Transcript Diagnosis & Treatment of Pediatric Epilepsy

Diagnosis & Treatment
of Pediatric Epilepsy
Joseph E. Sullivan, M.D.
Assistant Professor of Clinical Neurology & Pediatrics
Director, UCSF Pediatric Epilepsy Center
Outline
Proper seizure/epilepsy classification
Why treat?
When to treat?
Treatment options
Outcomes
Epilepsy Classification
History, history, history
Tests are ancillary and rarely
confirmatory
Describe what the observer saw FIRST!
Behavior arrest
Staring
Eye deviation
Myoclonic jerk
“New-onset” seizure clinic
History, history, history from the
WITNESS
74% were diagnosed epileptic (94/127)
36% had previous ambiguous event
41% had abnormal EEG
64% were imaged and 18% were
abnormal
Hamiwaka, LD, et.al. Epilepsia, 48(6):1062-66, 2007
Infantile Spasm
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Head drop/atonic
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Atonic-myoclonic
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Eyelid Myoclonia
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Focal Seizures
Focal sensory
Focal motor
Clonic
Asymmetric tonic posturing
With automatisms
Gelastic
Secondarily generalized seizures
Focal clonic
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Frontal
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Supplementary Motor
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EEG
Evaluate background
Screen for inter-ictal discharges or focal
slowing
Rarely capture an event/seizure
Video EEG
EEG
2-5% of normal children may have
abnormal EEG
50% of children with epilepsy may have
normal single EEG
3 EEG’s including sleep 90% abnormal
Treat patients NOT EEG abnormalities
Classification
59% of newly diagnosed children have
focal epilepsy
20% may have specific epilepsy
syndrome diagnosis
12% unable to be classified at
diagnosis
Neuroimaging
Reasons to order urgent
neuroimaging (usually in ED)?
Diagnose an underlying condition that
requires immediate intervention.
Hemorrhage
Stroke
Cerebral Abscess
Tumor with resultant hydrocephalus
Abnormal Imaging Scenarios
Must know prior to d/c from ED
New bleed, abscess
Good to know within 2-4 weeks
Tumor
Whenever
Malformation of cortical development,
remote encephalomalacia
Evidence based?
500 children with a first non-febrile seizure
475 imaged in the ER
8% with “clinically significant” abnormalities
3/475 had findings needed immediate intervention
1 shunt failure
1 increased intra-cranial pressure after head trauma
1 with new-onset infantile spasms and a neoplasm
Sharma et al. Pediatrics 2003;111:1-5
High risk groups
High-risk groups to image in the ER
Known bleeding or clotting disorders
Known hx of malignancy
HIV infection
Closed head injury
Less than 33 months with a focal seizure
Sharma et al. Pediatrics 2003;111:1-5
Who was missed
Age
History
2 mos
6 min seizure
3y
Status
epilepticus
Abnl mental
status
Abnl mental
status
9y
4 min seizure
Normal
10 y
10 min seizure
New Right
hemiparesis
12 y
5 min seizure
Normal
16 y
4 seizures
Physical Exam
Hypertension
Diagnosis
Management
Subdural
Child abuse
hematoma
eval, no surgery
Anoxic brain
ICU admit, pt
injury
died
5 mm arachnoid
AED started
cyst
Benign frontal Resection 6 wk
lobe tumor
later
Grey matter
AED started
heterotopia
Hypertensive Anti-HTN and
encephalopathy AED started
Sharma et al. Pediatrics 2003;111:1-5
But what about a brain tumor!
200 consecutive children with new
diagnosis of brain tumor
30/200 (9%) presented with a seizure
19/30 had focal seizures
11/30 had generalized seizures
Wilne et al. AJDC 2006;91:502-506
Of the 30 patients presenting with seizures
17 had no other symptoms and a normal
exam
14/17 focal seizures
3/17 generalized seizures
2/3 had focal slowing on EEG
1/3 atypical absence seizures
Wilne et al. AJDC 2006;91:502-506
AAN Practice Parameter Recommendation
“Evaluating a first nonfebrile seizure in children”
If a neuroimaging study is obtained, MRI is
the preferred modality.
