Mohamad Mikati MD
Wilburt C. Davison Professor of Pediatrics,
Professor of Neurobiology, Chief of Pediatric Neurology,
Duke University Medical Center
Milestones in AHC and
Parallels with Epilepsy
Defining the Syndrome:
 Verret and Steele, 1971
 Casaer and Azou, 1984
 Aicardi, 1987
 Silver&Andermann, 1993
 Bourgeois et al, 1993
Genetics:
 Mikati et al, 1992
 Swoboda et al, 2004
 Bassi et al, 2004
Registries:
 Mikati et al, 2000
 Sweney et al 2009,
 Panagiotakaki et al 2010
The Future:
 Find the causes and the
cures-the roles of drug
screening, serendipity,
and physiology
Outline

 Distinction Between
Seizures and AHC spells
 US Data on Seizures in AHC
 Japanese & European Data
EEG During Epileptic Seizures
Focal Ictal Discharge
Generalized Discharges
Normal EEG

EEG Changes in People with
Epileptic Seizure
Focal Discharges
Generalized Discharges
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
AHC Case:
Baseline EEG

AHC Case:
EEG in Dystonia

AHC Case:
EEG in Hemiplegia

AHC Case:
EEG of Myoclonic Jerks

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




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
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
USA Data

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
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/slowwaves, 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
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
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
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
European and Japanese
Data

Frequency of Seizures with Age
Cohort with > 24 year FU

*
*
*
Panagiotakaki E et al., Brain 2010: 133; 3598-3610
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
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
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
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
Status Epilepticus Cases

 Status epilepticus with clonic seizures with ocular
deviation, eyelid twitching, hemiclonic, blinking,
cyanosis
 Status epilepticus with clonic seizures with rightsided predominance
 Status epilepticus, prolonged post-ictal respiratory
arrest
 Status epilepticus, prolonged post-ictal respiratory
arrest
Saito et al., Epilepsy Research 2010: 90; 248-258
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
MRI in Patients with Status
Saito et al., Epilepsy Research 2010: 90; 248-258
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
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
Conclusions

 Our increasing knowledge is improving our ability
to help AHC patients and increasing our hopes for
major discoveries in the future
for your attention!