti-Epileptic Drugs (AEDs)

a) Mechanisms of action of AEDs:

Antiepileptic drugs (AEDs) protect against seizures through interactions with a variety of cellular targets. By affecting the functional activity of these targets (Table 4; Figure 5), AEDs suppress abnormal hypersynchronous activity in brain circuits, leading to protection against seizures. The actions on these targets can be categorized into four broad groups:

 modulation of voltage-gated ion channels, including sodium, calcium, and potassium channels;

 enhancement of GABA inhibition through effects on GABA receptors, the GAT-1 GABA transporter, or GABA transaminase;

 direct modulation of synaptic release through effects on components of the release machinery, including Synaptic vesicle protein 2A (SV2A) and a2d; and

 inhibition of synaptic excitation mediated by ionotropic glutamate receptors, including AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ) receptors (Table 4; Figure 5).

The ultimate effects of these interactions are to modify the bursting properties of neurons and to reduce synchronization in localized neuronal ensembles. In addition, AEDs inhibit the spread of abnormal firing to distant sites. Some seizures, including typical generalized absence seizures, result from thalamocortical synchronization. AEDs effective in these seizure types interfere with the rhythm-generating mechanisms that underlie synchronized activity in the thalamocortical circuit.

Table 4: Molecular Targets of Clinically Used AEDs

Molecular Target AEDs that act on target Voltage-gated ion channels Phenytoin, fosphenytoina, Carbamazepine, Oxcarbazepineb, Eslicarbazepine acetatec, Voltage gated sodium channels Lamotrigine and Lacosamide; possibly, topiramate, Zonisamide, and Rufinamide Voltage-gated calcium channels Ethosuximide Voltage-gated potassium channels Ezogabine GABA inhibition Phenobarbital, primidone and Benzodiazepines GABAA receptors including diazepam, lorazepam and clonazepam; possibly, topiramate and Felbamate GAT-1 GABA transporter Tiagabine GABA transaminase Vigabatrin Synaptic release machinery SV2A Levetiracetam  Gabapentin, gabapentin enacarbild ,and Pregabalin Ionotropic glutamate receptors AMPA receptor Perampanel Mixed/unknown Valproate, felbamate, topiramate, Zonisamide, and Rufinamide and adrenocorticotropin a: Fosphenytoin is a prodrug for phenytoin. b: Oxcarbazepine serves largely as a prodrug for licarbazepine, mainly S-licarbazepine. c: Eslicarbazepine acetate is a prodrug for S-licarbazepine. d: Gabapentin enacarbil is a prodrug for gabapentin. Many AED targets are ion channels, most notably voltage-gated sodium and potassium channels and GABA receptors (Figure 5). It is interesting to note that certain idiopathic epilepsy syndromes are believed to be the result of mutations in these same ion channels. (16)

Figure 5: Molecular Targets of Clinically Used AEDs (17) b) Basis of combinational treatment

All clinically used AEDs protect against seizures in animal models as single agents. Studies with early AEDs suggested that the seizure protection conferred by drug combinations is simply additive (18). Since the use of more than one agent compounds the risk of side effects, these and other observations led to the recommendation that AEDs should be tried sequentially in monotherapy before combining agents. More recent experimental data suggest that combining drugs with complementary mechanisms of action might lead to synergism for efficacy (19). Observational studies of results obtained in clinical practice have shown that combining newer AEDs with different mechanisms of action may have greater effectiveness (a combination of efficacy and tolerability) than combining drugs with similar mechanisms of

action (20). Consequently, an understanding of mechanism may impact clinical decision making in regard to the choice of drug combinations. B. Adenocorticotropin and Steroids

In 1950, Klein and Livingston reported on the efficacy of adrenocorticotropin (ACTH) therapy for childhood seizures after observing its benefits in various types of intractable generalized seizures (21) . Eight years later, Sorel and Dusaucy-Bauloye reported control of seizures and an improvement in electroencephalographic (EEG) findings for children with infantile spasms treated with the drug (22). The benefit of oral steroids in this condition was established soon after that of ACTH (23) (24) (25), and since then, both drugs have been used in a number of other epilepsy syndromes, including Ohtahara syndrome, Lennox–Gastaut syndrome, other myoclonic epilepsies, and Landau–Kleffner syndrome. ACTH and steroid therapy appear to have a unique beneficial effect upon epilepsy syndromes that have an age- related onset during a critical period of brain development that can cause a characteristic regression or plateau of acquired developmental milestones at seizure onset and subsequent long-term cognitive impairment. For some of these patients, ACTH or steroids, or both, can improve the short-term developmental trajectory and the long-term prognosis for language and cognitive development, in addition to the beneficial effects on the convulsive state (26) (27) (28) (29) (30). iii. Surgical treatments:

Epilepsy surgery is a highly effective option for selected patients with intractable epilepsy and has witnessed a dramatic growth over the last two decades, due to advances in electrophysiology, neuroimaging, neurointensive care, and neuroanesthesia, as well as to a better understanding of basic mechanisms of epilepsy (31).

The type of surgery depends largely on the location of the neurons that trigger the seizure and the age of the patient. Types of surgery include the following:

 Resective surgery: the most common one is temporal lobectomy, utilized for patients with medically intractable epilepsy and mesial temporal sclerosis (MTS), but this

procedure can also be utilized for a variety of other epileptogenic lesions including malformations of cortical development (MCD) as well as neoplastic and vascular lesions of the temporal lobe. (32)

 Multiple Subpial Transections (MST) is a novel technique used for the treatment of DRE in which the seizure focus involves eloquent cortical areas, with promising results when used in conjunction with resective techniques. (33)

 Vagal Nerve Stimulation (VNS) was approved for the treatment and prevention of refractory seizures in adults and adolescents by the European and US regulatory boards in 1994 and 1997, respectively. The mechanism of action of VNS is still not fully understood and its use is based on the empirical observation of its clinical efficacy. (31)

 Laser interstitial thermal therapy (LITT) is a less invasive surgery guided by MRI which uses a laser to pinpoint and destroy a small portion of brain tissue.

 Deep Brain Stimulation (DBS) is the use of an electrode — permanently implanted deep inside the brain — to release regularly timed electrical signals that disrupt abnormal, seizure-inducing activity. This procedure is also MRI-guided. The generator sending the electrical pulse is implanted in the chest.

 Corpus callosotomy is a surgery to sever — completely or partially — the bundle of nerves connecting the right and left sides of the brain (corpus callosum). This is usually used with children who experience abnormal brain activity that spreads from one side of the brain to the other.

 Hemispherectomy, hemispheric resections or disconnections are performed successfully to treat medically intractable hemispheric epilepsy in children and sometimes in adults, often resulting in remarkable improvement in seizure outcome and quality of life.

 Functional hemispherectomy, also primarily used in children, is the undercutting of the seizure-inducing hemisphere to sever its connections to the body's nervous system without the actual removal of brain tissue. (32)

II. Stereotactic Radiosurgery:

1) Definition of Stereotactic Radiosurgery

i. Leksell’s deﬁnition

―... Stereotactic radiosurgery is a technique for the non-invasive destruction of intracranial tissues or lesions that may be inaccessible to or unsuitable for open surgery (34) ‖. ii. Borje Larsson’s deﬁnition

―Radiosurgery signifies any kind of application of ionizing radiation energy, in experimental biology or clinical medicine, aiming at the precise and complete destruction of chosen target structures containing healthy and/or pathological cells without significant concomitant or late radiation damage to adjacent tissue (35)‖. iii. The Official Current USA definition / AANS:

The Ofﬁcial Current USA deﬁnition / AANS was published online at www.AANS.org, article ID 38198, on June 2006, reaffirmed on November 2009.

(a) ―Stereotactic radiosurgery is a distinct discipline that utilizes externally generated ionizing radiation in certain cases to inactivate or eradicate (a) deﬁned target(s) in the head and spine without the need to make an incision. The target is deﬁned by high-resolution stereotactic imaging.

To assure quality of patient care the procedure involves a multidisciplinary team consisting of a neurosurgeon, radiation oncologist, and medical physicist.‖

(b) Stereotactic radiosurgery typically is performed in a single session, using a rigidly attached stereotactic guiding device, other immobilization technology and/or a stereotactic image-guidance system, but can be performed in a limited number of sessions, up to a maximum of ﬁve.

(c) Technologies that are used to perform stereotactic radiosurgery include linear accelerators, particle beam accelerators, and multisource Cobalt 60 units. In order to enhance precision, various devices may incorporate robotics and real time imaging. (36) 2) Historical Review: The creation of Gamma Knife radiosurgery

The development of Gamma Knife Radiosurgery is attributed to Lars Leksell (Figure 6), a Swedish neurosurgeon and physicist who, alongside his associate Börje Larsson (Figure 7), began in the 1950s to research the combination of ionizing radiation with a stereotaxic guidance device capable of locating targets in the brain. The concomitant development of imaging and computer science was a major contribution. In 1968, researchers installed the first prototype using gamma rays from Cobalt 60 sources, which they named "Gamma Knife". The technique has since been termed "stereotactic radiosurgery", by the application of stereotaxic guidance to determine the target.

Figure 6 Lars Leksell (1907-1986) Figure 7 Börje Larsson (1931-1998)

Elekta was founded in 1972 by Lars Leksell. The company currently provides radiosurgery and radiotherapy devices, as well as the ancillary equipment and software they need. Elekta is also involved in the continuous development of these technologies.

In 1999, Elekta introduced an innovative automatic patient positioning system that was previously manual and mechanical, ensuring the safety of operators who can now manipulate

the device from the workstation. In 2006, it introduces the new generation of Gamma Knife® devices with the Leksell PerfeXion ™ (Elekta Instrument AB, Stockholm, Sweden) which allows greater flexibility, adaptability and speed of processing especially in the case of complex and / or multiple targets.

In 2015, the latest Leksell Gamma Knife Icon ™ model (Figure 8) (Elekta Instrument AB, Stockholm, Sweden) is born and brings several innovations such as the possibility of integrating imagery made under non-stereotaxic conditions, thanks to a co-recording done with a scanner integrated into the Leksell Gamma Knife Icon ™.

The Icon ™ device is equipped with a software that allows a continuous monitoring of the dose distribution even in the case of a multiple treatment, as well as a non-invasive fixation to the mask allowing fractionation of the treatment and a better comfort of the patient. (37)

Figure 8: Photograph showing the positioning of the patient in the device, as well as the benchmarks used for non-invasive fixation to the mask, an innovation introduced by the Gamma Knife Icon ™

Today, more than one million patients have been treated worldwide by Radiosurgery Gamma Knife over the past 40 years, an annual average of more than 70,000 patients and more than 2,800 publications. (37)

The historical review of the usage of SRS in the treatment of epilepsy will be detailed in the chapter ―Discussion‖.

3) General mechanism of action:

Stereotactic radiosurgery (SRS) refers to the precise and focused delivery of a single, high dose of radiation in a single session and has been used to treat various intracranial and skull base lesions. (38)

The fundamental principle of radiosurgery is that of selective ionization of tissue, by means of high-energy beams of radiation. Ionization is the production of ions and free radicals which are damaging to the cells. These ions and radicals, which may be formed from the water in the cell or biological materials, can produce irreparable damage to DNA, proteins, and lipids, resulting in the cell's death. Thus, biological inactivation is carried out in a volume of tissue to be treated, with a precise destructive effect. The radiation dose is usually measured in grays (one gray (Gy) is the absorption of one joule of energy per kilogram of mass). (39)

SRS is performed by using 1 of the 3 forms of high-energy radiation; it can be delivered with a linear accelerator, a Gamma Knife unit, or with charged particles. (38) The gamma rays used in the LGKS come from the disintegration of 192 cone-shaped Cobalt 60 sources in the latest generation devices (PerfeXion ™ and Icon ™) and 201 sources in the older models, arranged in a hemispherical array.

The dosimetric characteristics of SRS, namely a highly conformal isodose distribution and a very steep dose gradient of dose fall-off beyond the prescribed isodose line, lend themselves well to the delivery of an ablative dose of radiation to intracranial and skull base lesions. (38)

Radiosurgery ensures the specificity and the careful delineation of the target by a pre-planning based on stereotactic acquisitions of high-resolution imagery, and by the execution of the gesture by devices and instruments of remarkable finesse and reliability. Thus, only the pathological entity defined during dosimetry and ballistics planning receives gamma radiation, sparing the adjacent parenchyma and limiting the occurrence of deleterious radiation-induced effects.

The effects of SRS on epileptic lesions will be detailed in the chapter ―Discussion‖.

4) Description of the device:

A Gamma Knife unit (Figure 9; Figure 10) is composed of:

 The radiation unit with Cobalt-60 sources and dynamic shaping technology. (40)

 The patient’s bed coupled to the electrical positioning system. (40)

 The control console of the unit. (40)

 Leksell Gamma Plan ™ Intervention Planning Information System. (40)

The unit of radiation is made of cast iron and weighs about 18 tons, of spherical shape with orifices, in particular that of the door which is made of two horizontal shutters remotely guided by a computer system. It contains 192 cone-shaped sources of Cobalt-60 for new generation devices (201 hemispherical and truncated sources for older devices). The sources are arranged in capsules with holes on one side (Figure 11). These sources must be changed every 5-7 years.

The patient’s bed is located in the axis of the radiation unit door and coupled to a remotely guided positioning system.

The control console and planning system are in a room adjacent to the treatment room.

Figure 9: Photograph of the NCRNS Gamma Knife Icon ™ in Rabat, showing the radiation unit and the patient's bed. (38)

Figure 10: Photograph of the control console and the interface of the Leksell Gamma Knife Icon ™ software of the NCRNS Rabat (38)

Figure 11: Photograph of cobalt sources and capsules containing them (38) 5) Specificities of the intervention:

The treatment steps are detailed in the section "Surgical procedure". Since patients in our study have benefited from this treatment, this chapter will only include some specificities of the machine. i. Dynamic shaping:

The sources are usually in the posterior part of the radiation unit; the "home" position, to ensure the best protection of radiation. They are spread over 8 cone-shaped sectors each of which carries 24 sources (Figure 13). During treatment, these sectors are advanced in front of a tungsten cloak perforated with holes of three different calibers (4, 8 and 16 mm) representing the different calibers of shots (Figure 14).

Thanks to this arrangement, the "Dynamic shaping" is possible; the shape of the irradiated area resulting from beam convergence is spherical if all sectors are enabled, it can be altered by turning off one or more of the sectors or by using different calibers. This technique makes it possible to focus the radiation in the target zones and to save at best the healthy and / or sensitive adjacent areas such as the optic chiasma, the cochlea, the internal capsule or the brainstem. This step of Dynamic shaping is done thanks to the software GammaPlan which allows the computation and the visualization of the doses at the level of each zone (41).

The dose rate at the irradiation focus is between 3 and 4 Gray per minute for new Cobalt-60 sources.

Figure 12: Diagram showing the patient's position in the radiation unit during treatment. (35)

Figure 13: Right: Photo of the tungsten cape of new generation devices. Left: Image of a part of the tungsten cloak with the perforations of the different calibers for a sector (24 x 3 holes).

A: Cross Section of the Leksell Gamma Knife Icon Radiation Unit showing the tungsten cape and the cone of the sources. B: Detailed view of the 8 sliding sectors independently. C: Position of the sector in a collimator of 4 mm. D: Position of the sector in an 8 mm collimator. E: Position of the sector in a 16 mm collimator Figure 14: Cone collimator of Gamma Knife devices (40)

ii. Automatic positioning

The patient positioning system allows movements in 3 axes: anteroposterior to penetrate the irradiation zone, right / left and up / down to position the patient's head in such a way that the target is in the center of the collimator. (Figure 15)

The patient's head is secured to the bed by a stereotactic frame or a mask in the Icon model. The position of the head can thus be modified so that the coordinates of the targets specified during the planning are positioned in the center of the collimator.

The overall accuracy of the NCRNS Gamma Knife is of the order of 0.13 mm.

Gamma Knife has an automated functioning which makes the application of the treatment very easy, reduces the sources of errors and ensures the protection of the medical personnel and operators.

Figure 15: Schematic photograph showing the three axes of movement of the patient's bed (38)

6) General indications of Stereotactic Radiosurgery :

SRS is an effective noninvasive treatment for various pathologies, particularly for tumors and especially when unresectable, recurrent, or residual after surgery. Thus, SRS might come as an interesting alternative to treat: i. Tumoral Pathology:

 Benign Tumors: Thanks to its radio biological properties (single dose treatment), radiosurgery proved to be very effective in controlling the growth of benign tumors. The main benign tumors treated are:

o Intracranial neuromas

o Meningiomas

o Pituitary adenomas

o Other: juvenile astrocytomas, tumors of the pineal region, chemodectomas, craniopharyngiomas, chordomas, chondromas ...

