Pediatric Epilepsy Syndromes Gregory Neal Barnes MD/PhD Assistant Professor of Neurology and Pediatrics Director, Pediatric Epilepsy Monitoring Unit Vanderbilt University Medical Center Disclosure Investigator: NIH, Autism Speaks, HRSA Special Thanks to Dr Juliann Paolicchi Epilepsy: Incidence/100,000 200 150 100 50 0 0 20 40 60 80 100 Age Hauser, Epilepsia 33:1992 1
Epilepsy: Etiology vs. Age of Onset Perinatal injury Metabolic defect Congenital malformation Infection Genetic epilepsy Postnatal trauma Brain tumor Vascular disease Birth 2 3 5 10 20 30 50 70 Age (yr) Epilepsy Treatments * FDA-approved Age Indication Efficacy Side effects AEDs Ketogenic Diet Epilepsy Surgery Vagus Nerve Stimulator Children and adults Primarily early childhood Children and adults 12 yrs and older* Specific AEDs for specific seizure types All seizure types, typically intractable seizures Pharmaco- resistant and localization- related epilepsy Pharmaco- resistant and partial seizures* ~64% seizure- free (SF) 1 54% >50% seizure reduction @ 3 mos 2 ~70% SF in select patients 3 43% >50% seizure reduction at 3 yrs 4 Varies by AED Lipid disorder, ketoacidosis Surgery-related related risks; varies by location of surgery Voice alteration, cough, pharyngitis, dyspnea Epilepsy Treatments Age Indication Efficacy Side effects AEDs Ketogenic Diet Epilepsy Surgery Vagus Nerve Stimulator Children and adults Primarily early childhood Children and adults 12 yrs and older* Specific AEDs for specific seizure types All seizure types, typically intractable seizures Pharmaco- resistant and localization- related epilepsy Pharmaco- resistant and partial seizures* ~64% seizure- free (SF) 1 54% >50% seizure reduction @ 3 mos 2 ~70% SF in select patients 3 43% >50% seizure reduction at 3 yrs 4 Varies by AED Lipid disorder, ketoacidosis Surgery-related related risks; varies by location of surgery Voice alteration, cough, pharyngitis, dyspnea 2
Generalized Epilepsy Syndromes in Childhood The Good: Idiopathic Generalized Epilepsy Syndromes IGE Syndromes Childhood Absence Epilepsy Clinically: Multiple/day absence seizures Minimal automatisms, usually eye-blinking or oral Brief events, 5-30 sec No aura or postictal state Seizures can be induced by hyperventilation Typically presents 4-8 yrs of age, up to 12 yrs Normal development and neurologic examination 3
GENERALIZED SEIZURES 1 second Childhood Absence Epilepsy Diagnosis: EEG with generalized, 3 Hz spike wave Activated by Hyperventilation No indication for neuroimaging Increased neurocognitive deficits (ADHD) Prognosis: Likely remission by puberty IGE: Juvenile Absence Epilepsy Clinically: Multiple/day absence seizures, but typically less than CAE Minimal automatisms, usually eye-blinking or oral Brief events, 5-30 sec No aura or postictal state Intermittent myoclonic and GTCS present Seizures can be induced by hyperventilation Typically presents 8-12 yrs of age Normal development and neurologic examination 4
Juvenile Absence Epilespy Diagnosis: EEG with generalized, 3 Hz spike wave during absence seizures. May have polyspike wave interictal discharges Activated by Hyperventilation No indication for neuroimaging Prognosis: Likely remission in adolescence IGE: Juvenile Myoclonic Epilepsy Clinically Clinically Absence, GTCS, morning myoclonus Intermittent seizures, but can be intractable Seizures ppt d by lack of sleep, ETOH, stress Normal neurologic examination and development Presentation: variable 5yrs-20s, Absence 5-16 yrs, mean 10 yrs Myoclonus 8-26 yrs, mean 15 GTCS 9-28, mean 16 yrs 5
