1. Mohamad Mikati MD Wilburt C. Davison Professor of Pediatrics, Professor of Neurobiology, Chief of Pediatric Neurology, Duke University Medical Center

2. Milestones in AHC and Parallels with Epilepsy  Verret and Steele, 1971  Casaer and Azou, 1984  Aicardi, 1987  Silver&Andermann, 1993  Bourgeois et al, 1993  Mikati et al, 1992  Swoboda et al, 2004  Bassi et al, 2004  Mikati et al, 2000  Sweney et al 2009,  Panagiotakaki et al 2010  Find the causes and the cures-the roles of drug screening, serendipity, and physiology Defining the Syndrome: Genetics: Registries: The Future:

3.   Distinction Between Seizures and AHC spells  US Data on Seizures in AHC  Japanese & European Data Outline

4. EEG During Epileptic Seizures Generalized Discharges Focal Ictal Discharge

5.  Normal EEG

6. EEG Changes in People with Epileptic Seizure Generalized Discharges Focal Discharges

7.   Focal epileptic seizures starting with dystonia like movement, the generalized stiffening then focal weakness.  Dystonia in a case of AHC  Hemiplegia in a case of AHC  Myoclonic absence epileptic seizure in a case of AHC Video Illustrations Satio, Y. et al., 2010

8.  AHC Case: Baseline EEG

9.  AHC Case: EEG in Dystonia

10.  AHC Case: EEG in Hemiplegia

11.  AHC Case: EEG of Myoclonic Jerks

12.   Onset of spells at age of 2 weeks  Fulfilled the six AHC criteria of Aicardi  Failed Valproate, Keppra, Topiramate, and lamotrigine  Frequency of spells  Generalized myoclonic seizures: 1per hour  Generalized tonic/clonic seizures: once every week  Hemiplegia/dystonic spells (30 min-many hours): 10 per day  After VNS inserted at age of 17 years :  Generalized myoclonic seizures : none  Generalized tonic/clonic seizures: none  Hemiplegia/dystonic spells (10 min): 3/week Clinical History

13.  EEG During Epileptic Seizure in AHC Ictal EEG. Seizures were captured as frequent, jerky awakenings from sleep, followed by unilateral attacks with a slow, forced deviation of the head and eyes to the right or the left side accompanied by an ipsilateral tonic extension of the arm and the leg which lasted for a few minutes. They sometimes lasted longer; -i.e. up to 15 minutes when the tonic posturing could become global Saltik S. et al., Epileptic Disorders 2004: 6; 45-48

14.   Multidisciplinary first Thursday of the month  Interfaces with other programs we have  Goals:  Distinguish epileptic seizures from AHC events  Treat resistant patients with potentially promising therapies like the ketogenic diet and VNS  Rule out focal brain lesions in patients with focal seizures using advanced MRI techniques established with BIAC (Brain Imaging and Analysis Center) at Duke Duke AHC-Epilepsy Clinic Satio, Y. et al., 2010

15.  USA Data

16.   We studied 44 patients  8/44 (19%) fit the criteria  Not considered epileptic:  2 patients with tonic events with documented normal EEGs during these events  Many other patients with tonic episodes who though responding to IV Diazepam re-occurred despite antiepileptic drug treatment Frequency of Seizure Activity Mikati et al., Pediatric Neurology 2000: 23(1);134-141

17.   Focal or generalized twitching or rhythmic clonic activity with supporting consistent interictal paroxysmal EEG activity  Consistently focal tonic activity or abnormal eye movements (AOM) with consistently corresponding interictal focal spikes, spike/slow- waves, or paroxysmal sharp waves  Generalized tonic activity was considered epileptic if there is corresponding ictal EEG change  Not considered seizures:  Vibratory events  Isolated tonic or AOM events not associated with corresponding EEG changes Mikati et al., Pediatric Neurology 2000: 23(1);134-141 Strict Criteria to Diagnose Epileptic Seizures in AHC