 Malignant tumors:

o Brain metastases: The results are excellent in the local control of brain metastases, with a significant improvement in the quality of life in case of multiple metastases.

o Other malignant tumors (Glioblastomas): because of its delayed action, GKS is retained as a complementary treatment. ii. Vascular Pathology

Gamma-Knife radiosurgery was also proved very effective in vascular malformations. Its action on the vessels of vascular malformations induces an obliterative endarteriopathy resulting in the occlusion of the malformations within 2 to 3 years.

 The main lesions treated are:

o Arteriovenous malformations (AVM)

o Intracranial cavernomas;

o Dural Arteriovenous Fistulas (dAVFs). iii. Functional neurosurgery:

Indication of origin of Gamma Knife radiosurgery, it regained interest with the proven effects of radiosurgery in terms of neuromodulation.

The main indications of functional neurosurgery are:

 Facial neuralgia;

 Medically intractable epilepsy of mesial temporal origin or secondary to hypothalamic hamartoma;

 Parkinson's disease and other movement disorders. (42) 7) Contraindications of Stereotactic Radiosurgery:

In general, SRS is not suitable for tumors or lesions 4 cm or larger in diameter or immediately adjacent to eloquent structures such as the optic apparatus and brainstem if a dose of higher than 12 Gy is needed to control the tumor. According to the QUANTEC (Quantitative Analysis of Normal Tissue Effects in the Clinic), the maximum brainstem dose of 12.5 Gy is associated with low (< 5%) risk of injury to the brainstem. A 2- to 5-mm clearance from the optic pathway is usually needed for a lesion to be treated with SRS. The most commonly quoted tolerance for the optic apparatus is 8 Gy, but a study from the Mayo Clinic showed that a point dose of 12 Gy to the optic apparatus might be safe.

In the pediatric age group, Gamma Knife–based SRS using the old models is, in general, not suitable for patients whose skulls are not completely fused, because invasive pin placement for securing the stereotactic head frame is required. Witt et al from Indiana University

described the use of a modified Aquaplast for immobilization of a 14-month-old child who was successfully treated with Gamma Knife–based SRS, but routine use of this method based on this limited experience is not encouraged. Alternative SRS methods using a frameless system such as CyberKnife or ideally the newest version of GammaKnife (ICON) may be suitable for these very young pediatric patients.

In circumstances in which the tumor is located inferior to the skull base to a degree that the stereotactic head frame cannot be placed to enable adequate stereotactic localization, a frameless system such as CyberKnife (43) or ideally the ICON version of GammaKnife can be used. (38) 8) Complications

i. Head frame placement

Pain, bleeding, and infection can occur at the pin-sites. To minimize the risk of infection after head frame removal, an antiseptic is used in the surgical dressing. ii. Early effects

A. Seizure

Occasionally, some patients may develop seizures within the first 24-72 hours after Gamma Knife–based SRS for supratentorial lesions. For this reason, it is prudent to inform patients of this risk and to recommend against driving during that time interval. Recommendation against driving based on seizure risk other than that associated with SRS is made separately at the discretion of the neurosurgeon or neurologist. B. Brain edema

Acute brain edema is rare and can occur shortly after SRS and can present as headaches. Some centers, routinely administer an intravenous steroid in high-risk patients on the day of the procedure to decrease this risk.

C. Other acute symptoms

Acute symptoms such as headaches, nausea/vomiting, fatigue, and vertigo (in patients treated for vestibular schwannoma) have been observed, but are generally rare and mild. iii. Late effects

A. Optic neuropathy

Optic neuropathy can occur after SRS. (44) (45) The reported incidence of optic neuropathy is low. This may be related to the fact that extra caution is taken when planning SRS for tumors close to the optic apparatus, based on the early report from Harvard University of optic neuropathy after a single SRS dose of 8 Gy, which is likely a conservative constraint. (44) In a more recent report from the Mayo Clinic, where 3-dimensional dose computation was used, dose plans and clinical outcomes of 218 Gamma Knife procedures in 215 patients for tumors of the sellar and parasellar region were reviewed. The median follow-up was 40 months. The median maximum radiation dose to the optic nerve was 10 Gy (range, 0.4-16 Gy). Four patients (1.9%), all of whom had prior surgery and 3 of whom also had external beam radiotherapy, developed radiation-induced optic neuropathy at a median of 48 months after SRS. (45)The risk of developing a clinically significant radiation-induced optic neuropathy was 1.1% for patients receiving 12 Gy or less. In spite of the fact that 73% received greater than 8 Gy to a short segment of the optic apparatus, radiation-induced optic neuropathy occurred in less than 2% of patients. (45) B. Other cranial nerve toxicities

The cranial nerves in the cavernous sinus appear to be quite resistant to SRS. (46) Based on the SRS literature for skull base meningiomas, the III, IV, V, and VI nerves seem to be able to tolerate a high single dose of radiation, although the exact doses delivered to those nerves individually were not quantified, which is not surprising given the difficulty identifying those nerves on the planning CT or MR images. The risk of permanent III, IV, or VI neuropathy

and V neuropathy was 0.4% and 0.2%, respectively, based on a review of 1255 patients who underwent SRS for pituitary adenomas. (46)

The incidence of V and VII nerve deficit after SRS is typically lower than 10% with reduced- dose SRS (12-13 Gy) for vestibular schwannoma. (47) (48) (49) Hearing preservation (VIII nerve) ranged from 33-88%. (50) (51) (47) (52) (53) (54) (55) (48) (49)

Based on 2 meta-analyses for glomus tumors, SRS (15-16 Gy) resulted in approximately 10% risk of injury to IX, X, XI, and XII nerves. (56) (57) (58) C. Radiation necrosis

Based on data on Gamma Knife–based SRS for AVM, the risk of symptomatic radiation necrosis is related to the volume encompassed by the 12 Gy and the location of the AVM. (59) The volume encompassed by the 12 Gy also predicts risk of symptomatic necrosis for non- AVM intracranial tumors. (60) D. Vascular injury

Brain infarction can occur if the internal carotid artery is damaged by radiation. Witt from Indiana University reviewed the information on 1255 patients who underwent SRS for pituitary adenoma and found that the incidence of SRS-induced internal carotid artery stenosis was very low. Based on limited data in the literature, the prescribed dose should cover less than 50% of the diameter of the internal carotid artery or the maximum dose to the internal carotid artery should be limited to 30 Gy or less. (46)

Material and methods

I. Type of study:

This is a retrospective study performed in consecutive patients with medically intractable epilepsy who benefited from Gamma Knife Radiosurgery, at the National Center for Rehabilitation and Neuroscience (NCRNS), Hassan II Foundation, Radiosurgery Unit-Rabat between June 2008 and November 2019, totaling a sample of 10 patients. II. Inclusion / exclusion criteria:

Our study includes reports relating to epilepsy as a primary indication for radiosurgery.

RS in the curative treatment of arteriovenous malformations, cerebral tumors is not included, since the main indication for treatment is usually lesional. The same goes for two patients with HH who were excluded from this study as they were treated for another indication than epilepsy. III. Objectives:

The objectives of this study are to report the results obtained by the team of Radiosurgery at the National Center for Rehabilitation and Neuroscience (NCRNS) by exposing the different observations of patients in pre- and post-radiosurgery, and to summarize current literature specific to RS for the treatment of epilepsy, all in order to assess the role of radiosurgery in epilepsy management, prove its efficacy in the treatment of medically intractable epilepsy, and eventually come up with recommendations. IV. Sources and data collection

We have identified for each patient the epidemiological, clinical, therapeutic and follow-up data from:

 Medical records of patients,

 Computerized records,

 Leksell Gamma Plan Database,

 Information obtained by correspondence with patients.

These data were transcribed in a patient’s review form (appendix 1).

Systematic review of the literature was undertaken using the search engines Pubmed, Web of Science, Google Scholar and Sciencedirect, articles in English or French were searched using the following search terms: ―epilepsy AND radiosurgery‖ and ―epilepsy AND Gamma Knife‖, as well as their derivations, as keywords or text words. V. Pre and post-surgical assessment methodology of epilepsy

The evaluation of epilepsy is done through:

 The patient's personal or parental appreciation of his epilepsy and its evolution.

 ENGEL score

Patients are evaluated pre-surgically and after 6 months and 1 year of the intervention. In case of improvement, the pre-surgical value serves as a basis for evaluating the therapeutic effect. The assessment also includes performing an MRI before surgery and 1 year after the treatment, as well as a neuropsychological and psychiatric evaluation before and after surgery. Sometimes the patient is filmed to transcribe all aspects of his epilepsy and its evolution.

Results

Our study included all patients treated for medically intractable epilepsy at the NCRNS by LGKS. The NCRNS Gamma Knife unit in Rabat is the only one in Morocco. I. The radiosurgery procedure:

The decision of a radio-surgical treatment by Gamma Knife is a consensual one, made by the neurologist and the neurosurgeon. Once the indication is established, the patient will go through 3 phases:

 Phase 1: The preoperative consultation.

 Phase 2: The surgical procedure.

 Phase 3: The postoperative follow-up. 1) Phase 1: The preoperative consultation

 Duration: consultation lasts approximately 30 to 60 min.

 Objectives:

o To inform the patient about the procedure and answer his questions.

o Examine the patient clinically and reevaluate his epilepsy as a reference for follow-up and determine the side to be treated.

o Gather personal information and the patient's history.

o Determine the date of treatment.

o Otherwise, start the treatment coverage procedure.

 Participants: patient, neurosurgeon, neurologist and the responsible for the service agenda.

 Materials required: preoperative assessment sheet of the epilepsy, possibly a camera.

 Procedure: an anamnesis and a clinical examination are carried out, the information is transcribed in the patient's file, and a date is fixed for the treatment.

2) Phase 2: The surgical procedure

 Duration: the procedure takes about a day.

 Objectives: The goal is to irradiate the epileptic lesions with the Leksell Gamma Knife in order to treat the epilepsy.

 Participants: patient, neurosurgeon, neuroradiologist, physicist, technician, nurse, anesthesiologist.

 Stages: The patient is hospitalized the morning of the day of the treatment. He is fasting to perform imaging with injection in the best conditions.

 The treatment is performed in four stages all carried out during the same day as shown schematically in the figure below: (Figure 16)

Attaching the Imaging Treatment Treatment stereotactic frame planning application

Figure 16: Stages of LGKS treatment with the Leksell Coordinate Frame G stereotaxic frame (60) i. Attaching the stereotactic frame

A. Materials needed:

 Leksell Coordinate Frame G (Figure 17).

 Titanium fixing screws.

 Syringe, Lidocaine 1%.

 Compress when needed.

 Torque screwdriver or manual.

 Leksell Frame cap (Figure 17).

The stereotactic frame is made of aluminum. The choice of aluminum is due to its physical characteristics in particular its solidity in order to ensure the immobilization of the patient as it is a stable and reliable base for the spatial landmark system, its lightness in order to better preserve the comfort of the patient, and its paramagnetic nature to allow an MRI almost without artifact.

The stereotactic frame serves as a mechanical interface to spatial landmarks during imaging and during treatment. It guarantees the concordance between the target on the plan and the target irradiated by the sources with precision. It is also the guarantor of the total immobilization of the patient's head throughout the procedure (61).

Figure 17: Left: Stereotactic Frame: Leksell Coordinate Frame G. Right: Leksell Frame cap for Gamma Knife Icon B. Procedure:

The patient is sitting in a treatment room.

The material is prepared on an adjacent table. The nurse assists the neurosurgeon throughout the procedure.

The neurosurgeon performs local anesthesia with the injection of Lidocaine 1% at the fixation sites provided for each of the 4 titanium screws.

The stereotactic frame is put in place and once in a satisfactory position, the screws are progressively tightened diagonally opposite on the outer table of the vault of the skull. Finally, the pressure on each screw is adjusted to 45 cNm using a torque screwdriver or using two fingers with the specific manual screwdriver, and the fixity of the frame is checked manually (62).

Sometimes a test with the Leksell Frame cap is performed to verify that the head with the frame do not hit the surface of the collimator during treatment. ii. Imaging:

A. Materials needed:

 MR-Indicator box.

 CT-Indicator box.

 MRI 1.5 TESLA.

 GE Lightspeed RT CT Scan

In any stereotactic intervention, imaging must be reportable to a coordination system. It needs an orthonormal landmark. In our series, target tracking is made with the stereotactic frame on which particular markers are fixed during imaging. These markers are in the form of a cube- shaped helmet comprising the landmarks on their front face and their two lateral faces. These landmarks have an "N" shape and are made of channels filled with CuSO4 solution for MRI and thin plates of copper for CT scan (Figure 18).

The origin of the Leksell® coordinate system (where X, Y, and Z are numerically zero) is located outside the attachment system (stereotactic frame in our series) at a top, side, and rear

point of the right-hand frame of the patient, as shown in (Figure 19) below. This coordinate system is used to move the patient so that the irradiation targets points at the X, Y, Z coordinates defined during the treatment planning on Leksell GammaPlan (61)

Figure 18: Photos of stereotaxic "N" markers on the helmet for the scan on the left and the MRI on the right

Figure 19: Leksell coordinate system applied to Leksell Coordinate Frame G. the left (L), right (R), posterior (P) and anterior (A) sides of the frame.

B. Procedure:

The specific marker for MRI, MR-Indicator box (Figure 18), is set up on the frame and the patient is sent to MRI where 3D T1 MPR (Multiplanar Reconstruction) sequences with and without Gadolinium injection, T2 CISS high ventriculographic resolution sequence, and DTI tractography (diffusion tensor images) are performed. Then, the specific marker for MRI is removed and that of the scanner (Figure 18), CT-Indicator box, is set up and the patient is sent to the scanner where 3D sequences are made.

The specific marker of the scanner is removed and the patient is taken to a room.

While keeping the frame, the patient can eat and rest.

Imaging results are sent to the Leksell GammaPlan® unit via an internal network iii. Treatment planning:

A. Materials needed:

 Internal network

 Leksell GammaPlan Unit Version 10 (Figure 20).

Figure 20: Photo of the Leksell Gamma Plan Unit.

B. Procedure:

a) Tracking in space

At the Leksell GammaPlan unit, an automatic determination of the markers on the stereotactic frame is performed. The neurosurgeon validates the latter and proceeds to the creation of the treatment plan.

b) Locating the target lesion

This is performed on an interface combining different injected and non-injected 3D MRI/ MRM cut axes, which can be set according to the surgeon's preference.

Sometimes the comparison with the results of the anatomical atlas provided with the Leksell Gamma Plan can be used.

c) Dose prescription

The dose prescribed in our series was not uniform, ranging from 12 to 24 Gy extremes to 50% isodose, administered through the 4/8/16 mm collimators.

Dosimetry is adapted to the lesional volume, and particularly, modulated according to the anatomical location of the lesion. Localizations at eloquent zones and highly radiosensitive brain regions require the prescription of effective minimum doses in order to limit the actinic effect of gamma rays on healthy brain structures.

d) Setting up shots and correction

The neurosurgeon places the shot(s) and uses Dynamic shaping to optimize the treatment, in order to achieve a maximum irradiation of the targeted structures by sparing the adjacent healthy brain parenchyma. The shots are delivered through the 3 collimators of 4, 8 and 16 mm allowing to adapt the irradiation zone to the shape of the lesion.

Other considerations may be taken into account by the surgeon and impose modulations of the shots delivered, including the deliberate inclusion of the hemosiderotic parenchyma immediately adjacent to the lesion.

Gamma Plan ™ estimates the duration of treatment according to the irradiation dose rate provided by the sources. The older the sources, the longer the treatment.

e) Coordinates’ verification:

The verification of coordinates is done automatically and is intended to prevent any collision during the procedure.

f) Export and printing of treatment

The treatment is exported to the control unit of the Leksell Gamma Knife. The treatment is printed and validated by the neurosurgeon (63) (61). iv. Treatment application

A. Materials needed: Gamma Knife Perfexion.

The device used to treat the majority of our patients is the Leksell Gamma Knife Perfexion (Figure 21), the first Gamma Knife of its kind in Africa. Currently, the device at the NCRNS has been updated to the latest version: Leksell Gamma Knife Icon.

Figure 21: Photo of Elekta’s Gamma Knife Perfexion (66)

B. Procedure:

The patient is taken to the treatment room and lies down on the bed of the Gamma Knife where his head is fixed by the frame. Once the patient is settled and the team members have left the irradiation room, the treatment is started and the bed moves in the collimator automatically according to the predefined plan.

Throughout the duration of treatment, the patient is under visual control through a camera and can communicate with the technician who supervises the treatment through a microphone installed in the bed.

The patient feels no pain. He can sleep or listen to a soundtrack of his choice during the treatment (eg Koran, music). He can also benefit from a break.

Once the treatment is complete, the patient is released from the frame. He is kept under surveillance until the next day, then returns home in the absence of complications. (63) 3) Phase 3: The postoperative follow-up

 Duration: Follow-up visits last approximately 15 to 20 minutes. The frequency may vary depending on the symptoms associated with the epilepsy and the possible treatments followed. An evaluation at 6 months and 1 year was recommended in most cases of our series.