Juvenile Myoclonic Epilepsy Diagnosis Diagnosis EEG: Generalized fast, poly spike wave discharges Activated by PS (20-30%) No indication for neuroimaging Prognosis: chronic Alleviation of seizures by 4 th decade is common Variable reports of remission, 6-24% Intractable seizures, 12-17% 17% Associated neurocognitive deficits. The Bad: Jerky babies and kids Benign Myoclonic Epilepsy Myoclonic-Astatic Doose Syndrome Not all jerky babies. Benign Myoclonic Epilepsy of Infancy Also described by Dravet et al, 1992 Clinical features: Normal development at onset No underlying neurologic disorder Frequent family history of epilepsy or FS (30%) Seizures: Massive myoclonic jerks with upper body flexion. Falls are common. Events can be isolated or in brief clusters Subtle head drops secondary to myoclonus are common, and easily missed by parents Can have coincident GTCS 6
Not all jerky babies BME Diagnosis: Extensive testing is negative! Prognosis: In general, excellent Can d/c AEDs after 2-3 yrs Development outcome good, if treated early Significant anxiety for physician Myoclonic-Static Epilepsy, Progressive Myoclonic Epilepsies The Ugly Otahara s Syndrome Early Myoclonic Encephalopathy Infantile Spasms Dravet Syndrome Lennox-Gastaut syndrome Progressive Myoclonic Epilepsy 7
Epileptic Encephalopathies Age dependent spectrum from Otahara syndrome, IS, and LGS Common features: Predominance in a certain age group Frequent, characteristic generalized seizures Severe and continuous epileptic EEG abnormality Heterogenous etiology Cognitive and developmental regression or retardation Medical intractability and poor outcome Evolution with age Infantile Spasms First identified by Dr. William West in Lancet, 1841 IS, hypsarrhythmia, developmental regression Incidence: 1.6-4.5:10,000 live births Clinically: Onset 3-12 mos Seizures: clusters of axial spasms that can occur in flexion or extension, or both Commonly occur when falling or waking from sleep Infantile Spasms Prognosis: Prognosis: Developmental regression: 75-93% High mortality rate 11-33% Seizures remit 6-16% Etiology: Varied: early brain injury (HIE, stroke, infection) Anatomic: Cortical dysplasia, lissencephaly(17p13.3), hemimegalencephaly Genetic: TS, Down s, NF, Several X-linked syndromes (Aicardi s; CDKL5; ARX-related, Xp22.13) Prognosis linked to seizure and EEG resolution 8
Dravet s Syndrome Severe Myoclonic Epilepsy of Infancy First described by Dravet in 1982 Genetics: Missense and truncation mutations in SCN1A Voltage gated Na channel subunit gene Present in >70% of patients Dravet s Syndrome Severe Myoclonic Epilepsy of Infancy First described by Dravet in 1982 Genetics: Missense and truncation mutations in SCN1A Voltage gated Na channel subunit gene Present in >70% of patients Progressive Course: Developmentally normal or mildly delayed Febrile status epilepticus Afebrile generalized and unilateral clonic seizures Development of myoclonus, atypical absence, partial seizures Significant cognitive and developmental deterioration, eventually nonverbal and nonambulatory 9
Dravet s treated with Keto diet Lennox-Gastaut Syndrome Triad: Multiple seizure types Tonic Atonic Atypical absence Myoclonic GTCS Cognitive impairment EEG with slow, <2.5 Hz, generalized slow spike wave pattern 10