18.   8/44 patients (19%) experienced seizures sometime in their life  4 had infrequent seizures (50%) with a total of 3 or fewer seizures each  4 had frequent seizures (50%) with one having history of status epilepticus Frequency of Seizure Activity Mikati et al., Pediatric Neurology 2000: 23(1);134-141

19.   4 patients had generalized tonic-clonic seizures  3 patients had focal clonic seizures one of whom had a focal clonic status for few hours  1 patient had generalized myoclonic seizures Types of Seizure Activity Mikati et al., Pediatric Neurology 2000: 23(1);134-141

20.   44/103 (43%) were reported to have epilepsy  However could not rule out possible over-diagnosis  Generalized tonic or tonic-clonic seizures  Mean age of onset 6 years  Most, 34, (77%) were reported to have onset < age 10 years Additional Findings Sweney M et al 2009

21.  European and Japanese Data

22.  Frequency of Seizures with Age Cohort with > 24 year FU Panagiotakaki E et al., Brain 2010: 133; 3598-3610 * * *

23.   Retrospective review of clinical information on 9 patients (age: 4-40 years), seven/nine thought to have epilepsy.  Presumptive epileptic seizures in seven patients  Age of onset ranging from 2 – 16 years Saito et al., Epilepsy Research 2010: 90; 248-258 Recent Japanese Data: Frequency

24.   Tonic  Tonic with cyanosis, nystagmus, twitching of face and extremities, clonic, cyanosis  anosis  Tonic, Eyelid twitching, cyanosis  Tonic, upward gaze, tonic  Generalized tremor, myoclonus, Blinking, twitching of face and extremities, clonic movements, cyanosis  Ocular deviation, clonic/myoclonic, post-ictal respiratory arrest  Sudden fall, nystagmus, generalized clonic, cyanosis  Generalized tonic-clonic seizure  Generalized seizures  Febrile seizures Types of Seizures Saito et al., Epilepsy Research 2010: 90; 248-258

25.   Normal  Slow Background  Unremarkable  Superimposed slow waves  Frontal Spikes  Central/Parietal Spikes  Left Occipital Spikes  Frontal Sharp Waves Inter-ictal EEG for Late-onset Seizure Saito et al., Epilepsy Research 2010: 90; 248-258

26.   Focal: Left centro-parietal slow waves simultaneous with right-sided myoclonus  Focal: Left occipital Polyspike-wave activity  Bilateral: Frontal slow activity, diffuse sharp waves, fast activity, spike-wave bursts  Bilateral: Widespread sharp waves, polyspike-wave activity Ictal EEG of Seizures Saito et al., Epilepsy Research 2010: 90; 248-258

27.   Status epilepticus with clonic seizures with ocular deviation, eyelid twitching, hemiclonic, blinking, cyanosis  Status epilepticus with clonic seizures with right- sided predominance  Status epilepticus, prolonged post-ictal respiratory arrest Status Epilepticus Cases Saito et al., Epilepsy Research 2010: 90; 248-258

28.   Four patients with neonatal disease onset showed:  Lower psychomotor developmental achievements  Repeated status epilepticus followed by progressive deterioration  MRI – brain atrophy cerebellar and hippocampal high signal changes Neonatal Onset Seizures Saito et al., Epilepsy Research 2010: 90; 248-258

29. MRI in Patients with Status Saito et al., Epilepsy Research 2010: 90; 248-258

30.   Tonic Spells Can be difficult to distinguish if epileptic or not  Video EEG is helpful  Focal, generalized tonic clonic or myoclonic seizures occur AHC AHC and Seizures: Conclusions

31.   Most patients are well controlled  Some patients who have neonatal onset of seizures can have associated apnea, subsequent status epilepticus and severe developmental  Variations in clinical phenotypes of seizures in AHC probably imply multiple causative genes Conclusions

32.   Our increasing knowledge is improving our ability to help AHC patients and increasing our hopes for major discoveries in the future Conclusions

33. for your attention!