 Objectives:

o Evaluate the epilepsy.

o Evaluate the occurrence of effects and complications of Gamma Knife radiosurgery as well as their clinical and imaging evolution.

o Evaluate the psychological impact.

o Adapt the medication.

o Perform an MRI at 1 year of surgery.

 Participants: patient, neurologist, neurosurgeon.

 Materials needed: postoperative evaluation sheet of the epilepsy, possibly a camera.

 Procedure: an interview and a clinical examination are carried out and the information is transcribed in the patient's file. A date is set for the next follow-up appointment. II. Statistics of Radiosurgical interventions at the NCRNS:

From June 2008 until November 2019, 1934 patients were treated (Table 5), an average of 175 patients / year. All treated patients were selected during multidisciplinary team discussions including neurosurgeons and neuroradiologists, and the treatment planning has always been concerted between the neurosurgeon, the radiation therapist and the medical physicist. The most frequent indication is represented by arteriovenous malformations (25,3 %), followed by benign tumors like meningiomas (22,6 %), vestibular schwannoma (10,2%), and pituitary adenomas (6,7%). Malignant tumors are represented by brain metastases with 258 cases (13,3%). 40 patients with functional disorders were treated including 10 cases of epilepsy (0,5%). (Figure 22)

The device mainly used for treating patients in our series was the Leksell Gamma Knife® PerfeXion ™. Only three patients in our series, treated during the last quarter of 2017, received treatment delivered by the Gamma Knife Icon ™ device, updated in February 2017.

Table 5: Statistics of RS interventions at the NCRNS from June 2008 to November 2019 according to Elekta’s Database of the GK unit

Pathology Number of patients Percentage Epilepsy 10 0,5% Arteriovenous malformation 490 25,3% Cavernomas 20 1,0% Meningiomas 438 22,6% Tremor 16 0,8%

59 Metastasis 258 13,3% Pineal region tumor 12 0,6% Gliomas 45 2,3% Vestibular schwanoma 198 10,2% Trigeminal neuralgia 14 0,7% Pituitary adenoma 130 6,7% Craniopharyngioma 44 2,3% Other benign 64 3,3% Other malignant 23 1,2% Other 172 8,9% Total 1934 100%

Gliomas Epilepsy Other 2,3% 0,5% Other malignant 8,9% 1,2% Arteriovenous malformation Other benign 25,3% 3,3%

Craniopharyngioma 2,3%

Pituitary adenoma 6,7%

Trigeminal neuralgia 0,7% Cavernomas 60 1,0% Vestibular schwanoma 10,2%

Pineal region tumor 0,6% Meningiomas 22,6% Metastasis 13,3% Tremor 0,8%

Figure 22: Percentage of cases in each pathology treated at the NCRNS GK unit from June 2008 to November 2019, according to Elekta’s Database

III. Statistics of the radiosurgical treatment of epilepsy at the NCRNS:

Since the start of the Gamma Knife Radiosurgery unit at the National Center for Rehabilitation and Neuroscience in June 2008 until November 2019, over a period of eleven years, statistics on patients treated for epilepsy are (Figure 23):

 Number of patients treated: 10, including one patient treated twice.

 Number of interventions: 11.

 Annual average of 0.96 interventions.

 Extremes of 2 interventions in 2012, 2014 and 2017 and none from 2009 to 2010 nor in 2013 or 2018.

2 2 2

1 1 1 1

0 0 2011 2012 2013 2014 2015 2016 2017 2018 2019

Figure 23: Annual number of interventions on medically intractable epilepsies by LGKS at the NCRNS

IV. Descriptive study of patients

1) Distribution of patients by age

In our series, the average age of our patients is 14,4 years with extremes of 2,5 and 37 years old. The study of the distribution of patients according to age categories shows a marked predominance of the 0-10 yo age group (Figure 24). The adult population represents nearly 33% of our sample, or three patients aged 20, 29 and 37 years.

1; 10%

2; 20% 0 to 10 yo 10 to 20 yo 5; 50% 20 to 30 yo 30 to 40 yo

2; 20%

Figure 24: Distribution of patients by age categories 2) Distribution of patients by Gender:

A clear masculine predominance has been noticed (Figure 25), as males represent 60% of our studied population, with a sex ratio male to female of 3/1.

4; 40% Male Female

6; 60%

Figure 25: Distribution of patients by gender 3) Medical History:

i. Personal history

Out of 7 patients for whom this information is available, 4 patients had a history of neonatal suffering and 5 patients had an anomaly of psychomotor development. ii. Family history

1 patient had epilepsy in her family, 2 patients had a history of parents’ consanguinity. These information were not available for 3 patients. 4) Etiology of epilepsy:

When it comes to the etiology of epilepsy: (Figure 26)

 5 patients had Hypothalamic Hamartoma, representing 50% of cases.

 1 patient had Tuberous Sclerosis (10%)

 1 patient had Lennox-Gastaut syndrome (10%)

 1 patient had Frontal Cavernoma (10%)

 1 patient had Mesial Temporal Glioma (10%)

 1 patient had left frontal Heterotopia (10%)

1; 10% Hypothalamic Hamartoma

1; 10% Tuberous Sclerosis

Lennox-Gastraut syndrome 1; 10% 5; 50% Frontal Cavernoma

Mesio Temporal Glioma 1; 10% Left frontal Heterotopia

1; 10%

Figure 26: Etiologies of medically intractable epilepsy in our case series 5) Duration of evolution of epilepsy before radiosurgery

The average duration of epilepsy progression before LGKS was 10 years, with extremes of 5 and 30 years. This information is not available for 3 patients.

15 30 29

10 Number Number of years 15 5 9 6 6 5 0 1 2 3 4 5 6 7 8 9 10 Cases

Figure 27: Duration of evolution of epilepsy for each patient. 6) Seizure Frequency for each case:

Table 6: Seizure frequency for each case before LGKS

Etiology of epilepsy Seizure Frequency

Case 1 Frontal Cavernoma 1-3 seizures/ month

Case 2 Mesial temporal Glioma 2-3 seizures/ day

Case 3 Hypothalamic Hamartoma 3-4 seizures/ week

Case 4 Hypothalamic Hamartoma 6-8 seizures/ day

Case 5 Hypothalamic Hamartoma 4-5 seizures/ day

Case 6 Left frontal Heterotopia Daily seizures (unprecised)

Case 7 Tuberous Sclerosis 15-16 seizures/ day

Case 8 Lennox-Gastaut syndrome Daily seizures (unprecised)

Case 9 Hypothalamic Hamartoma 4-5 seizures/ day

Case 10 Hypothalamic hamartoma 10-15 seizures/ day

As shown in the table above (Table 6), the majority of our patients had multiple seizures per day, which makes their epileptic condition disabling and difficult to control under AEDs alone. Thus, the need to consider the radiosurgical treatment. 7) Use of ketogenic diet, ACTH and steroids:

None of the patients were under KD, ACTH or steroids before LGKS in our series. 8) Number and nature of antiepileptic drugs used before radiosurgery

Out of 7 patients for whom this information is available, 57% had tried three AEDs combined before being treated surgically. (Figure 28)

2 Number Number of patients 1

0 1 2 3 4

Figure 28: Number of patients under 1, 2 or 3 AEDs before LGKS

The most frequent AEDs used were: carbamazepine (4), phenobarbital (3), valproate (4), lamotrigine (3), clonazepam (1), clobazam (1).

clobazam clonazepam lamotrigine valproate phenobarbital carbamazepine

0 1 2 3 4 5

Figure 29: Most frequent AEDs used 9) Illustrative case of each pathology:

i. Hypothalamic Hamartoma

We report the case of K.A, 6 years old, who presented along with a behavioral disorder, a history of persistent convulsive frontal seizures since the age of 40 days with the notion of status epilepticus, followed by an onset of gelastic seizures (4-5/day) at the age of 4, resistant to AEDs (Phenobarbital + Valproate + Carbamazepine). Neurological examination was normal. Video-EEG revealed gelastic seizures with a right temporo-centro-parietal corollary. Brain MRI with spectroscopy revealed a diencephalic tumor in favor of a Hypothalamic Hamartoma, with a volume of 14.46 cc.

A radiosurgical treatment was decided on a multidisciplinary staff meeting including neurologists, neuroradiologists and neurosurgeons based on the following criteria:

 The young age of the patient and her normal clinical state.

 Difficulty and risk of the surgical approach

 Symptomatic tumor

 Benign tumor responding well to radiosurgery.

After placing the Leksell G-type stereotactic frame under local anesthesia, an MRI with gadolinium injection was performed, allowing the tumor’s anatomical relationships to adjacent brain structures to be precisely defined. Then, a brain scan was performed to better approximate the bone relations of the lesion and to control its spatial location.

We defined by confrontation of the different sequences the target tumor volume. A presurgical multi-isocentric planning was elaborated comprising 44 collimators of 4 and 8 mm.

We decided to deliver to a peripheral reference isodose of 50% a dose of 12 Gy taking into account the volume, the location and the histological nature of the lesion.

The treatment was carried out without any technical difficulty. Removal of the stereotactic frame. Duration of the procedure was 06 hours.

During a period of follow-up of 56 months, the patient was reportedly seizure free since the intervention, with a cessation of AEDs 3 years later.

Pre-LGKS

Post-LGKS

Figure 30: MRI images of a HH before and after LGKS ii. Frontal Cavernoma:

This is the case of M.E, a 37-year-old female who presented a frontal tonico-clonic epilepsy since the age of 7 with a frequency of 2 seizures/month, and the discovery of a right frontal cavernoma on brain MRI in 2010. The patient was under Phenobarbital, Carbamazepine and Lamotrigine. Physical examination was without abnormalities. MRI on the day of treatment found a lesion of 0.7 cc of volume.

Pre LGKS

Post LGKS

Figure 31: MRI images of a frontal cavernoma before and after LGKS After placing the Leksell G-type stereotactic frame under local anesthesia, an MRI with gadolinium injection was performed, allowing the tumor’s anatomical relationships to adjacent brain structures to be precisely defined. Then, a brain scan was performed to better approximate the bone relations of the lesion and to control its spatial location.

We defined by confrontation of the different sequences the target tumor volume. A presurgical multi-isocentric planning was elaborated comprising 6 collimators of 4 and 8 mm.

We decided to deliver to a peripheral reference isodose of 50% a dose of 24 Gy taking into account the volume, the location and the histological nature of the lesion.

The treatment was carried out without any technical difficulty. Removal of the stereotactic frame. Duration of the procedure was 04 hours.

During a period of follow-up of 96 months, the patient was first seizure free immediately after the intervention, then later on reported a seizure recurrence (1-3 episodes/month) concomitant to an attempt of AED reduction, before regaining seizure freedom again and maintaining it since 2017, as in 6 years after LGKS. The patient was kept under a double AED therapy: carbamazepine and lamotrigine. Tuberous Sclerosis:

We report the case of S.S, 5 years old, with a history of Tuberous Sclerosis diagnosed at the age of 1, who presented a severe medically intractable epilepsy with 15-16 partial seizures a day under triple AED therapy: Valproate, Carbamazepine, Lamotrigine. MRI showed multiple brain tubers. The patient had a normal clinical state other than Hypomelanic macules ("ash leaf spots"). Brain MRI on the day of treatment found a lesion of 10.4 cc of volume.

Pre-LGKS

Post-LGKS

Figure 32: MRI images of brain tubers before and after LGKS

We defined by confrontation of the different sequences the target tumor volume. A presurgical multi-isocentric planning was elaborated comprising 10 collimators of 4, 8 mm and 16mm.

We decided to deliver to a peripheral reference isodose of 50% a dose of 22 and 24 Gy taking into account the volume, the location and the histological nature of the lesion.

The treatment was carried out without any technical difficulty. Removal of the stereotactic frame. Duration of the procedure was 06 hours.

During a period of follow-up of 48 months, the patient’s parents reported a worthwhile improvement of his epilepsy, with a decrease to 4-5 seizures per day, and was still under the same triple AED therapy. iii. Lennox Gastaut Syndrome:

The following is the case of Y. El B, a 15-year-old male with a history of severe autism and West Syndrome who had progressed to Lennox Gastaut syndrome since the age of 2 months, causing a medically intractable epilepsy with daily atonic seizures under a triple AED therapy: Valproate, Lamotrigine, Clobazam. Clinical examination found severe epileptic sequelae. A radiosurgical callosotomy was decided at a multidisciplinary staff meeting.

Figure 33: MRI images of a delineation of the corpus callosum (pre-LGKS)

We defined by confrontation of the different sequences the target tumor volume. A presurgical multi-isocentric planning was elaborated comprising 27 collimators of 4 and 8 mm.

We decided to deliver to a peripheral reference isodose of 50% a dose of 24 Gy taking into account the volume, the location and the histological nature of the lesion.

The treatment was carried out without any technical difficulty. Removal of the stereotactic frame. Duration of the procedure was 05 hours.

During a period of follow-up of 18 months, the patient’s parents did not report any change in his condition, with a persistence of daily seizures at the same frequency, and was still under the same triple AED therapy. iv. Mesial Temporal Glioma:

This is the case of A.B, 12 years old, who presented a medically intractable epilepsy caused by a mesial temporal grade II astrocytoma. Data on his clinical state (nature and frequency of seizures) as well as his medication is unavailable. Brain MRI on the day of treatment found a lesion of 13 cc of volume.

We defined by confrontation of the different sequences the target tumor volume. A presurgical multi-isocentric planning was elaborated comprising 52 collimators of 4 and 8 mm.

We decided to deliver to a peripheral reference isodose of 50% a dose of 14 Gy taking into account the volume, the location and the histological nature of the lesion.

Pre-LGKS

Post-LGKS

Figure 34: MRI images of a Mesial temporal glioma before and after LGKS

The treatment was carried out without any technical difficulty. Removal of the stereotactic frame. Duration of the procedure was 05 hours.

During a follow up of 72 months, the patient became seizure free but only 2 years after the procedure. it is unknown whether or not he is still under AEDs. v. Periventricular Nodular Heterotopia (PVNH):

This is the case of K.A, a 20-year-old male with medically intractable epilepsy originating from the left frontal lobe. The patient reported several daily seizures. The nature of his AEDs is unknown. Brain MRI and Video EEG Monitoring showed a left frontal focus related to a left frontal PVNH.

Brain MRI on the day of treatment revealed a lesion of 1.17 cc of volume.

Figure 35: MRI images of a left frontal PVNH of 1.17cc (pre-LGKS)

We defined by confrontation of the different sequences the target tumor volume. A presurgical multi-isocentric planning was elaborated comprising 14 collimators of 4 mm.

We decided to deliver to a peripheral reference isodose of 50% a dose of 24 Gy taking into account the volume, the location and the histological nature of the lesion.

The treatment was carried out without any technical difficulty. Removal of the stereotactic frame. Duration of the procedure was 05 hours.

6 months after the procedure, the patient reported no change in the frequency of his epileptic seizures and was kept under medication. V. Surgical characteristics:

1) Number of shots delivered in each case:

Our patients received doses that varied from 12 Gy to 24 Gy at 50% isodose line depending on the volume, localization and histological nature of the lesion, delivered through the 4, 8

and 16mm collimators of Leksell Gamma Knife Perfexion and Icon, with the use of the Dynamic Shaping option to protect visual pathways in one case.

The average number of shots used was 24 delivered through the 4/ 8 / 16 mm collimators.

 More than 24 shots during 6 interventions, as in 60 % of cases.

 Less than the average during 4 interventions, or 40 % cases.

1 Number Number of patients

0 0-20 20-40 40-60 60-80

Figure 36: Number of shots delivered during RS for each case 2) Treatment duration

Since the start of the Gamma Knife unit in 2008, the sources have only been changed in 2017, thus an increase of the treatment duration is observed between early and late treated patients.

Regarding the duration of treatment:

 The average was 5.1 hours.

 The extremes were 4 hours for the shortest duration and 6 hours for the longest.

2; 20% 3; 30%

4 hours 5 hours 6 hours

5; 50%

Figure 37: Duration of treatment in hours 3) Irradiated target volume

The average irradiated volume is 5.17 cm3 with extremes of 0.7 cm3 and 14.46 cm3.

7 6 5 4 3 2

1 Number Number of patients 0 0-5 5-10 10-15 Targeted volume (cc)

Figure 38: Irradiated volume (in cm3)

4) Post-surgical evaluation of patients

i. Follow-up duration

The mean follow-up duration in our series was 48 months with extremes at 6 and 96 months.

120

100 96 80 84 60 72 56

40 48 48 48

up duration (months) up duration - 20

Follow 6 18 6 0 1 2 3 4 5 6 7 8 9 10 Cases

Figure 39: Follow-up duration for each cases of our series ii. Success/ failure rates:

Of the 10 interventions made at the NCRNS in Rabat:

 8 patients reported an improvement in their epilepsy, becoming seizure free or witnessing a significant decrease in their seizure frequency.

 2 patients did not report improvement in their epilepsy.

No change

Improvement

0 2 4 6 8 10

Figure 40: Post-radiosurgical status of patients

Based on the exploitable data concerning 10 interventions (8 successes and 2 failures), the success rate of Gamma Knife Radiosurgery for epilepsy is 80%, against a failure rate of 20%.

