Seizures in Alternating Hemiplegia of Childhood

1. Seizures in Alternating Hemiplegia of Childhood 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: Registries: The Future: Genetics:

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

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. Video Illustrations • 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 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. Clinical History • 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

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. Duke AHC-Epilepsy Clinic • 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 Satio, Y. et al., 2010

15. USA Data

16. Frequency of Seizure Activity • 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 Mikati et al., Pediatric Neurology 2000: 23(1);134-141

17. Strict Criteria to Diagnose Epileptic Seizures in AHC • 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

18. Frequency of Seizure Activity • 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 Mikati et al., Pediatric Neurology 2000: 23(1);134-141

19. Types of Seizure Activity • 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 Mikati et al., Pediatric Neurology 2000: 23(1);134-141

20. Additional Findings • 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 Sweney M et al 2009

21. European and Japanese Data

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

23. Recent Japanese Data: Frequency • 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

24. Types of Seizures • 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 Saito et al., Epilepsy Research 2010: 90; 248-258

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

26. Ictal EEG of Seizures • 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 Saito et al., Epilepsy Research 2010: 90; 248-258

27. Status Epilepticus Cases • 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, prolonged post-ictal respiratory arrest Saito et al., Epilepsy Research 2010: 90; 248-258

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

31. Conclusions • 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

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

33. Thank you for your attention!