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• Anti-epileptic Drugs• Metabolism-based

Treatment (KGD)• Neuromodulation• Epilepsy Surgery

Quality of Life• Co-Morbidities

AEDs

KetogenicDiet

Neurostimulation or Nonresective

Surgery

ResectiveSurgery

Therapeutic Selection for Patients With Refractory Epilepsy

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-Morbidities

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

Seizures and EEG anormalities

Cognitive Impairment

Secondary Injury?

AEDs: Old and New

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)

New AEDs

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)

Why is Epilepsy Refractory?

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

Status Epilepticus

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

Buccal Midazolam

Buccal Midazolam versus Rectal Diazepam: McIntyre J (Lancet 2005)

• Diazepam • MidazolamAGE DOSE3 -11 months 2.5 mg1- 4 years 5 mg5 – 9 years 7.5 mg10 -12 years 10 mg

Therapeutic Success: 61/109 (56%) for MDZ versus 30/110 for DZPNo 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

MDZ plasma concentrations by various routes; Wermeling DP

Importance of Research

• Mechanism-Specific Drugs• Disease-Specific Treatments

Epileptic Encephalopathy Genes

Tuberous Sclerosis: Disease Modifying Treatments

mTOR Pathway in Epilepsy Tx

Epileptic Encephalopathies: Recognition and Treatment

Epileptic Encephalopathy

• An epileptic encephalopathy is a disorder in which the spike and sharp wave (epileptiform) activity on the EEG impairs brain function. This typically occurs when the epileptiform activity occur during sleep. This activity may respond to anti-seizure medications. Certain seizures and epilepsy syndromes commonly cause an epileptic encephalopathy.

The Center for Epileptic Encephalopathies (CEE) at NYU:

EEG Findings in Epileptic Encephalopathies

• An epileptic encephalopathy may exist without an actual clinical seizure. The EEG is critical to evaluate a child for an epileptic encephalopathy: to identify the epileptiform activity and quantify its abundance, especially during sleep. The hallmark EEG finding is electrical status epilepticus of sleep (ESES). The more sleep-activated the EEG, the more likely an associated cognitive or behavioral problem. The severity is determined by scoring the spike-wave index, done only by very specialized epilepsy centers.

The Center for Epileptic Encephalopathies (CEE) at NYU:

• Successful treatment requires the teamwork of various specialists, including an epileptologist, psychopharmacologist , neuropsychiatrist, neuropsychologist, nurse practitioner, and dietician. Is this different than a neuropsychiatrist?

EEG: Electrical Status Epilepticus of Sleepand the Ideal Treatment Situation:

An “all or none” EEG response.

EEG “normalizes” with a spike suppressor.

NKH: before and after dextromethorphan

Inflammation and Epilepsy

Inflammatory Cascade In Epilepsy

IVIG in Intractable Childhood Epilepsy

IVIG in Intractable Childhood Epilepsy

• Dosing: – IVIG 2 grams/kg given in 4 divided doses over four

days– IVIG 1 gram/kg over 2 days over 6 months; then

discontinued• Response: Defined as a > 50 % decrease in

seizure frequency during the 6th month• If relapse, IVIG restarted at 1 gram/kg every

month for 1 year

Results:

• Males responded better than females

Metabolism-Based Treatments (Ketogenic Diet): Four Versions

Four Versions• 1) Classic ketogenic diet• 2) MCT ketogenic diet

– can’t do 3/1 ratio, usually g-tube fed

• 3) Low glycemic index treatment

• 4) Modified Atkins/ modified ketogenic diet

Certain Syndromes• Myoclonic-Atonic Epilepsy

(Doose Syndrome)• Severe Myoclonic Epilepsy of

Infancy (Dravet Syndrome)• Infantile Spasms• Tuberous Sclerosis• Rett Syndrome• Pyruvate dehydrogenase

Deficiency• Glucose Transporter Defect

Ketogenic Diet: Efficacy

• Benefits: – Seizure control without AED side effects

• Results:– Original Hopkins cohort of 150 children at 3 years

(2001), 13% (20) were seizure free and 14% (21) had a greater than 90% seizure reduction1

– Systematic review (2000): 11 studies; 16% were seizure free; 32% had a greater than 90% reduction2

– Italian multicenter cohort (2002): 12.5% seizure free (7/56)3 1.Hemmingway C, et al. Pediatrics. 2001;108:898-905.

2.Lefevre F, Aronson N. Pediatrics. 2000;105:E463.Coppola G, et al. Epilepsy Rev. 2002;48:221-227

Ketogenic Diet: Contraindications

• Carnitene Deficiency– Primary, CPT I or II, translocase deficiency

• B-Oxidation defects• Pyruvate Carboxylase Deficiency• Porphyria• Relative Contraindications:

– Inability to maintain adequate nutrition– Surgical Focus– Parent or Caregiver Noncompliance

Neuromodulation

• Vagus Nerve Stimulation• Deep Brain Stimulation (anterior thalamic

nucleus)• Responsive Neurostimulation• Transcranial Magnetic Stimulation

The END