2; 20%

Success Failure

8; 80%

Figure 41: Success and failure rates of RS in epilepsy.

A. Success rates in Hypothalamic Hamartoma

4 patients reported a cessation of their epileptic seizures since the same year they had their procedure done, and 1 reported rare disabling seizures within a 6-month follow-up. B. Success rate in Cavernoma

The only case of frontal cavernoma was first seizure free immediately after the intervention then later on reported a seizure recurrence concomitant to an attempt of AED reduction, before regaining seizure freedom again and maintaining it since 2017, as in 6 years after LGKS. C. Success rate in Tuberous Sclerosis

The one case of TS reported a worthwhile improvement with a frequency decrease of his epileptic seizures, from 15-16 per day to 4-5/day. D. Success rate in Lennox-Gastaut Syndrome

The case with callosotomy reported no change in his condition, with the persistence of daily seizures at the same frequency.

E. Success rate in Heterotopia:

The patient treated for epilepsy related to heterotopia reported no change; with the same seizure frequency. F. Mesial Temporal Glioma:

The case with epilepsy related to mesial temporal glioma became seizure free but only two years after the procedure.

Hypothalamic hamartoma Tuberous Sclerosis Lennox Gastaut Syndrome

Success Success Success Failure Failure Failure

5; 100% 1; 100% 1; 100%

81 Heterotopia Mesial Temporal Glioma Cavernoma

Success Success Success Failure Failure Failure

1; 100% 1; 100% 100%

Figure 42: Success and failure rates of GKS for each etiology in our study

iii. Appearance of the first therapeutic effects of radiosurgery

The median time to onset of the first effects of LGKS is immediately after the treatment. Extremes are 0 and 24 months.

Out of 8 cases who reported effects of RS, 6 presented them immediately after the intervention, as in 75% of the patients, including 1 case who later on reported seizure recurrence. iv. Personal appreciation of the patient's improvement

Patients' personal appreciation of their improvement at 6 months and 1 year is estimated at 71%. 4 patients became seizure free immediately after their intervention, including 1 patient who later on reported seizure recurrence concomitant to an attempt of AED reduction, before regaining again seizure freedom 6 years after GKS. 2 patients became seizure free respectively 3 months and 2 years after their intervention, 2 patients reported a significant reduction of their seizure frequency immediately after their intervention. 2 patients did not report any change after their procedure, with the persistence of epileptic seizures at the same frequency. v. Engel Epilepsy Surgery Outcome Scale:

In order to classify the post-therapeutic outcomes of epilepsy surgery, Jerome Engel proposed a classification; "Engel Epilepsy Surgery Outcome Scale ", which has since taken its place as standard de facto for the evaluation of post therapeutic results in academic medical publications.

 Class I: Free of disabling seizures

 Class II: Rare disabling seizures ("almost seizure-free")

 Class III: Worthwhile improvement

 Class IV: No worthwhile improvement

 Out of 10 patients, 6 were class I, 1 was class II, 1 was class III and 2 were class IV.

Class IV 20%

Class III 10%

Class I 60%

Class II 10%

Figure 43: Engel Epilepsy Surgery Outcome Scale vi. Complications:

No complications have occurred during or after RS, with 0% mortality.

Table 7: Summary table of the clinical aspects of our patients

Age at Familial Age Duration of evolution ID Gender Neonalal suffering Anomaly PMD Treatment history At first seizure (years)

1 Female 37 yo No No No 7 yo 30 2 Male 12 yo No NA NA NA NA 3 Male 9 yo No Yes Yes 3 yo 6

4 Female 2 yo No NA NA NA NA 84

5 Female 6 yo No Yes Yes 40 Days 6 6 Male 20 yo No NA NA NA NA 7 Male 5 yo No Yes Yes 3 Weeks 5 8 Male 15 yo No Yes Yes 2 Months 15 9 Male 29 yo No No No 3 Months 29 10 Female 9 yo No No Yes 5 days 9

Table 8 : Summary table of the clinical aspects of our patients (continued)

Epileptic ID Seizure description Seizures frequency MRI Etiology AED state Carbamazepine, 1 Tonico-clonic seizures 1-3 seizures/month No Right frontal cavernoma Frontal Cavernoma Lamotrigine, Phenobarbital Grade II mesial temporal 2 Temporal seizures 2-3 seizures/day NA Mesial temporal Glioma NA Astrocytoma Gelastic + atonic seizures with Hypothalamic hamartoma 3 3-4 seizures/week No Hypothalamic Hamartoma Carbamazepine cognitive delay (pre-mamilar, left paramedian) Gelastic seizures, no 4 6-8 seizures/day NA Hypothalamic hamartoma Hypothalamic Hamartoma NA neurological damage Frontal seizures at 25 days, Valproate, Carbamazepine, 5 4-5 seizures/day Yes Hypothalamic hamartoma Hypothalamic Hamartoma gelastic seizures at 4 yo Phenobarbital

85 Nodular left frontal para- 6 Frontal seizures Daily seizures NA Left frontal Heterotopia NA ventricular heterotopia Simple partial seizures with Valproate, Carbamazepine, 7 15-16 seizures/day No Multiple cerebral tubers Tuberous Sclerosis motor signs Lamotrigine Atonic seizures (Lennox Valproate, Clobazame, 8 Gastaut Sd) + severe epileptic Daily seizures No (Corpus callosotomy) Lennox-Gastaut syndrome Lamotrigine sequelae 9 Gelastic seizures 4-5 seizures/day No Hypothalamic hamartoma Hypothalamic Hamartoma Clonazepam, Phenobarbital Gelastic and dacrystic seizures 10 with psychomotor and 10-15 seizures/day No Hypothalamic hamartoma Hypothalamic Hamartoma Valproate language delay

Table 9 : Summary table of our patients’ treatments with LGKS

Dose at 50% Year of Stereotactic Targeted Treatment ID System used isodose line Number of shots Complications intervention device volume (cc) duration (Gy)

1 2011 PERFEXION LGKS 0.7 24 6 collimators (4-8mm) 4 hours No

2 2012 PERFEXION LGKS 13 14 52 collimators (4-8mm) 5 hours No

3 2012 PERFEXION LGKS 1.03 14 17 collimators (4-8mm) 5 hours No

33 collimators (4-8- 4 2014 PERFEXION LGKS 3.87 14 6 hours No 16mm)

86 5 2014 PERFEXION LGKS 14.46 12 44 (4 - 8 mm) 6 hours No

6 2015 PERFEXION LGKS 1.17 24 14 collimators (4mm) 5 hours No

7 2016 PERFEXION LGKS 10.4 22.24 10 (4,8 and 16mm) 6 hours No

8 2017 ICON LGKS 2,4 24 27 collimators (4-8mm) 5 hours No

9 2017 ICON LGKS 1 20 15 (4 mm) 4 hours No

10 2019 ICON LGKS 3,7 13 67 (4-8mm) 5 hours No

Table 10 : Summary table of our patients’ evolution after treatment with LGKS

Delay of Medical Follow up ENGEL AEDs used I appearance of Seizures frequency Treatment D duration (months) first effects after GKS Classification After GKS needed

96 After GKS, then Seizure free (6 Carbamazepine, Lamotrigine 1 Class I Yes recurrence years after GKS)

2 72 2 years Seizure free Class I NA NA

3 84 Since GKS Seizure free Class I No -

4 48 Since GKS Seizure free Class I No -

5 56 Since GKS Seizure free Class I No - 87

6 6 - No change Class IV Yes NA

Since GKS Valproate, Carbamazepine, 7 48 4-5 seizures/day Class III Yes Lamotrigine

Valproate, Clobazame, 8 18 - No change Class IV Yes Lamotrigine

3 months Carbamazepine, Lamotrigine, 9 48 Seizure free Class I Yes Clobazame

10 6 Since GKS Daily seizures Class II No -

Discussion

I. Defining medically intractable epilepsy:

In 2010, the International League Against Epilepsy established the current definition of drug- resistant epilepsy as ―failure to achieve sustained seizure freedom with adequate trials of at least two appropriately chosen and used AED regimens (whether administered as monotherapies or in combination)‖ (64). However:

-Inappropriately or inadequately used AEDs do not count toward establishing drug resistance, and if the former cannot be assessed, the outcome of that particular AED is considered as ―undetermined‖ for the individual patient.

-AED side effects are of crucial importance in clinical practice but were not included as a defining factor of drug resistance because the focus was on lack of response, rather than poor tolerability (65).

-Seizure freedom refers to seizure freedom from all seizure types, big and small, as recognized by patients, caregivers, and the clinical team.

-Sustained seizure freedom has to last at least 1 year or three times the previous longest seizure-free period, whichever is longer.

This time period has a practical rationale (e.g., employment, driving, decision to start or change AED) and was derived from the statistical ―rule of 3,‖ in which the 95% probability of seizures not occurring is roughly equivalent to three times the longest seizure-free period previously experienced by the patient (65). This definition has clear implications for considering surgical evaluation and candidacy earlier, rather than later. II. Historical review: The beginnings of Stereotactic Radiosurgery in epilepsy:

Lars Leksell conceived Gamma Knife (GK) radiosurgery as a tool for functional neurosurgery (66) (67). Accordingly, he used GK in movement disorders, trigeminal neuralgia and other pain syndromes, but not for epilepsy surgery (68). The ﬁrst radiosurgical treatments for

epilepsy surgery were performed by Talairach in the 1950s (69). Talairach was another pioneering expert in stereotaxis. Unlike Leksell, he had specific involvement in epilepsy surgery and led one of the first large, comprehensive programs for epilepsy surgery. As early as 1974, he reported on the use of radioactive yttrium implants in patients with mesial temporal lobe epilepsy (MTLE) without space-occupying lesions and showed a high rate of seizure control in patients with epilepsies confined to the mesial structures of the temporal lobe (69). In 1980, Elooma (70), apparently ignoring the pioneer work of Talairach, promoted the idea of the use of focal irradiation for the treatment of temporal lobe epilepsy, based on the preliminary reports of Tracy, Von Wieser, and Baudouin (71) (72). Furthermore, clinical experience of the use of GK- and linac-based radiosurgery in arteriovenous malformations (AVMs) and cortico-subcortical tumors (mostly metastases and low-grade glial tumors) revealed an antiepileptic effect of radiosurgery in absence of necrotizing effect (73) (74) (75). A series of experimental studies in small animals confirmed this effect (76) (77) and has emphasized its relationship to the dose delivered (78) (79) (80) (81). Barcia-Salorio et al., and later Lindquist et al., reported small and heterogenous groups of patients treated with the aim of seizure cessation; results were however poor (82) (83) (68) (84). Unfortunately, these data were never published in peer-reviewed papers and precise information is unavailable (23-26) III. Mechanism of action: Effects of radiosurgery on epileptic lesions:

Investigations of the effects of focal irradiation on epileptic lesions in experimental animal models of partial epilepsy are few but carry some common findings that are important when evaluating trials of GKS in human epilepsy. (85)

First, experimental models of focal epilepsy demonstrate that destruction of neuronal tissue through radionecrosis is not required for amelioration of seizures or their experimental surrogates. Second, seizure response, either in successful remission or in a paradoxical worsening, varies with target, dose, or postoperative duration. Third, the treatment target,

dose, and volume remain empirically determined, and scaling up from experimental models to humans is not straightforward. (86)

It is not known how gamma irradiation produces an antiepileptic effect. Sensitivity to ionizing irradiation is largely dependent on mitotic rate; therefore, neurons are relatively radioresistant. In flurothyl-kindled mice, although total brain irradiation terminates seizure-induced mitotic activity in hippocampal dentate gyri, irradiated mice have no changes in seizure threshold or clinical seizure phenotype. Therefore, the differences in mitotic activity in epileptic areas may not underlie antiepileptic effect. (86) Tissue necrosis is not necessary. (87) (78) (79) (80) Histologic examination of irradiated rat hippocampi shows changes of experimental hippocampal sclerosis rather than changes typical of acute or chronic severe radiation injury. (87) (78) (79) (80)

Although neurons themselves are resistant to radionecrosis, supporting structures— vasculature and glia—are not. The major pathological findings after irradiation consist of endothelial damage to small blood vessels and astrocytic reactions. One hypothesis, therefore, is that neuronal damage results from ischemia caused by vascular inflammation.

Other hypotheses suggest that irradiated neuronal circuits undergo neuromodulation that renders an anticonvulsant (or, sometimes, a paradoxically proconvulsant) effect. Differential susceptibility to irradiation or ischemia among different neuronal populations within epileptogenic circuits may account for this phenomenon. (88)

Given these possible mechanisms, studies with the use of well-validated models of partial epilepsy address some of the questions of target, administration, time course, and clinical sequelae. These models include electrically kindled rats (87) (89) studied through surrogate markers of triggered seizure threshold and severity, as well as rat models that experience spontaneous seizures induced either by kainic acid (79) (80) or by electrically provoked, self- sustained limbic status epilepticus (78).

The earliest of these series established that there might be a proconvulsant or anticonvulsant effect of GKS that varies with postoperative duration or dose. Kindled rats with doses of 25 Gy or less to the amygdala experience clinically more intense seizures. (89) Kindled rats treated with 40 Gy to a single hippocampus initially experience a decrease in seizure 91

threshold compared with controls within the first month. Thereafter, however, treated animals develop increased seizure thresholds. (87)

Other experiments established relationships between dose and latency with experimental spontaneously occurring seizures. (78) (79) (80) In animals monitored for 6 weeks, doses of 80 and 100 Gy cause seizure reductions within 2 to 4 weeks postoperatively, whereas lesser doses cause reductions of slower onset. (141) Increasing doses of radiosurgery correlate with higher percentages of rats that became seizure-free. (80) Other studies indicate that there is a threshold effect, with single treatments of 30 Gy being as effective as 60 Gy in reducing seizures. (79) This suggests that, once a tissue-damaging level has been reached, there is little advantage in increasing the radiation dose. Long-term electroencephalogram monitoring for periods of up to 10 months establishes that the anticonvulsant effects of GKS are durable (78).

In summary, it seems clear from the preclinical literature that there is a dose-dependent response to radiation. These experiments help define a therapeutic window of treatment dose bounded by ineffectiveness, paradoxic exacerbation, or delayed remission at the lower doses and by tissue necrosis at higher doses. Evaluation of human studies, therefore, requires particular attention to treatment dose, volume, and target. IV. Specific Indications of Stereotactic Radiosurgery in epilepsy:

1) Treatment of lesional epilepsy

The anticonvulsant benefits of GKS were first observed as additional benefits during its use as a treatment of tumors (90) or arteriovenous malformations (AVMs). (73) (91) (92) (93) (94) i. Supratentorial Tumors

Given the variety of types, pathological features, and locations of central nervous system tumors, the studies of effects of GKS on tumor-associated epilepsy are few. Schröttner et al,

(90) however, concentrated on patients with medically intractable epilepsy resulting from tumors, dividing 24 patients into 2 groups by the amount of radiation directed to surrounding tissue. Outcome was retrospectively ranked at mean duration of approximately 2 years as ―excellent‖ (Engel class 1 or 2) or not. Patients in the high-dose group achieved a 66% improvement rate compared with 42% for the low-dose group. Because all patients achieved tumor control with GKS (thus removing tumor response as a potential confounder), the differing rates of seizure improvement suggest that higher GKS doses are important in modifying epileptogenic changes in cortex adjacent to tumor.

Our study includes 1 patient treated for tumor-associated epilepsy as he presented with a mesial temporal glioma (grade II astrocytoma). During a follow up of 72 months, the patient reported seizure freedom 2 years after GKS. ii. Arteriovenous Malformations

The potential efficacy of GKS in the treatment of symptomatic localization-related epilepsies is most evident in the treatment of AVM (73) (91) (92) (93) (94) (Table 11). Representative is the large series accumulated by Steiner et al, (91) who reported that seizures remit after GKS in 69% of patients with AVM and epilepsy. Subsequent studies of both proton beam treatment and GKS show a combined rate of seizure remission of approximately 70% (Table 11). A recent large case series emphasized that the incidence of seizure remission is better with smaller AVMs. (94) However, Steiner et al (91) noted that seizures remitted independent of radiologic remission of the AVM, a finding that suggests that the effects of irradiation near the lesion, rather than the improvement of the AVM itself, may be important in control of seizures after GKS.

