Pediatric Epilepsy Update James J. Riviello, Jr., MD
The IOM Report, Epilepsy • IOM Committee on the • Public Health Dimensions of • the Epilepsies
IOM Report: Types of Patient Education • Epilepsy-specific knowledge & skills • Seizures • Treatment • Safety • Comorbid conditions • Chronic care knowledge & skills • Healthy lifestyle • Partnership with health care team • Independent living
Care of the Child with Epilepsy:Understanding the Mechanisms Treatment Quality of Life Co-Morbidities • Anti-epileptic Drugs • Metabolism-based Treatment (KGD) • Neuromodulation • Epilepsy Surgery
Therapeutic Selection for Patients With Refractory Epilepsy AEDs ResectiveSurgery Ketogenic Diet Neurostimulation or Nonresective Surgery
When To Refer for Epilepsy Surgery • Medically Refractory Epilepsy • Children • Uncontrolled by medical therapy • Failure two or three AEDs • Disabling seizures, side effects • MRI reveals surgical lesion (epileptogenic lesion) • Criteria and Referral for evaluation of pediatric epilepsy surgery; ILAE Epilepsia 2006;47:952-959.
Epilepsy Quality Measures Approved AAN, January 2012 • the frequency of each seizure type should be reported at each visit • -the etiology (or epilepsy syndrome) should be reported at each visit • - counseling for women of child bearing potential with epilepsy should be provided annually
Co-Morbidity – Definitions and Concepts • Co-morbidity refers to the co-occurrence of two supposedly separate conditions that occur together more than chance. • Depression occurs more frequently in patients with epilepsy than in the normal population, thus epilepsy and depression are co-morbidities.
Co-Morbidity - Definitions and Concepts Co-morbidities may be related to the epilepsy or treatment, e.g.: Frequent absence seizures may result in attention deficit Headaches can occur following seizures Cognitive impairment may be related to epileptiform discharges/seizures AED-induced agitation, ADHD, suicidality
Co-Morbidity - Definitions and Concepts • Co-morbidities are not necessarily causal. • Both conditions may have a common biological substrate • An independent variable triggers one of the co-morbidities • Phenobarbital triggers depression • Gabapentin triggers agitation • Co-morbidities often precede onset of the epilepsy
Co-Morbidity Paradigm Brain Disorder Epilepsy Co-Morbidities
Behavior Problems in Children with Epilepsy: Austin 2002 Major risk factors for behavior problems in pediatric epilepsy: neurological dysfunction seizure variables family environment side effects of AEDs Children with new-onset seizures (rank order of total behavior problems): recurrent seizures > single seizure > sibling Raises possibilities that both are caused by an underlying neurological disorder.
Behavioral Problems in New-Onset Epilepsy: Austin 2002 Evaluated 224 children with new-onset seizures (aged 4-14 years) and 159 siblings (4-18 years). During the 2-year evaluation period, 163 (73%) children had at least one additional seizure, and 61 (27%) had none. Children had more behavioral problems when experiencing recurrent seizures than when not experiencing recurrent seizures. Siblings had significantly lower behavioral problems than both children experiencing and not experiencing recurrent seizures. Recurrent seizures significantly predicted behavior problems very early in the course of a seizure condition.
Practice Tools for Cognitive and Behavioral Effects of Epilepsy (AES) • Cognitive (neuropsychological) well being: Children with epilepsy are at an increased risk for cognitive and behavioral impairment. Consider referral for neuropsychological evaluation for children/adolescents with epilepsy who are experiencing difficulty at home or in school. In particular, children are at risk of neuropsychological deficits who present with two or more of the following: • epileptiform activity on EEG; • regression in academic abilities or motor function • abnormality on MRI (or symptomatic epilepsy syndrome**); • absence seizures; • use of antiepileptic medications; • undercontrolled (pharmacoresistent) seizures • Cognition generally improved for individuals who are seizure free.
Practice Tools for Cognitive and Behavioral Effects of Epilepsy (AES) • Anti-epileptic drugs: Discuss / review potential impact of anti-epileptic drugs (AEDs) on child’s cognitive functioning and behavior. Cognitive and behavioral functions generally improve for individuals who are seizure free. • Academic Success: Verify with parent that school has assessed child for attention deficits, intellectual delays, and learning disability to determine if an individualized educational plan is warranted. Assess for regression in academic abilities. • Behavioral/psychological/psychiatric problems: Screen for symptoms of depression and anxiety and other behavioral problems and treat or refer accordingly.
Practice Tools for Cognitive and Behavioral Effects of Epilepsy (AES) • Attention: Screen for attention problems/ Attention Deficit Hyperactivity Disorder (ADHD) and treat or refer accordingly • Sleep: Assess sleep behaviors/environment and provide children, adolescents and parents with lifestyle changes to improve sleep for optimizing seizure control and cognitive and behavioral functioning. Consider evaluation of seizure patterns to assess if having negative impact on sleep. If sleep problems persist after implementing lifestyle changes, consider formal sleep consultation. • Quality of Life/Psychosocial adjustment: Ask patient how epilepsy affects them the most in everyday activities and explore resources to address those concerns/needs. More information/resources available at www.epilepsy.com. • Note: Neuropsychological evaluation is not a substitute for Psychiatric evaluation. Both are likely to benefit patient and family.