Lennox-Gastaut Syndrome Presentation is typically <7yrs, should be before 10 yrs Etiology: heterogenous and vast IS (25%) TS, HIE, Infections, esp encephalitis, TBI Essentially, any injury to the developing brain Progressive Myoclonic Epilepsy Syndromes Clinical: As a group, present in middle of childhood, 8-13 yrs NCL presents in infantile forms Characterized by severe myoclonic epilepsy, in addition to other seizure types Progressive neurologic deterioration EEG: Diffuse theta activity Ictal activity: 3-5 Hz Gen SW and PSW EEG: Late in course, EEG burns out 11
PME: NCL Progressive Myoclonic Epilepsy Syndromes Unverricht- Lundborg 21q22 Cystatin B MERRF mt DNA t-rna LYS Lafora disease 6q24 Tyrosine Phosphatase Infantile NCL 11p15 Lysosomal peptidase Infantile NCL variants 13q, 15q Membrane proteins? Juvenile NCL 16p Hydrophobic pt Sialidosis type l 6p21 Neuraminidase Sialidosis type ll 20q13 Generalized Epilepsy Syndromes Good: Idiopathic Epilepsy Syndromes Relatively straightforward treatment Standard AEDS: ETX, LCT, VPA, LEV Not benign neurocognitively: need screening Bad:Remitting Generalized Epilepsy Syndromes Doose syndrome, BME. GEFS+ Ugly: Progressive Epileptic Encephalopathies: IS, LGS, Dravet s syndrome, PME 12
Partial Epilepsy Syndromes In Childhood Benign Partial Epilepsy in Infancy Benign NEONATAL convulsions Fifth day fits : 90% occur between days 4-6 Seizure: Brief, unifocal clonic Usually only occur for 24-48hrs Diagnosis by exclusion Treatment, as needed, depending on seizure severity and duration Benign FAMILIAL neonatal convulsions Occurs in 14:100,000 births Aut D pattern, 85% penetrance: EBN1: Chrom 20 deletion, Voltage gated K channel, KCNQ2 EBN2: Chrom 8, KCNQ3 Diagnosis: Focal clonic or tonic seizures, FHx, Nl neuro Onset day 1-7 Typically remit by 2-3mos, higher incidence of post-natal epilepsy. Benign Partial Epilepsy Syndromes Idiopathic syndromes that occur in developmentally and neurologically normal children Have a benign course, typically remitting in adolescence Most common syndromes: BECTs Benign Occipital epilepsy Panayiotopoulos Syndrome EEG characteristics: Normal background Sharp and slow wave complexes: bilateral or unilateral Occur in clusters of discharges Activated by sleep Pseudo slowing 13
Benign Epilepsy with Centrotemporal Spikes Seizure: SPS involving the face Since the perisylvian sensorimotor cortex involved: facial numbness, guttural vocalizations, drooling, dysphasia, speech arrest Motor activity typically spreads to arm Overall, ½ pts have secondary generalized seizure ¾ occur at night or on awakening. Benign Epilepsy with Centrotemporal Spikes 10-20% of all childhood epilepsies Onset 3-13 yrs, peak 7-9yrs 25% of patients have a FHx of epilepsy No clear genetic pattern, but the characteristic EEG pattern likely inherited as autosomal dominant trait 14
Benign Epilepsy with Centrotemporal Spikes Prognosis: Spontaneous remission 12-13 yrs In an analysis of almost 800 pts: 16%: 1 seizure 5% : >15 seizures Low incidence of SE (Kramer et al, Jnl Child Neurol 2002) Malignant Partial Epilepsy: Transformation to ESES ( Electric Status Epilepticus of Sleep) Paniotopoulus Syndrome Onset 1-14 yrs, mean of 5 years Seizures: marked autonomic signs: Pallor, miosis, incontinence, coughing, hypersalivation Tachycardia Consciousness affected over the duration of the seizure, typically with staring and eye deviation 1/3- ½ episodes > 30 mins. GTC SE rare Panayiotopoulos Syndrome EEG: 75% pts have interictal EEG w/ occipital spikes Morphology similar to BECTs Prognosis and Treatment: Benign, remits 2-3 yrs after onset Moderate dose of AED. If HA also a feature, consider VPA or TPM 15
Quiz Which spelling was correct? Paniotopoulus Panayiotopoulos Panipaolicchilus Questions? 16