Table 11: Seizure remission after stereotactic radiosurgery of arteriovenous malformations Number of Duration of Remission Study Outcome2 patients Follow-up1 Nb (%) HEIKKINEN ET AL, 29 2-6 years Cessation 16(55) 1989 STEINER ET AL, 1992 59 24-96 mo Cessation 41(69) GERSZTEN ET AL, 1996 15 47 mo Cessation 11(73) KURITA ET AL, 1998 35 43 mo Cessation 28(80) SCHAUBLE ET AL, 2004 65 4 years EC, < 4 48(74) TOTAL 204 144(70) Abbreviation: EC: Engel class 1: Reported as mean or range 2: Definition of clinical seizure improvement

All patients with AVMs treated by GKS in our center benefited from a curative treatment targeting the lesion (rather than the epilepsy itself as a primary indication), therefore, were excluded from this study. iii. Cavernous Malformations

With the favorable results encountered in treatment of seizures associated with AVMs and tumors, investigators began to explore the efficacy of GKS in other epileptic lesions. Table 12 shows a summary of the efficacy of GKS in the treatment of seizures associated with cavernous malformations. (95) (96) In general, seizure remission is lower than that encountered in cases after treatment of AVMs. The effect of dose to adjacent brain around the margin of the cavernous malformation, thought important in the case of tumors (90) and possibly AVMs, (146) has not been systematically studied in terms of seizure control (although higher doses may have more problems with radiotoxicity and lower doses with rebleeding). (96) Excess morbidity in terms of postoperative hemorrhage remains a concern. For example, the early Swedish experience determined that GKS did not appreciably alter the natural course of cavernous malformation while exposing patients to radiation-induced complications that exceeded by 7 times those expected for the same dose for AVMs. A recent retrospective comparison concluded that traditional open resection resulted in better seizure control and rebleeding avoidance than did GKS. (96)

Our study includes 1 patient with frontal cavernoma. Within a follow-up period of 96 months, the patient was first seizure free immediately after the intervention then later on reported a seizure recurrence concomitant to an attempt of AED reduction, before regaining seizure freedom again and maintaining it since 2017, as in 6 years after LGKS.

Table 12: Seizure remission after stereotactic radiosurgery of Cavernous Malformations

Number of Duration of Remission Study Outcome2 patients Follow-up1 Nb (%) BARTOLOMEI ET AL 49 24 mo EC, 1 26(53) 1999 KIM ET AL, 2005 12 30 mo Cessation 9(75) LISCAK ET AL 2005 44 48 mo Cessation 20(45) LIU ET AL 2005 28 5,4 years EC, < 4 15(54) SHIH AND PAN 2005 16 46 mo Cessation 4(25) Our study 2019 1 96 mo Cessation 1(100) TOTAL 150 75(50) Abbreviation: EC: Engel class 1: Reported as mean or range 2: Definition of clinical seizure improvement

iv. Hypothalamic Hamartomas

Hypothalamic hamartomas are an important cause of an epileptic encephalopathy marked by medically intractable gelastic and other seizures, behavioral and cognitive decline and/or neuroendocrine dysfunction. Although HHs are difficult to excise with the use of standard surgical techniques, GKS has the advantage of providing noninvasive access while sparing adjacent tissue. This was first described in a case report of an adult patient in 1988. A multicenter retrospective study of GK RS by Régis and colleagues (97) in 2000 showed promising results in 10 patients, with 4/10 becoming seizure free and 3/10 showing significant improvement, without persistent adverse effects. This paved the way to a prospective study by Régis and colleagues (98) (99) (100) in Marseille, from 1999 onwards, which has to date recruited over 60 patients; long-term data is available in 48 patients (101). An ongoing prospective observational GK study by Mathieu and colleagues (102) (103) has to date

reported 12 patients. Results are summarized in Table …, which highlights the small number of studies with adequate follow-up data.

Prospective trials with GK showed an effect of lesion size and topological classification, whereby small intrahypothalamic hamartomas had the best outcome (101). Although various means of classifying HH exist (104), Régis and colleagues proposed a classification of HH into 5 categories (appendix 3) according to anatomical features and size (99) and used this in analyzing the results of their prospective trial, as did the Quebec group in their prospective observational study (103). These studies agree that Régis classification types I–III HH, especially type I HH (small hamartomas located within the hypothalamus and extending more or less into the third ventricle) are associated with best results. While Mathieu et al. suggested that good epilepsy outcome in smaller HH may be due to treatment of the whole lesion (103), the study by Régis and colleagues observed seizure free outcome in 2 patients who had only partial coverage of the lesion (97). This is in keeping with findings from HH surgery, whereby marked seizure improvement is not inevitably related to complete resection (105). Observational studies indicate a possible effect of dose in HH: GK doses >17 Gy were used in all patients who became seizure-free, whereas doses of <13 Gy were never associated with seizure freedom (97). Outcome according to dose was however not specifically reported in their prospective study results (99) (100). Mathieu and colleagues (103) reported that 4/6 patients with smaller (Régis grade I–III) HH treated with 14–20 Gy became seizure free. Multi-isocentric dose planning is often required for optimal coverage of the lesion, with a range of 2–36 isocenters (median 9) reported by Régis et al (99).

Various surgical approaches for HH have been proposed (106). Available data from prospective trials indicate comparable or better results using GK, at least for smaller HH, with markedly reduced rate of adverse eﬀects. A single small retrospective study of LINAC-treated patients with HH (107) found similar results to those reported with GK.

Improvement in seizure control (seizure free or only rare gelastic seizures) was reported in 60% of patients in the French prospective trial (99) and 66% in the smaller Canadian prospective observational study (103). The Canadian study found poor results in all cases of

attempted radiosurgical disconnection of the HH in patients with large (Régis grade IV–VI) lesions (103).

Improvements not only in seizure control but also in behavior and sleep pattern have been frequently observed (100). Positive eﬀect on behavior tended to occur early, in the ﬁrst weeks following GK, and continued to improve during a 2–6-month period post-GK, despite persistent seizures at this time (100). Interestingly this period corresponds to improved sleep patterns and EEG normalization (100). Reduction in seizures was typically observed at a later phase, sometimes preceded by a seizure ―peak‖ as described for GK treatment of MTLE (108) (109), followed by disappearance of seizures and stabilization of the clinical picture. Longer term experience highlights the need to allow at least 3 years follow up for adequate evaluation of seizure outcome (99) and even longer for assessment of cognition and behavior (103). Good seizure control (Engels Class I or Class II) was seen in 68.8% at >3 years follow up in the prospective cohort (101). Studies agree on the tendency for neurobehavioral improvement after GK for HH, which seems not entirely dependent upon seizure outcome (110); neuropsychological function and quality of life measures are encouraging (102) (101). No major adverse events have been reported (103) (100); rare cases of poikilothermia (98) and transient worsening of seizures have been described but no endocrine disturbance (100).

In our study, which includes 5 patients with HH, the average duration of follow up is 48 months. 4 patients reported a cessation of their epileptic seizures since the same year they had their procedure done, and 1 reported rare disabling seizures within a 6-month follow-up. The series of cases with HH is by far the most successful one, with 100% seizure remission.

Table 13: Hypothalamic hamartoma outcomes in prospective or retrospective studies with >4 adult patients included and at least 2 years’ follow-up data provided Marginal Treatment Minimum Satisfactory Case Neurocognitive Psychosocial Author, year Age1 dose volume follow up Adverse Effects seizure number outcome outcome (Gy)1 (mm3)1 (months) outcome2 NB from Régis et al 2016 (in press): 45 patients with  No major adverse 57 psychiatric effects. Régis et al. 20063 treated morbidity: 28-1600  Transient no decline for (99) 48 with 3-50 14.25 36  resolution 15/45 (398) poikilothermia 3/57 33/48 (68.8) available Régis et al, 20073 follow- (16.5) (17) (33%), (6%). information: 39 (100) up  improved in  1 case of thyroid 23/45 (51%), dysfunction  stable in 6 (14%);  deterioration in 1/45 (2%) Matthieu et al,  No serious adverse 300-1000 20103 (103) 24 effects: 3/ 4 improved 7 12-57 14.20 mm3 6/7 (86%) Improved QOLlE 98 Bourgeois et al,  3 transient psychiatric 1/4 stable 3 (102) 2013 disturbances 134-  No serious adverse Régis et al 20004 1-32 2674.8 events. 7 24 5/7 (72%)  Not specified Not reported in detail (97) (14) mm3  1 case non-disabling (646,7) poikilothermia  1 poikilothermia, 5.7- 169-3000 16-20  1 increased depression;  No adverse QoL considered Abla et al 20104 29.3 mm3 (111) 8 (median  2 weight gain/increased 3/8 (37.5%) effects on improved in 9/10 (mean (mean 18) appetite; cognition; patients 15.1) 695)  1 anxiety 5 2-29 12-20 100-1446 6  1 weight gain + 5/5 (100%) Not specified Not specified (9) (median mm3 Our study4 endocronological effect 14) (median (Mean at 370) 48) 1: Reported as range (median) 3: Prospective studies 2: Engel class I or II 4: Retrospective studies

v. The particular case of Tuberous Sclerosis

For tuberous sclerosis complex patients with intractable seizures arising from well-mapped epileptogenic zone that may be localized in or adjacent to eloquent cortex, stereotactic radiosurgery has the potential to represent a suitable alternative to resective surgery in the future. One of the authors (Rodas, unpublished data) has used Linear accelerator stereotactic radiosurgery to treat four tuberous sclerosis complex patients: two with subependymal nodules and two with subependymal giant cell astrocytomas. One patient presented with intractable seizures, two with obstructive hydrocephalus, and one with medically controlled seizures. The patient with intractable seizures had right paraventricular-frontal subependymal nodules. After subtotal resection of the nodule, the seizures remained medically refractory. Radiosurgical treatment of the residual lesion (volume: 8.4 cm3) was then offered with a 40% reduction in seizure frequency within the first week after stereotactic radiosurgery. This patient is currently seizure-free (off medications, with magnetic resonance imaging evidence of tumor shrinkage) 22 months after stereotactic radiosurgery. To the best of our knowledge, this is the first report illustrating the use of stereotactic radiosurgery in tuberous sclerosis complex patients with intractable seizures. Although these findings by no means can be considered as indicative of the efficacy of the method, which still needs rigorous clinical verification, they have provided some encouragement for future studies. (112)

We report one case of a patient treated by GKS radiosurgery for epilepsy related to Tuberous sclerosis. During a period of follow-up of 48 months, the patient’s parents reported a significant improvement of his epilepsy, with a decrease to 4-5 seizures per day, and was still under the same triple AED therapy. 2) Treatment of physiologic epilepsies

i. Mesial Temporal Lobe Epilepsy

Mesial temporal lobe epilepsy consists of atrophy, specific neuronal loss, and gliosis within the limbic system, most notably within the amygdala-hippocampus. Mesial temporal lobe

epilepsy is the most frequent cause of medically intractable epilepsy in adults. The rationale for its treatment with GKS is less compelling than in the disorders discussed earlier because MTLE is amenable to open surgery.

Open surgery, however, has a small, but real, risk of perisurgical complications such as bleeding, infection, and postoperative pain. Second, open surgery is expensive. Although a formal cost comparison for epilepsy treatment has not been done, the average cost per patient for open microsurgery was nearly 50% more than that for GKS for treatment of similar disorders. (113) Third, some of the reported adverse events of temporal lobectomy involve changes in results of neuropsychological testing. Fourth, some patients are reluctant to undergo elective open surgery with required inpatient stay and general anesthesia despite proven efficacy. Thus, GKS may offer a noninvasive alternative to open surgery in the pursuit of less postsurgical morbidity and less cost.

Unfortunately, initial attempts at epilepsy radiosurgery in Sweden were not encouraging. (114) Barcia et al (115) in 1994 described 11 patients treated for ―idiopathic focal epilepsy‖; only 4 became seizure-free. Régis and colleagues (116) revived interest in GKS for MTLE in 1995 when their pilot studies showed high rates of seizure remission. Table 14 summarizes published cases; notably, all differ in treatment protocols and results, with most failing to achieve complete remission from seizures. (117) (118) The variability in results of GKS therapy for MTLE underscores the difficulties in the determination of basic variables of anatomic target, dose, and target volume.

Anatomic targets in GKS for MTLE are the least variable factor. All of the studies in Table 14 specify that the 50% isodose volume contains regions thought most important in the generation of mesial seizures: the amygdala, the head and anterior body of the hippocampus, and the parahippocampal gyrus (Figure 44). Dose and target volume are more variable. Comparison of the studies listed in Table 14 suggests that low-dose protocols are less successful than higher-dose protocols. Volume-response curves from preliminary studies by Régis demonstrate a relatively steep curve that separates ineffective treatment from excessive toxicity stemming from radiation-provoked edema (Figure 45) (Jean Régis, MD, oral and written communication, October 17, 2005).

100

Régis et al (118) outlined the typical postoperative course, and in most respects, it follows the polyphasic course described after GKS for HHs (99). No significant clinical or neuroimaging changes occur until 9 to 12 months after surgery. (116) (117)-, (118) Nearly all patients experience transient exacerbations in auras before seizures decrease or remit. (118) The most dramatic drop in seizure rate occurs between 12 and 18 months, coinciding with the development and resolution of maximal changes on magnetic resonance images (Figure 46).

Other morbidities reported by Régis et al (118) include visual field deficits in 52% of patients, mostly quadrantanopia as usual after standard anterior temporal lobectomy. One subject had a hemianopia (indicating direct involvement of the optic tract) and another had mixed deficits. (118) Other ―transient minor morbidities‖ consisted of headache, nausea, vomiting, and depression. Headache requires special comment because it coincides in some subjects with postoperative edema. (118) Corticosteroids, given in response to headache, visual field changes, or magnetic resonance imaging changes, were used in most of the patients included in Table 14, but no clear evidence supports specific guidelines for corticosteroid initiation, its effectiveness in treating symptoms, or its effects on eventual seizure remission. In fact, Régis et al (118) reported that 38% of subjects were not treated with corticosteroids at any point in the postoperative course.

One important factor in consideration of GKS compared with open surgery is that the delayed effect of treatment may expose patients to the continued morbidity of ongoing seizures, including sudden unexpected death in epilepsy and traumatic injury. Two deaths occurred during the latency period in a case series of 5 patients treated with ―low-dose‖ radiation (119) (Table 14). Allowing enough time for maturation of the radiosurgical lesion may have allowed some patients treated with lower doses to demonstrate remission, given that animal models treated with lower doses demonstrated improvements at a slower rate than those treated with higher doses. (79) (80) Future trials of GKS may need to consider supplementary seizure prophylaxis during the period of transient exacerbation of auras and seizures.

Beyond seizure efficacy, studies have begun to evaluate secondary outcome measures such as cognition and quality of life. Epileptic rats demonstrate no behavioral effects attributable to GKS. (79) In humans, 3 reports of neuropsychological outcome after GKS for MTLE are

101

available: the previously noted prospective, multicenter trial (118) and 2 studies of small series of participants. (119), (120) Prospective trial results report no mean neurocognitive changes through a 2-year follow-up period. (118) Similarly, Srikijvilaikul et al (119) reported no group mean changes at 6 months of follow-up, although some individuals showed decline in at least 1 cognitive domain. McDonald et al (120) reported on 27-month follow-up in 3 participants who underwent dominant-hemisphere low-dose GKS treatment. No long-term consistent changes in neurocognitive measures were found, although each patient showed decline in a measure of verbal memory. They concluded that neurocognitive changes after GKS appeared similar to those of anterior temporal lobectomy.

In summary, GKS for MTLE appears to have promise, but dose and relative benefits have yet to be clearly demarcated from those of open surgery. A National Institutes of Health– sponsored multicenter pilot study on the safety of GKS for MTLE has recently been completed. In that study, patients who would normally qualify for anterior temporal lobectomy for unilateral MTLE were randomized to either a 20- or 24-Gy dose. A total of 30 subjects were enrolled and followed up for 3 years. Preliminary results are promising, with safety well within that expected after routine GKS with favorable efficacy and neuropsychological profiles.

Table 14: Seizure remission rates (defined as Engel Class 1) of SRS for MTLE

102

Figure 44: A screen capture of GK planning for a patient with right MTLE

The 50% isodose lines (yellow) delineate the treatment volume that contains the amygdala, anterior 2 cm of the hippocampus, and the parahippocampal gyrus that will be exposed to at 50% of a total treatment of 24 Gy. Green lines indicate 8 to 10 Gy 50% isodose lines so as to limit radiation exposure to brainstem or optic nerve. Note that the treatment volume excludes the brainstem and optic nerve from excessive radiation exposure. To achieve this plan, 6 separate dose isocenters created the complex shape required.

103

Figure 45: Volume-dose relationships of preliminary studies of GK treatment of MTLE (unpublished data courtesy of Jean Régis, MD, October 17, 2005).

Volume along the x-axis denotes the 50% isodose volume with treatment doses of either 20 or 24 Gy, and on the y-axis a 5-point scale denotes the qualitative severity of magnetic resonance imaging changes due to Gamma Knife surgery. A narrow window ranging from 5.5 to 7.0 mL defines a breakpoint between low remission of seizures and excess toxic effects as determined by magnetic resonance imaging.

Figure 46: Serial MRI changes (top row, T2 weighted; bottom row, fluid- attenuated inversion recovery) in a representative patient with right unilateral MTLE treated with 20 Gy

104

As described in earlier reports, high-intensity changes and swelling representing reactive edema develop at and around the surgical target at approximately 9 to 12 months after surgery. Auras may worsen between 6 and 12 months, and frank seizures begin to remit at around the same interval. Edema resolves by 24 months after surgery, leaving behind a small region of tissue loss and trace high-intensity signal within the target.