Epilepsy and Common Comorbidities: Improving the Outpatient Encounter • Screen for adverse AED effects • Assess physical fitness, activity • Review sleep hygiene • Screen for mood disorders (depression, anxiety) • Screen for educational functioning • Screen for behavior problems • Assess other family, patient concerns
Relationship BetweenSeizures & Cognitive Dysfunction Brain Injury Cognitive Impairment Secondary Injury? Seizures and EEG anormalities
Understanding the Mechanism of Action:Sodium (Na) Channels • Phenytoin • Carbamazepine/Oxcarbazepine • Lamotrigine • Zonisamide • Lacosamide • Rufinamide
Understanding the Mechanism of Action:Calcium Channels • Ethosuximide (blocks the T-type calcium channel)
Understanding the Mechanism of Action:GABA Receptor • Phenobarbital/Primidone • Tiagabine • Vigabatrin • Benzodiazepines • Valproate
Understanding the Mechanism of Action:Glutamate Receptor • Perampanel (AMPA receptor)
Understanding the Mechanism of Action:Multiple Mechanisms of Action • Valproate • Felbamate • Topiramate
Understanding the Mechanism of Action • Gabapentin: binds to calcium channel alpha-2-delta protein • Pregabalin: binds to calcium channel alpha-2-delta protein • Levetiracetam: exact MOA unknown; binds to synaptic vesicle glycoprotein SV2A, inhibits pre-synaptic calcium channels • Ezogabine: activates the potassium channel (unique MOA)
Sulthiame, Sultiame (Opsolot) • MOA: carbonic anhydrase inhibitor • Used for focal (partial) seizures • Tablet Size: 50, 200 mg • It is a good spike suppressor; used for the benign focal epilepsies and as a spike suppressor for the epileptic encephalopathies
Pregabalin (Lyrica) • MOA: binds to the alpha 2 delta subunit of the calcium channel; decreases release of glutamate, norepinephrine, substance P, and calcitonin • Tablet Size: 25, 50, 75, 100, 150, 200, 225, 300 mg • Solution: 20 mg/mL • Used more for neuropathic pain
Lacosamide (Vimpat) • MOA: stabilizes the Na channel (enhances slow inactivation; the slow inactive state) • Tablet Size: 50,100,150, 200 mg • Solution: 10 mg/mL
Rufinamide (Banzel) • MOA: unknown; presumably stabilizes the inactive state of the sodium channel (keeping it closed) • Approved for Lennox-Gastaut Syndrome, ages > 4 years • Efficacy for focal seizures • Tablet Size: 200,400 mg • Suspension: 40 mg/mL
Ezogabine (Potiga)Retigabine (international name) • MOA: activates the Potassium Channel, NCNQ/Kv7 • Relatively free drug interactions • Tablet Size: 50,200,300,400 mg • Urinary Retention • Mood, Behavior Changes
Perampanel (Fycompa) • MOA: non-competitive AMPA receptor antagonist • Tablet Size: 2,4,6,8,10,12 mg • AEs: dizziness, somnolence, vertigo, aggression, anger, ataxia, blurred vision, irritability, dysarthria; weight gain (2.5 pounds)
Multiple Drug Resistance Genes • ABCB1 (ATP-binding cassette subfamily B member) transporter • MDR1 and P-glycoprotein 170 • Functions as an active drug-efflux pump, may be involved in maintaining the BBB • Calcium channel blockers (verapamil) inhibit the expression of p-glycoprotein
Pre-Verapamil Verapamil Treatment
Mechanistic Definition: Failure of the mechanisms that normally stop seizures BZPs are GABAergic • Kapur (1994) loss GABA-a Receptors • Kapur, McDonald (1997): functional change in GABA receptors • Goodkin (2005): internalization of GABA receptors
“Home Remedies” or No IV access • No IV access • Midazolam, nasal, buccal, IM • Diazepam, rectal • Home Remedies • Diazepam, rectal • Midazolam, nasal, buccal
Diazepam: Comparison of IV, IM, Oral, and Rectal Moolenaar et al. Int. J. Pharm 1980;5:127-137
Diazepam Midazolam Buccal Midazolam versus Rectal Diazepam: McIntyre J (Lancet 2005) Therapeutic Success: 61/109 (56%) for MDZ versus 30/110 for DZP No difference respiratory depression: 9/109 for MDZ; 13/110 for DZP
Nasal AEDs • Midazolam: • At first, the solution was used • Now, pharmacies have made an aerosol • 5mg/ml (0.1 ml = 0.5 mg) • Start at 3 sprays/nostril • May repeat after 5 minutes
Importance of Research • Mechanism-Specific Drugs • Disease-Specific Treatments