Transcript Pediatric Epilepsy Update

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
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Seizures
Treatment
Safety
Comorbid conditions
• Chronic care knowledge & skills
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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
Therapeutic Selection for Patients With Refractory
Epilepsy
AEDs
Resective
Surgery
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-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 comorbidities.
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 comorbidities
• 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
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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:
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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 antiepileptic drugs (AEDs) on child’s cognitive functioning and behavior.
Cognitive and behavioral functions generally improve for individuals
who are seizure free.
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• 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.
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• 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)
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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
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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 Between
Seizures & Cognitive Dysfunction
Brain Injury
Seizures and
EEG anormalities
Cognitive
Impairment
AEDs: Old and New
Understanding the Mechanism of Action:
Sodium (Na) Channels
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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
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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-2delta protein
• Pregabalin: binds to calcium channel alpha-2delta 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)
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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 GABAa 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
• Midazolam
AGE
3 -11 months
1- 4 years
DOSE
2.5 mg
5 mg
5 – 9 years
10 -12 years
7.5 mg
10 mg
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
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 sleepactivated 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 Sleep
and 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
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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:E46
3.Coppola G, et al. Epilepsy Rev. 2002;48:221-227
Ketogenic Diet: Contraindications
• Carnitene Deficiency
– Primary, CPT I or II, translocase deficiency
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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