In our series, this indication of GKS was not performed as all patients with MTLE benefited from an open surgical resection due to the lack of invasive monitoring enabling a precise localization of seizures at the level of mesial structures. This technique is still not available in our center. ii. Other Non-lesional Epilepsies

There are not enough published data on the use of GKS for non-lesional neocortical foci. Because localization of seizure onset in these cases usually requires invasive techniques, the noninvasive nature of GKS loses some advantage. One may speculate that, if noninvasive localization and brain mapping were rigorous enough to identify foci and function of the neocortex, GKS may have a future role. A. Corpus callosotomy

Resection of the corpus callosum decreases the severity and number of primary generalized or rapidly propagating secondarily generalized seizures in patients who are not otherwise good surgical candidates. Small case series report that improvement in seizures after GKS resection of the corpus callosum was comparable to that reported after open callosotomy, with lack of notable complications. (121), (122).

In RS anterior corpus callosotomy, high doses of radiation (55–170Gy) (123) (124) (121) (122) within a relatively small volume produce focal destruction of callosal ﬁbers (Figure). There is thus a much higher dose-volume ratio in RS corpus callosotomy than in MTLE. A total of ~19 children and adult cases have been described in the literature. Reports have described anterior (123) (124) (121) (122) and, less commonly, posterior (121) (125) callosotomy in adults and children, often in Lennox Gastaut syndrome with drop attacks.

105

While nearly all have used GK, a single case study showed similar outcome using LINAC (124) . Although no seizure freedom has been reported, signiﬁcant improvement in disabling seizures (generalized tonic-clonic seizures (GTCS) and/or drop attacks) has been described across all published studies, with no serious adverse eﬀects so far indicated. Seizure types other than drop attacks and GTCS responded less well in the largest single series (8 patients). (126)

Improvement in seizure control occurs earlier than in GK treated MTLE, with median delay of around 3 months (122) Focal radionecrosis followed by atrophy in the corpus callosum has been shown on MRI, and diﬀusion tensor imaging in a single subject (127) suggests that GK produces axonal degeneration of callosal ﬁbers.

Figure 47: Dose-planning of a callosotomy. The sagittal view is showing that the 50% isodose line (55 Gy) covers more than the anterior half of the corpus callosum

Our study includes one patient who benefited from a corpus callosotomy by GKS as he suffered from Lennox Gastaut Syndrome with daily drop attacks and severe epileptic sequelae. However, within a follow-up period of 18 months, no change in his condition was reported, as he continued to have daily seizures at the same frequency, and was therefore kept under the same triple AED therapy.

106

B. Periventricular nodular heterotopia (PVNH)

PVNH is a neuronal migration disorder characterized by masses of gray matter located along the lateral ventricles in varying distribution. Although the clinical symptoms in these patients can vary, the most common presentation of PVH cases is epilepsy. Resective surgery for PVNH is limited by its deep location, and the overlying eloquent cortex or white matter. Noninvasive modalities of ablating this epileptogenic focus must therefore be considered.

Our study includes one patient with periventricular heterotopia, who reports no change in his condition 6 months after the procedure. V. Limits of our study:

 The small sample of patients, with many lost to follow-up.

 The diversity of etiologies within a small population does not allow to have a representative sample for each etiological profile.

 The limited follow-up period for some patients.

 The placebo effect cannot be ruled out because of the knowledge of the intervention performed by the patients and the examiners and the absence of a control group.

107

Conclusion

108

Radiosurgery Gamma Knife is an effective and safe technique for the treatment of drug- resistant epilepsies, and an interesting alternative to be considered in elective cases. Not only the results obtained by this technique are comparable to those obtained by other surgical treatments especially in cases of tumor-related epilepsies, AVMs and MTLE, but it is also considered the gold standard treatment for Hypothalamic Hamartoma.

It has several advantages, including the few contraindications for this non-invasive technique, the patient's comfort with a short hospital stay, the absence of infectious and hemorrhagic risks, and the relatively low cost compared to deep brain stimulation and other surgical techniques.

It has a stable long-term effect with little recurrence of epilepsy in case of seizure freedom. Its complications are often transient and if persistent, are rarely disabling. Its disadvantages are the lack of electrophysiological tracking and intraoperative evaluation of the results.

This technique is undeniably a contribution to the therapeutic arsenal of drug-resistant epilepsy in its various etiologies. Despite its availability in Morocco for more than a decade, it is still little known by health professionals (40). A communication network between neurologists and neurosurgeons is necessary to raise awareness about the innovations concerning each specialty, especially for pathologies such as epilepsy, the management of which is multidisciplinary.

The Gamma Knife Radiosurgery unit of the NCRNS is a reference center for all of Morocco and a good number of African countries. The development of a standardized evaluation procedure and a common monitoring protocol would be desirable in order to ensure better patient management, early detection of complications and the possibility of long-term scientific studies.

Finally, research continues to better understand the pathophysiology of epilepsy, refine current treatment techniques and develop new therapeutic methods.

109

Abstracts

110

Abstracts

Résumé

Titre : Traitement radiochirurgical par Gamma-Knife de l’épilepsie: Expérience du Centre Gamma-Knife de Rabat: à propos de 10 cas.

Auteur : El Ouartassi Hajar

Mots clés : Épilepsie - Radiochirurgie fonctionnelle - Chirurgie Leksell GammaKnife

Sur une période de 11 ans, 10 patients atteints d'épilepsie pharmaco-résistante ont été traité par radiochirurgie au CNRNS de Rabat, dont un patient traité deux fois (11 interventions). L'âge moyen de nos patients était de 14,4 ans, 60% d'hommes, 40% de femmes. Les étiologies de l'épilepsie variaient : hamartome hypothalamique (50%), sclérose tubéreuse (10%), syndrome de Lennox-Gastaut (10%), cavernome frontal (10%), gliome mésiotemporal (10%), hétérotopie frontale gauche (10%). 80% des patients avaient des crises pluriquotidiennes et 57% étaient déjà sous triple thérapie anti-épileptique avant d'être traités chirurgicalement. Le traitement était effectué avec les versions Perfexion et ICON de GK. Les doses variaient de 12 à 24 Gy à l’isodose périphérique de 50%. Le nombre moyen de tirs était de 24 à travers les collimateurs de 4, 8 et 16 mm. L’appréciation des résultats s’est faite suivant la classification d’ENGEL. Le taux de réussite était de 80%. La moyenne du suivi post-opératoire était de 48 mois avec des extrêmes de 6 et 96 mois. Le délai médian d'apparition des premiers effets thérapeutiques était immédiatement après la LGKS. Aucune complication n'est survenue pour nos patients. Les avantages de cette technique sont le peu de contre-indications, le coût relativement faible, le confort du patient et l'absence de risques infectieux et hémorragiques. La radiochirurgie GK est une option thérapeutique efficace pour le traitement de l'épilepsie, en particulier chez les patients présentant des contre-indications à la chirurgie.

111

Abstract

Title: Gamma-Knife Radiosurgical Treatment of Epilepsy: Experience of the Gamma- Knife Center of Rabat: About 10 cases.

Author: El Ouartassi Hajar

Key words: Epilepsy – Functional Radiosurgery - Leksell GammaKnife Surgery

Over a period of 11 years, 10 patients with DRE were treated with Radiosurgery at the NCRNS of Rabat, including one patient treated twice (11 interventions).

The average age of our patients was 14,4 years, 60 % were men, 40 % women. Etiologies of the epilepsy varied: Hypothalamic Hamartoma (50 %), Tuberous Sclerosis (10%), Lennox- Gastaut syndrome (10%), Frontal Cavernoma (10%), Mesial Temporal Glioma (10%), left frontal Heterotopia (10%). 80 % of patients had multiple seizures per day and 57% were already under a triple AED-therapy before being treated surgically. The treatment was conducted with the Perfexion and ICON versions of GammaKnife. Doses varied from 12 Gy to 24 Gy at 50% isodose line. The average number of shots was 24 delivered through the 4, 8- and 16-mm collimators. Post-therapeutic outcome relied on ENGEL classification. The success rate was 80 %. The mean follow-up duration was 48 months with extremes at 6 and 96 months. The median time to onset of the first therapeutic effects was immediately after LGKS. No complications occurred for our patients.

The advantages of this technique are the few contraindications, the relatively low cost, the patient's comfort and the absence of infectious and hemorrhagic risks.

GammaKnife Radiosurgery is an effective therapeutic option for the treatment of DRE, especially in patients with contraindications to surgery.

112

ملخص

العىوان: العالج بالجراحة االشعاعية "غاما وايف" للصرع: تجربة مركز "غاما وايف" بالرباط: عه 01 حاالت.

المؤلف: الورطاسي هاجر

كلمات البحث: الصرع - الجراحة اإلشعاعية الوظيفية - جراحة لكسيل غاما وايف

ػهً يذي فرشج ػ 11ا ًيا، ذى ػالج 11 يشضً ؼَاَىٌ يٍ صشع يقاوو نألدوَح تاندشاحح اإلشؼاػُح "غايا َاَف" فٍ انًشكض انىطٍُ نهرشوَض وانؼهىو انؼصثُح تانشتاط، تًا فٍ رنك يشَض واحذ ػىنح يشذٍُ )11 ذذخ ًال(.

كاٌ يرىسظ ػًش يشضاَا 14,4 سُح، 61٪ يُهى سخال، 41٪ َساء. كاَد يسثثاخ انصشع: وسو ػاتٍ نهغذج انُخايُح )51٪(، انرصهة انذسٍَ )11٪(، يرالصيح نُُىكس غاسرى )11٪( وسو كهفٍ )11٪(، وسو دتقٍ صذغٍ )11٪(، وهُرشوذىتُا انًادج انذياغُح )11٪(. كاٌ 81٪ يٍ انًشضً ؼَاَىٌ يٍ َىتاخ يرؼذدج َىيًُا و57٪ يُهى َخضؼىٌ نؼالج تثالز أَىاع يٍ األدوَح انًضادج نهصشع قثم انؼالج اندشاحٍ. ذى إخشاء انؼالج تاسرخذاو إصذاساخ غايا َاَف " nocI" و "neixefrcI"

ذشاوحد اندشػاخ يٍ 11 إنً 14 غشاٌ ػُذ خظ إَضودوص 51٪. وكاٌ يرىسظ ػذد انطهقاخ 14 ذى ذسهًُها يٍ خالل يُضاءاخ 4، 8 و16 يهى. ذى ذقُُى انُرائح وف ًقا نرصُُف اَدم "NEGNE"

كاٌ يؼذل انُداذ 81 ٪. كاٌ يرىسظ يذج انًراتؼح 48 شهشا تحذود قصىي فٍ 6 و96 شهشا. كاٌ انىقد انًرىسظ نظهىس أول آثاس ػالخُح: يثاششج تؼذ انؼالج. نى ذحذز أٌ يضاػفاخ نًشضاَا.

ذرًثم يضاَا هزِ انرقُُح فٍ يىاَغ االسرؼًال انًحذودج، انركهفح انًُخفضح َسثًُا، ساحح انًشَض وغُاب يخاطش انؼذوي وانُضَف.

اندشاحح االشؼاػُح "غايا َاَف" ذؼذ خُا ًس ا ػالخًُا فؼا ًال نؼالج انصشع انًقاوو نألدوَح خاصح ػُذ انًشضً انزٍَ ؼَاَىٌ يٍ يىاَغ نهدشاحح.

113

List of figures

Figure 1: Framework for classification of the epilepsies. *Denotes onset of seizure. Epilepsia ILAE...... 17

Figure 2: The ILAE 2017 Classification of Seizure Types, expended vesrion (7) ...... 18

Figure 3: Indications and contraindications of KD (15) ...... 23

Figure 4: Side effects of KD ...... 24

Figure 5: Molecular Targets of Clinically Used AEDs (17) ...... 27

Figure 6 Lars Leksell (1907-1986) ...... 31

Figure 7 Börje Larsson (1931-1998) ...... 31

Figure 8: Photograph showing the positioning of the patient in the device, as well as the benchmarks used for non-invasive fixation to the mask, an innovation introduced by the Gamma Knife Icon ™ ...... 32

Figure 9: Photograph of the NCRNS Gamma Knife Icon ™ in Rabat, showing the radiation unit and the patient's bed. (38) ...... 35

Figure 10: Photograph of the control console and the interface of the Leksell Gamma Knife Icon ™ software of the NCRNS Rabat (38) ...... 35

Figure 11: Photograph of cobalt sources and capsules containing them (38) ...... 36

Figure 12: Diagram showing the patient's position in the radiation unit during treatment. (35) 37

Figure 13: Right: Photo of the tungsten cape of new generation devices. Left: Image of a part of the tungsten cloak with the perforations of the different calibers for a sector (24 x 3 holes)...... 38

Figure 14: Cone collimator of Gamma Knife devices (40) ...... 38

Figure 15: Schematic photograph showing the three axes of movement of the patient's bed (38) ...... 39

Figure 16: Stages of LGKS treatment with the Leksell Coordinate Frame G stereotaxic frame (60) ...... 50

114

Figure 17: Left: Stereotactic Frame: Leksell Coordinate Frame G. Right: Leksell Frame cap for Gamma Knife Icon...... 51

Figure 18: Photos of stereotaxic "N" markers on the helmet for the scan on the left and the MRI on the right ...... 53

Figure 19: Leksell coordinate system applied to Leksell Coordinate Frame G. the left (L), right (R), posterior (P) and anterior (A) sides of the frame...... 53

Figure 20: Photo of the Leksell Gamma Plan Unit...... 54

Figure 21: Photo of Elekta’s Gamma Knife Perfexion (66) ...... 56

Figure 22: Percentage of cases in each pathology treated at the NCRNS GK unit from June 2008 to November 2019, according to Elekta’s Database ...... 60

Figure 23: Annual number of interventions on medically intractable epilepsies by LGKS at the NCRNS ...... 61

Figure 24: Distribution of patients by age categories ...... 62

Figure 25: Distribution of patients by gender ...... 63

Figure 26: Etiologies of medically intractable epilepsy in our case series ...... 64

Figure 27: Duration of evolution of epilepsy for each patient...... 65

Figure 28: Number of patients under 1, 2 or 3 AEDs before LGKS ...... 66

Figure 29: Most frequent AEDs used ...... 67

Figure 30: MRI images of a HH before and after LGKS ...... 69

Figure 31: MRI images of a frontal cavernoma before and after LGKS ...... 70

Figure 32: MRI images of brain tubers before and after LGKS ...... 71

Figure 33: MRI images of a delineation of the corpus callosum (pre-LGKS) ...... 72

Figure 34: MRI images of a Mesial temporal glioma before and after LGKS ...... 74

Figure 35: MRI images of a left frontal PVNH of 1.17cc (pre-LGKS) ...... 75

Figure 36: Number of shots delivered during RS for each case ...... 76

Figure 37: Duration of treatment in hours ...... 77

115

Figure 38: Irradiated volume (in cm3) ...... 77

Figure 39: Follow-up duration for each cases of our series ...... 78

Figure 40: Post-radiosurgical status of patients ...... 79

Figure 41: Success and failure rates of RS in epilepsy...... 79

Figure 42: Success and failure rates of GKS for each etiology in our study ...... 81

Figure 43: Engel Epilepsy Surgery Outcome Scale ...... 83

Figure 44: A screen capture of GK planning for a patient with right MTLE ...... 103

Figure 45: Volume-dose relationships of preliminary studies of GK treatment of MTLE (unpublished data courtesy of Jean Régis, MD, October 17, 2005)...... 104

Figure 46: Serial MRI changes (top row, T2 weighted; bottom row, fluid-attenuated inversion recovery) in a representative patient with right unilateral MTLE treated with 20 Gy ...... 104

Figure 47: Dose-planning of a callosotomy. The sagittal view is showing that the 50% isodose line (55 Gy) covers more than the anterior half of the corpus callosum ...... 106

116

List of tables

Table 1 : ILAE clinical and electroencephalographic classification of partial seizures ...... 12

Table 2: ILAE clinical and electroencephalographic classification of generalized seizures ...... 13

Table 3 Syndromes based on anatomic localization ...... 14

Table 4: Molecular Targets of Clinically Used AEDs ...... 26

Table 5: Statistics of RS interventions at the NCRNS from June 2008 to November 2019 according to Elekta’s Database of the GK unit ...... 59

Table 6: Seizure frequency for each case before LGKS ...... 65

Table 7: Summary table of the clinical aspects of our patients ...... 84

Table 8 : Summary table of the clinical aspects of our patients (continued) ...... 85

Table 9 : Summary table of our patients’ treatments with LGKS ...... 86

Table 10 : Summary table of our patients’ evolution after treatment with LGKS ...... 87

Table 11: Seizure remission after stereotactic radiosurgery of arteriovenous malformations ..... 94

Table 12: Seizure remission after stereotactic radiosurgery of Cavernous Malformations ...... 95

Table 13: Hypothalamic hamartoma outcomes in prospective or retrospective studies with >4 adult patients included and at least 2 years’ follow-up data provided ...... 98

Table 14: Seizure remission rates (defined as Engel Class 1) of SRS for MTLE ...... 102

117

Appendixes

118

Appendix 1: Chart review fiorm Chart review form Identity ID : …………………………………… Age : …………………………………… Name : …………………………………… Gender : ☐ Male ☐ Female

Past history

Familial history Personal history Epilepsy ☐ Yes ☐ No Neonatal suffering ☐ Yes ☐ No Parents consanguinity ☐ Yes ☐ No APD ☐ Yes ☐ No

Clinical features

Age at first seizure : ……………………………………………………………………………………… ……………………………………………………………………………………… Seizure description : ……………………………………………………………………………………… ☐ 1/several years ☐ 1/6 seizures/week Seizure frequency : ☐ 1-3 seizures/month ☐ Daily seizures

☐ 1-11 seizures/year Epileptic state : ☐ Yes ☐ No

Exploration

MRI : …………………………………………………………………………………………… EEG : ……………………………………………………………………………………………

Etiology

…………………………………………………………………………………………………………

Treatment

Anticonvulsant : ☐ Yes ☐ No Molecules : ……………………………………………………………………………… ☐ Yes ☐ No Other : ………………………………………………………………………………

119

Gamma knife radiosurgery

Date of treatment : ……………………… 50% isodose line : ……………………… Stereotactic device : ……………………… Number of shots : ………………………

System used : … …………………… Radiosurgery duration : ……………………… Targeted volume : ……………………… (cc/mm3)

Outcome

Short term

☐ Yes ☐ No Complications : …………………………………………………………………………

Follow up

Follow up duration : ………………………………………………………………………… (months) ☐ Seizure free ☐ 1-11 seizures/year Seizure frequency : ☐ 1/several years ☐ 1/6 seizures/week ☐ 1-3 seizures/month ☐ Daily seizures ☐ Class I ☐ Class III Engel Outcome Scale : ☐ Class II ☐ Class IV

Exploration

☐ Yes ☐ No MRI Results : ……………………………………………………………………………

Treatment needed after GKS

Medical : ☐ Yes ☐ No Molecules : ……………………………………………………………………

: ☐ Yes ☐ No Surgical …………………………………………………………………

120

Appendix 2: Engel surgery outcome scale

Class I: Free of disabling seizures

 IA: Completely seizure-free since surgery  IB: Non disabling simple partial seizures only since surgery  IC: Some disabling seizures after surgery, but free of disabling seizures for at least 2 years  ID: Generalized convulsions with antiepileptic drug withdrawal only

Class II: Rare disabling seizures (“almost seizure-free”)

 IIA: Initially free of disabling seizures but has rare seizures now  IIB: Rare disabling seizures since surgery  IIC: More than rare disabling seizures after surgery, but rare seizures for at least 2 years  IID: Nocturnal seizures only

Class III: Worthwhile improvement

 IIIA: Worthwhile seizure reduction  IIIB: Prolonged seizure-free intervals amounting to greater than half the follow-up period, but not less than 2 years

Class IV: No worthwhile improvement

 IVA: Significant seizure reduction  IVB: No appreciable change  IVC: Seizures worse

121

References 1. Engle JJP, Timothy A. Epilepsy: A comprehensive textbook. Philadelphia : Lippincott-Raven Publishers, 1997.

2. Melhaoui A, Arkha Y, Mansouri A, El Gueddari BK, El Khamlichi A. Expérience préliminaire du traitement par radiochirurgie Gamma Knife Perfexion au Maroc. Neurochirurgie. 2009, Vol. 55.

3. Robert S. Fisher, Carlos Acevedo. A practical clinical definition of epilepsy. www.ilae.org/guidelines. [Online] 2014.

4. David Y Ko, MD. Epilepsy and Seizures. [Online] 2019. https://emedicine.medscape.com/article/1184846-overview#a3.

5. International League Against Epilepsy. Sons, Reproduced with permission from John Wiley &. 1981.

6. International League Against Epilepsy . Sons, Reproduced with permission from John Wiley &. 1989.

7. Fisher RS, Cross JH, D'Souza C, French JA, Haut SR et al. Instruction manual for the ILAE operational classification of seizure types. Epilepsia. 2017, Vol. 58, 4.

8. David Y Ko, . Epilepsy and seizures clinical presentation. [Online] Medscape, 2019. https://emedicine.medscape.com/article/1184846-clinical.

9. Wilder RM, . The effect of ketonemia on the course of epilepsy. Mayo Clin Bulletin. 1921.

10. Neal EG, Chaffe HM, Edwards N, et al. Growth of children on classical and medium chain triglyceride diets. Pediatrics. 2008, Vol. 122, 2.

122

11. Kossoff EH, Dorward JL, Turner Z, et al. Prospective study of the modified Atkins diet in combination with a ketogenic liquid supplement during the initial month. J Child Neurol. 2011, Vol. 26, 2.

12. Hartman AL, Rubenstein JE, Kossoff EH. Intermittent fasting: a ―new‖ historical strategy for controlling seizures? Epilepsy Res. 2013, Vol. 104, 3.

13. Hartman AL, Stafstrom CE. Harnessing the power of metabolism for seizure prevention: focus on dietary treatments. Epilepsy Behav. 2013, Vol. 26, 3.

14. Payne NE, Cross JH, Sander JW, et al. The ketogenic and related diets in adolescents and adults a review. Epilepsia. 2011, Vol. 52, 11.

15. Kossoff EH, Zupec-Kania BA, Amark PE, et al. Optimal clinical management of children receiving the ketogenic diet: recommendations of the International Ketogenic Diet Study Group. Epilepsia. 2009, Vol. 50, 2.

16. Elaine Wyllie MD, . Wyllie’s Treatment of Epilepsy : Principles and Practice. s.l. : Wolters Kluwer, 2015.

17. Shih, Jean & Tatum, William & Rudzinski, Leslie. New drug classes for the treatment of partial onset epilepsy: Focus on perampanel. Therapeutics and Clinical Risk Management. 2013, Vol. 9.

18. Leppik IE, Sherwin AL. Anticonvulsant activity of phenobarbital and phenytoin in combination. s.l. : J Pharmacol Exp Ther, 1977.

19. Deckers CL, Czuczwar SJ, Hekster YA , et al. Selection of antiepileptic drug polytherapy based on mechanisms of action: the evidence reviewed. Epilepsia. 2000, Vol. 41, 11.

123

20. Margolis JM, Chu BC, Wang ZJ , et al. Effectiveness of antiepileptic drug combination therapy for partial-onset seizures based on mechanisms of action. JAMA Neurol. 2014, Vol. 71, 8.

21. Klein R, Livingston S. The effect of adrencorticotrophic hormone in epilepsy. . s.l. : J Pediatr., 1950. 37:733–742.

22. Sorel L, Dusaucy-Bauloye A. A propos de cas d’hypsarythmia de Gibbs: son traitement spectulaire par l’ACTH. s.l. : Acta Neurol Belg, 1958.

23. Gastaut H, Salfiel J, Raybaud C, et al. A propos du traitement par l’ACTH des encéphalites myoclonique de la première enfance avec majeure (hypsarythmie). 1959.

24. Low NL. Infantile spasms with mental retardation: Treatment with cortisone and adrenocorticotropin. Pediatrics. 1958, Vol. 22, 6.

25. Trojaborg W, Plum P. Treatment of hypsarrhythmia with ACTH. Acta Paediatr. 1960, Vol. 49.

26. Koo B, Hwang P, Logan W. Infantile spasms: outcome and prognostic factors of cryptogenic and symptomatic groups. Neurology. 1993, Vol. 43, 11.

27. Kivity S, Lerman P, Ariel R, et al. Long-term cognitive outcomes of a cohort of children with cryptogenic infantile spasms treated with high-dose adrenocorticotropic hormone. Epilepsia. 2004, Vol. 45, 3.

28. Lombroso C.T. A prospective study of infantile spasms: clinical and therapeutic correlations. . Epilepsia. 1983, Vol. 24.

29. Lerman P, Kivity S. The efficacy of corticotropin in primary infantile spasms. J Pediatr. 1982;, Vol. 101, 2.

124

30. Marescaux C, Hirsch E, Finck S, et al. Landau–Kleffner syndrome: a pharmacologic study of five cases. . s.l. : Epilepsia. , 1990.

31. Pantaleo Romanelli et al. Non-resective surgery and radiosurgery for treatment of drug-resistant epilepsy. Epilepsy Res. 2011, Vol. 99, 3.

32. Mayoclinic. https://www.mayoclinic.org/tests-procedures/epilepsy- surgery/about/pac-20393981. [Online]

33. Shaikhouni, Ammar. Surgical Treatment for Epilepsy. Epilepsy and Brain Tumors. 2015.

34. Leksell L. Stereotactic Radiosurgery. J Neurol Neurosurg Psychiat. 1983, Vol. 46.

35. Larsson B. Radiological fundamentals in radiosurgery. Raven Press. 1992.

36. AANS/CNS/ASTRO. American Association of Neurological Surgeons. [Online] june 2006. [Cited: july 10, 2018.] www.aans.com.

37. Team EW. Elekta AB. https://www.elekta.com/radiosurgery.html#sectionId1. [Online] Radiosurgery, January 18, 2018.

38. Simon S Lo, A.Sloan, V.Colussi, J.Sohn, B Wessels, N.Galanopoulos, J.Miller, A.Hoffer, R.Fine, W.Selman, M.Machtay. Stereotactic Radiosurgery. 2018.

39. Wikipedia. https://en.wikipedia.org/wiki/Radiosurgery. [Online]

40. Elammari L., . Thalamotomie par Radiochirurgie Gamma Knife du VIM comme traitement chirurgical du tremblement pharmaco-resistant. Rabat : FMPR, 2017.

125

41. Massager N . La radiochirurgie par Gamma Knife. Rev Med Brux. 2012, Vol. 33.

42. Fondation Hassan II,. Bilan d'activité du CNRNS. http://www.neurochirurgie.ma/. [Online] 2016.

43. Ding C, Saw CB, Timmerman RD. Cyberknife stereotactic radiosurgery and radiation therapy treatment planning system. Med Dosim. 2018, Vol. 43, 2.

44. Tishler RB, Loeffler JS, Lunsford LD, Duma C, Alexander E 3rd, Kooy HM, et al. Tolerance of cranial n erves of the cavernous sinus to radiosurgery. Int J Radiat Oncol Biol Phys. 1993, Vol. 27, 2.

45. Stafford SL, Pollock BE, Leavitt JA, Foote RL, Brown PD, Link MJ, Gorman DA, Schomberg PJ. A study on the radiation tolerance of the optic nerves and chiasm after stereotactic radiosurgery. Int J Radiat Oncol Biol Phys. 2003, Vol. 55, 5, pp. 1177–1181.

46. Witt TC, . Stereotactic radiosurgery for pituitary tumors. Neurosurg Focus. 2003, Vol. 14, 5.

47. Lunsford LD, Niranjan A, Flickinger JC, Maitz A, Kondziolka D. Radiosurgery of vestibular schwannomas: summary of experience in 829 cases. J Neurosurg. 2005, Vol. 102, Suppl.

48. Murphy ES, Barnett GH, Vogelbaum MA, Neyman G, Stevens GH, Cohen BH, Elson P, Vassil AD, Suh JH. Long-term outcomes of Gamma Knife radiosurgery in patients with vestibular schwannomas. J Neurosurg. 2011, Vol. 114, 2.

126

49. Roos DE, Potter AE, Zacest AC. Hearing preservation after low dose linac radiosurgery for acoustic neuroma depends on initial hearing and time. Radiother Oncol. 2011, Vol. 101, 3.

50. Karpinos M, Teh BS, Zeck O, Carpenter LS, Phan C, Mai WY, Lu HH, Chiu JK, Butler EB, Gormley WB, Woo SY. Treatment of acoustic neuroma: stereotactic radiosurgery vs. microsurgery. Int J Radiat Oncol Biol Phys. 2002, Vol. 54, 5.

51. Pollock BE, Lunsford LD, Kondziolka D, Flickinger JC, Bissonette DJ, Kelsey SF, Jannetta PJ. Outcome analysis of acoustic neuroma management: a comparison of microsurgery and stereotactic radiosurgery. Neurosurgery. 1995, Vol. 36, 1.

52. Kondziolka D, Lunsford LD, McLaughlin MR, Flickinger JC. Long-term outcomes after radiosurgery for acoustic neuromas. N Engl J Med. 1998, Vol. 339, 20.

53. Rowe JG, Radatz MW, Walton L, Soanes T, Rodgers J, Kemeny AA. Clinical experience with gamma knife stereotactic radiosurgery in the management of vestibular schwannomas secondary to type 2 neurofibromatosis. J Neurol Neurosurg Psychiatry. 2003, Vol. 74, 9.

54. Subach BR, Kondziolka D, Lunsford LD, Bissonette DJ, Flickinger JC, Maitz AH. Stereotactic radiosurgery in the management of acoustic neuromas associated with neurofibromatosis Type 2. J Neurosurg. 1999, Vol. 90, 5.

55. Podlock BE. Vestibular schwannoma management: an evidence-based comparison of stereotactic radiosurgery and microsurgical resection. Prog Neurol Surg. 2008, Vol. 21.

127

56. Ivan ME, Sughrue ME, Clark AJ, Kane AJ, Aranda D, Barani IJ, Parsa AT. A meta-analysis of tumor control rates and treatment-related morbidity for patients with glomus jugulare tumors. J Neurosurg. 2011, Vol. 114.

57. Guss ZD, Batra S, Limb CJ, et al. Radiosurgery of Glomus Jugulare Tumors: A Meta-Analysis. Int J Radiat Oncol Biol Phys. 2011, Vol. 81, 4.

58. Knisely JP, Linskey ME. Less common indications for stereotactic radiosurgery or fractionated radiotherapy for patients with benign brain tumors. Neurosurg Clin N Am. 2006, Vol. 17, 2.

59. Flickinger JC, Kondziolka D, Lunsford LD, Kassam A, Phuong LK, Liscak R, et al. Development of a model to predict permanent symptomatic postradiosurgery injury for arteriovenous malformation patients. Arteriovenous Malformation Radiosurgery Study Group. Int J Radiat Oncol Biol Phys. 2000, Vol. 46, 5.

60. Korytko T, Radivoyevitch T, Colussi V, Wessels BW, Pillai K, Maciunas RJ, Einstein DB. 12 Gy gamma knife radiosurgical volume is a predictor for radiation necrosis in non-AVM intracranial tumors. Int J Radiat Oncol Biol Phys. 2006, Vol. 64, 2, pp. 419–424.

61. Teghida A, . Radiochirurgie Gammaknife. Rabat : FMPR, 2016.

62. Rojas-Villabona A. Evaluation of the stability of the stereotactic Leksell. Journal of applied clinical medical physics. 2016, Vol. 17, 3.

63. AB., E. I. Leksell Gamma Knife® Icon™ Instructions for Use. 2015.

64. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the LAE Commission on Therapeutic Strategies. Epilepsia. 2010, Vol. 51, 6.

128

65. Wiebe S . Definition of drug-resistant epilepsy: is it evidence based? Epilepsia. 2013, Vol. 54, s2.

66. Leksell L.,. The stereotaxic method and radiosurgery of the brain. Acta Chirurg Scand. 1951, Vol. 102, 4.

67. Leksell L,. Sterotaxic radiosurgery in trigeminal neuralgia. Acta Chir Scand. 1971, Vol. 37.

68. Lindquist C, Hellstrand E, Kilström L, et al. Stereotactic localization of epileptic foci by magnetoencephalography and MRI followed by gamma surgery. Presented at International Stereotactic Radiosurgery Symposium. 1991.

69. Talairach J, Bancaud J, Szikla G, et al. Approche de la neurochirurgie de l’epilepsie. Méthodologie stéréotaxique et résultats thérapeutiques. Marseille : Masson, 1974.

70. Elomaa E. Focal irradiation of the brain: an alternative to temporal lobe resection in intractable focal epilepsy? Med Hypotheses. Med Hypotheses. 1980, Vol. 6, 5.

71. Baudouin M, Stuhl L, Perrard A. Un cas d’épilepsie focale traité par la radiothérapie. Rev Neurol. 1951, Vol. 84.

72. Von Wieser W. Die Roentgentherapie der traumatischen Epilepsie. Mschr Psychiat Neurol. 1939, Vol. 101, 3.

73. Heikkinen ER, Konnov B, Melnikov L, Yalynych N, Zubkov YuN, Garmashov YuA, Pak VA. Relief of epilepsy by radiosurgery of cerebral arteriovenous malformations. Stereotact Funct Neurosurg. 1989, Vol. 53, 3.

129

74. Rogers L, Morris H, Lupica K. Effect of cranial irradiation on seizure frequency in adults with low-grade astrocytoma and medically intractable epilepsy. Neurology. 1993, Vol. 43, 8.

75. Rossi G, Scerrati M, Roselli R. Epileptogenic cerebral low grade tumors: effect of interstital stereotactic irradiation on seizures. Appl Neurophysiol. 1985, Vol. 48, 1-6.

76. Barcia-Salorio JL, Vanaclocha V, Cerda M, Roldan P. Focus irradiation in epilepsy. Experimental study in the cat. Stereotactic and Functional Neurosurgery. 1985, Vol. 48, 1-6.

77. Gaffey C, Monotoya V, Lyman J, Howard J. Restriction of the spread of epileptic discharges in cats by mean of Bragg Peak intracranial irradiation. Int J Appl Radiat Isotope. 1981, Vol. 32, 11.

78. Chen ZF, Kamiryo T, Henson SL, et al. Anticonvulsant effects of gamma surgery in a model of chronic spontaneous limbic epilepsy in rats. JNeurosurg. 2001, Vol. 94, 2.

79. Maesawa S, Kondziolka D, Dixon CE, Balzer J, Fellows W, Lunsford LD. Subnecrotic stereotactic radiosurgery controlling epilepsy produced by kainic acid injection in rats. J Neurosurg. 2000, Vol. 93, 6, pp. 1033-40.

80. Mori Y, Kondziolka D, Balzer J, et al. Effects of stereotactic radiosurgery on an animal model of hippocampal epilepsy. Neurosurgery. 2000, Vol. 46, 1.

81. Ronne-Engström E, Kihlström L, Flink R, et al. Gamma Knife surgery in epilepsy: an experimental model in the rat. 1993.

130

82. Barcia-Salorio JL, Garcia JA, Hernandez G, Lopez-Gomez L. Radiosurgery of epilepsy: long-term results. Acta Neurochir Suppl. 1994, Vol. 62, 1.

83. Lindquist C.,. Gamma knife surgery in focal epilepsy, 1 year followup in 4 cases. 1992.

84. Lindquist C, Kihlström L, Hellstrand E, Knutsson E. Stereotactic radiosurgery instead of conventional epilepsy surgery. Presented at European Society for Stereotactic and Functional Neurosurgery,. 1993.

85. Quigg M, Barbaro NM. Stereotactic radiosurgery for treatment of epilepsy. Arch Neurol. 2008, Vol. 65, 2.

86. Ferland RJ, JP Williams, Gross RA, Applegate CD. The effects of brain- irradiation-induced decreases in hippocampal mitotic activity on flurothyl- induced epileptogenesis in adult C57BL/6J mice. Exp Neurol. 2003, Vol. 179, 1.

87. Sun B, DeSalles AA, Medin PM, Solberg TD, Hoebel B, Felder-Allen M, Krahl SE, Ackermann RF. Reduction of hippocampal-kindled seizure activity in rats by stereotactic radiosurgery. Exp Neurol. 1998, Vol. 154, 2.

88. Tsuchitani S, Drummond J, Kamiryo T et al.,. Selective vulnerability of interneurons to low dosage radiosurgery. Society for Neuroscience Annual Meeting. 2003.

89. Elisevich KV, Jenrow KA, Ratkewicz AE,. Enhanced excitability induced by ionizing radiation in the kindled rat. Exp Neurol. 2001, Vol. 169, 1.

90. Schröttner O1, Eder HG, Unger F, Feichtinger K, Pendl G. Radiosurgery in lesional epilepsy: brain tumors. Stereotact Funct Neurosurg. 1998, Vol. 70, suppl 1.

131

91. Steiner L, Lindquist C, Adler JR, Torner JC, Alves W, Steiner M. Clinical outcome of radiosurgery for cerebral arteriovenous malformations. J Neurosurg. 1992, Vol. 77, 1.

92. Gerszten PC, Adelson PD, Kondziolka D, Flickinger JC, Lunsford LD. Seizure outcome in children treated for arteriovenous malformations using gamma knife radiosurgery. Pediatr Neurosurg. 1996, Vol. 24, 3.

93. Kurita H, Kawamoto S, Suzuki I et al.,. Control of epilepsy associated with cerebral arteriovenous malformations after radiosurgery. J Neurol Neurosurg Psychiatry. 1998, Vol. 65, 5.

94. Schäuble B, Cascino GD, Pollock BE, Gorman DA, Weigand S, Cohen- Gadol AA, McClelland RL. Seizure outcomes after stereotactic radiosurgery for cerebral arteriovenous malformations. Neurology. 2004, Vol. 63, 4.

95. Bartolomei F, Régis J, Kida Y, Kobayashi T, Vladyka V, Liscàk R, Forster DM, Kemeny A, Shrötner O, Pendl G. Gamma Knife radiosurgery for epilepsy associated with cavernous hemangiomas: a retrospective study of 49 cases. Stereotact Funct Neurosurg. 1999, Vol. 72, 1.

96. Shih YH, Pan DH. Management of supratentorial cavernous malformations: craniotomy versus gammaknife radiosurgery. Clin Neurol Neurosurg. 2005, Vol. 107, 2.

97. Régis, J., Bartolomei, F., de Toﬀol, B., Genton, P., Kobayashi, T., Mori, Y., Takakura, K., Hori, T., Inoue, H., Schröttner, O., Pendl, G., Wolf, A., Arita, K., Chauvel, P. Gamma knife surgery for epilepsy related to hypothalamic hamartomas. 2000, Vol. 14, 2.

132

98. Régis, J., Hayashi, M., Eupierre, L.P., Villeneuve, N., Bartolomei, F., Brue, T., Chauvel, P. Gamma knife surgery for epilepsy related to hypothalamic hamartomas. Acta Neurochir.Suppl. 2004, Vol. 14, 2.

99. Régis J., Scavarda D., Tamura M., Nagayi M., Villeneuve N., Bartolomei F., Brue T., Dafonseca D., Chauvel P. Epilepsy related to hypothalamic hamartomas: surgical management with special reference to gamma knife surgery. Childs Nerv. Syst. 2006, Vol. 22, 8.

100. Régis, J., Scavarda, D., Tamura, M., Villeneuve, N., Bartolomei, F., Brue, T., Morange, I.,Dafonseca, D., Chauvel, P. Gamma knife surgery for epilepsy related to hypothalamic hamartomas. Semin. Pediatr. Neurol. 2007, Vol. 14, 2.

101. Régis, J., Lagmari, M., Carron, R., Hayashi, M., McGonigal, A., Daquin, G., Villeneuve, N., Bartolomei, F., Chauvel, P.,. Safety and eﬃcacy of gamma knife radiosurgery in hypothalamic hamartomas with severe epilepsies: a prospective trial in 48 patients. Epilepsia. 2016, Vol. 58 , Suppl 2.

102. Bourgeois P., Mathieu D., Duval J., Deacon C.,. Gamma knife surgery in hypothalamic hamartoma: an eﬀective treatment of refractory epilepsy with good outcome on quality of life and cognition. Clin. Neurophysiol. 2013, Vol. 124, 6.

103. Mathieu D., Deacon C., Pinard C.A., Kenny B., Duval J.,. Gamma Knife surgery for hypothalamic hamartomas causing refractory epilepsy: preliminary results from a prospective observational study. J. Neurosurg. 2010, Vol. 113, Suppl.

133

104. Kerrigan JF, Parsons A, Rice SG, Simeone K, Shetter AG, Abla AA, Prenger E, Coons SW. Hypothalamic hamartomas: neuropathological features with and without prior gamma knife radiosurgery. Stereotact. Funct. Neurosurg. 2013, Vol. 91, 1.

105. Harvey A.S., Freeman J.L., Berkovic S.F., Rosenfeld J.V. Transcallosal resection of hypothalamic hamartomas in patients with intractable epilepsy. Epileptic. Disord. 2003, Vol. 5.

106. Mittal S., Mittal M., Montes J.L., Farmer J.P., Andermann F. Hypothalamic hamartomas. Part 2. Surgical considerations and outcome. Neurosurg. 2013, Vol. 34, 6.

107. Selch M.T., Gorgulho A., Mattozo C., Solberg T.D., et al. Linear accelerator stereotactic radiosurgery for the treatment of gelastic seizures due to hypothalamic hamartoma. Minim. Invasive Neurosurg. 2005, Vol. 48, 5.

108. Barbaro N.M., Quigg M., Broshek D.K., Ward M.M., Lamborn K.R., Laxer K.D., Larson D.A., Dillon W., Verhey L., Garcia P., Steiner L., Heck C., Kondziolka D., Beach R., Olivero W., Witt T.C., Salanova V., Goodman R.,. A multicenter, prospective pilot study of gamma knife radiosurgery for mesial temporal lobe epilepsy: seizure response, adverse events, and verbal memory. Ann. Neurol. 2009, Vol. 65, 2.

109. Bartolomei F., Hayashi M., Tamura M., Rey M., et al. Long-term eﬃcacy of gamma knife radiosurgery in mesial temporal lobe epilepsy. Neurology. 2008, Vol. 70.

134

110. Régis J., Laghmari M., Daquin G., Villeneuve N., Chauvel P. Prospective evaluation of gamma knife surgery in hypothalamic hamartomas: about a series of 64 patients. J. Radiosurg. 2013.

111. Abla AA, Shetter AG, Chang SW, Wait SD, Brachman DG, Ng YT, Rekate HL, Kerrigan JF. Gamma Knife surgery for hypothalamic hamartomas and epilepsy: patient selection and outcomes. J. Neurosurg. 2010, Vol. 113, Suppl, pp. 207–214.

112. Romanelli, P., Verdecchia, M., Rodas, R., Seri, S., & Curatolo, P. Epilepsy surgery for tuberous sclerosis. Pediatric Neurology,. 2004, Vol. 31, 4.

113. Steiger HJ, Wellis G, Nagel R, Vollmar C,. Direct costs of microsurgical management of radiosurgically amenable intracranial pathology in Germany: an analysis of meningiomas, acoustic neuromas, metastases and arteriovenous malformations of less than 3 cm in diameter. Acta Neurochir. 2003, Vol. 145, 4.

114. Lindquist C, Kihlström L, Hellstrand E. Functional neurosurgery—a future for the gamma knife? Stereotact Funct Neurosurg. 1991, Vol. 57, 1-2.

115. Barcia JA, Barcia-Salorio JL, López-Gómez L, Hernández G. Stereotactic radiosurgery may be effective in the treatment of idiopathic epilepsy: report on the methods and results in a series of eleven cases. Stereotact Funct Neurosurg. 1994, Vol. 63, 1-4.

116. Régis J, Peragui J, Rey M, et al.,. First selective amygdalohippocampal radiosurgery for ―mesial temporal lobe epilepsy.‖. Stereotact Funct Neurosurg. 1995, Vol. 64, 1.

117. Régis J, Bartolomei F, Rey M, et al.,. Gamma knife surgery for mesial temporal lobe epilepsy. Epilepsia. 1999, Vol. 45, 5.

135

118. Régis J, Rey M, Bartolomei F. Gamma knife surgery in mesial temporal lobe epilepsy: a prospective multicenter study. Epilepsia. 2004, Vol. 45, 5.

119. Srikijvilaikul T, Najm I, Foldvary-Schaefer N, Lineweaver T, Suh JH, Bingaman WE. Failure of gamma knife radiosurgery for mesial temporal lobe epilepsy: report of five cases. Neurosurgery. 2004, Vol. 54, 6.

120. McDonald CR, MA Norman, E Tecoma, J Alksne, V Iragui . Neuropsychological change following gamma knife surgery in patients with left temporal lobe epilepsy: a review of three cases. Epilepsy Behav. 2004, Vol. 5, 6.

121. Eder H.G., Feichtinger M., Pieper T., Kurschel S., Schroettner O. Gamma knife radiosurgery for callosotomy in children with drug-resistant epilepsy. Child’s Nerv. Syst. 2006, Vol. 22.

122. Pendl G., Eder H.G., Schroettner O., Leber K.A. Corpus callosotomy with radiosurgery. Neurosurgery. 1999, Vol. 45, 2.

123. Bodaghabadi, M., Bitaraf, M.A., Aran, S., Alikhani, M., Ashraﬁan, H., Zahiri, A., Alahverdi, M. Corpus callosotomy with gamma knife radiosurgery for a case of intractable generalised epilepsy. Epileptic. Disord. 2011, Vol. 13, 2.

124. Celis, M.A., Moreno-Jimenez, S., Larraga-Gutierrez, J.M., Alonso- Vanegas, M.A., GarciaGarduno, O.A., Martinez-Juarez, I.E., Fernandez- Gonzalez, M.C. Corpus callosotomy using conformal stereotactic radiosurgery. Childs Nerv. Syst. 2007, Vol. 23, 8.

125. Smyth MD, Klein EE, Dodson WE, Mansur DB. Radiosurgical posterior corpus callosotomy in a child with Lennox-Gastaut syndrome. Case report. J. Neurosurg. 2007, Vol. 106, 4 Suppl.

136

126. Feichtinger, M., Schröttner, O., Eder, H., Holthausen, H., Pieper, T., Unger, F., Holl, A., Gruber, L., Körner, E., Trinka, E. Eﬃcacy and safety of radiosurgical callosotomy: a retrospective analysis. Epilepsia. 2006, Vol. 47, 7.

127. Moreno-Jimenez, S., San-Juan, D., Larraga-Gutierrez, J.M., Celis, M.A., Alonso-Vanegas, M.A., Anschel, D.J. Diﬀusion tensor imaging in radiosurgical callosotomy. Seizure. 2012, Vol. 21, 6.

137

The Hippocratic Oath Serment d’Hippocrate

Au moment d'être admis à devenir membre de la profession médicale, je m'engage solennellement à consacrer ma vie au service de l'humanité.

Je traiterai mes maîtres avec le respect et la reconnaissance qui leur sont dus.

Je pratiquerai ma profession avec conscience et dignité. La santé de mes malades sera mon premier but.

Je ne trahirai pas les secrets qui me seront confiés.

Je maintiendrai par tous les moyens en mon pouvoir l'honneur et les nobles traditions de la profession médicale.

Les médecins seront mes frères.

Aucune considération de religion, de nationalité, de race, aucune considération politique et sociale ne s'interposera entre mon devoir et mon patient.

Je maintiendrai le respect de la vie humaine dès la conception.

Même sous la menace, je n'userai pas de mes connaissances médicales d'une façon contraire aux lois de l'humanité.

Je m'y engage librement et sur mon honneur.

138

قطم أبقزاط

بسم اهلل الرمحان الرحيم أقسم باهلل العظيم في هذه اللحظت التي ًتم فيها قبىلي غضىا في املهىت الطبيت أتػهد غالهيت:

بأن أكزص حياتي لخدمت إلاوطاهيت. وأن أحترم أضاتذتي وأغترف لهم بالجميل الذي ٌطتحقىهه. وأن أمارص مهىتي بىاسع من ضميري وشزفي جاغ ال صحت مزٍض ي هدفي ألاول. وأن ال أفش ي ألاضزار املػهىدة إلي. وأن أحافظ بكل ما لدي من وضائل غلى الشزف والتقاليد الىبيلت ملهىت الطب. وأن أغتبر ضائز ألاطباء إخىة لي. وأن أقوووىم بوووىاج ي هحوووى مزضووواي بووودون أي اغتبوووار دً وووي أو وط وووي أو غز وووي أو ضيا ووو ي أو اجتماعي. وأن أحافظ بكل حشم غلى احترام الحياة إلاوطاهيت مىذ وشأتها. وأن ال أضووووتػمل مػلىمووووواتي الطبيوووووت بطزٍوووووه ًضوووووز بحقوووووى إلاوطوووووان مهموووووا القيووووو مووووون تهدًد.

بكل هذا أتػهد غن كامل اختيار ومقطما بشزفي.

واهلل على ما أقىل شهيد

139

اململكة املغربية

جامعة حممد اخلامس بالرباط كلية الطب والصيدلة الرباط

دنـة : 2019 أرروحة رقم: 512 العالج باجلراحة اإلشعاعية "غاما نايف" للصرع: جتربة مركز "غاما نايف بالرباط. بصدد 01 حاالت أط روحة قدمت ونوقشت عالنوة يوم : / /2019

من طرف الشيدة هاجر الورطاسي املزدادة يف 82 نونبـر 0998 ابلرابط طبيبة داخلية ابملركز االستشفائي اجلامعي ابن سينا ابلرابط

لـنـوـل ذـهـادة دكـتـور فــي الطب

الكلمات األساسية : الصرع؛ الجراحة اإلشعاعية الوظيفية؛ "جراحة لكسيل غاما نايف"

جلنة التحكوم: السود يادر ارخا رئوس أستاذ يف جراحة الدماغ واألعصاب السود عادل ملحاوي مشرف أستاذ يف جراحة الدماغ واألعصاب السودة حمجوبة بورربوش عضو أستاذ يف جراحة الدماغ واألعصاب السودة يامنة كريويل عضو أستاذة يف طب األطفال السودة وفاء ركراكي عضو أستاذة يف طب األعصاب