Emergent neuroimaging should be performed
if there is a post-ictal focal deficit not quickly
resolving, or who has not returned to baseline
within several hours after the seizure.
Hirtz, D Neurology 2000;55:616-623
Who to admit
Children less than 1 year old
Prolonged seizure (>15 minutes)
Not back to baseline after 4 hours
What to tell parents
Back to some key components in the history
Child neurologically normal?
Did the seizure occur while awake or asleep?
Simple questions but very important
Overall Recurrence
Risk
42% recurrence
Mean time to recurrence 11.3 months
36% in first month
53% in 6 months
88% in 2 years
Normal Child vs Abnormal Child
Cryptogenic (ie otherwise normal)=37%
Remote symptomatic (ie neonatal HIE,
history of stroke, autism, etc)=68%
But the seizure was 1 hour long!
First time seizure as status does NOT affect
recurrence risk
12% of Shinnar cohort presented with status
Recurrence risk at 2 years is still 38% for
cryptogenic kids
Of those with status 21% of those who had
a recurrence had recurrence of status.
Don’t be afraid to give Diastat in these
cases
Why do we treat?
Reduce recurrence risk
Prevent prolonged seizures
Minimize impact on
development/academic achievement
Does NOT affect natural history
if you are going to outgrow it, you will
regardless of treatment
The Normal Child
Awake, and normal EEG=19%
Asleep, normal EEG-37%
Awake, abnormal EEG=42%
Asleep, abnormal EEG=63%
Shinnar, S Pediatrics 1996 ; 98:216-225
When to treat?
Depends on the patient/family and
seizure frequency
Daily, weekly, monthly seizures
Every 6 months
Yearly
Prolonged seizures/convulsions
Treatment?
Every child/family is different
Treatment may reduce recurrence risk by
as much as 50%.
AED’s are toxic medications!
For the most part we do not treat after a first
time seizure.
The one exception- Remote symptomatic
presenting in status.
Shinnar, S Pediatrics 1996 ; 98:216-225
Treatment options
Daily anti-epileptic drugs (AED’s)
Abortive medications
Specialized diets
Surgery
Resective
Devices, ie Vagal nerve stimulator
No seizures and No
side effects!
Medications
16 anti-epileptic drugs (AED’s) available
in U.S.
Many used “off-label”
Very few studies in children
First vs Second generation
First generation
Second generation
Phenobarbital
Ox-carbazepine (Trileptal)
Phenytoin (Dilantin)
Lamotrigine (Lamictal)
Carbamazepine
(Tegretol)
Gabapentin (Neurontin)
Ethosuxamide (Zarontin)
Valproate
(Depakote,Depakene)
Benzodiazepines
Lorazepam (Ativan)
Midazolam (Versed)
Diazepam (Valium)
Clonazepam (Klonipin)
Chlorazepate (Tranxene)
Topiramate (Topamax)
Levetiracetam (Keppra)
Zonisamide (Zonegran)
Pregabalin (Lyrica)
Lacosamide (Vimpat)
Special siutation AED’s
Vigabatrin (Sabril)-infantile spasms,
seizures in setting of tuberous sclerosis
ACTH/steroids-infantile spasms
Felbatol-medically resistant atonic/drop
seizures
What is the difference?
2nd generation AED’s have wider
therapeutic windows
No need to follow levels
Can increase based on side effects
Less interactions with other drugs
Most have similar efficacy
Just pick a drug from a hat?
Some AED’s are better for specific seizure
types/syndromes
Absence-Ethosuxamide (carbamazpine is contraindicated)
Juvenile myoclonic epilepsy-valproate, lamotrigine, levetiracetam
Co-morbidities
Avoid AED’s that could worsen co-morbidities
Favor AED’s that may help co-morbidities
Formulation (liquid, sprinkle, tablet,
capsule)
Common Co-morbidities
Weight gain-ox-carbazepine, valproate,
gabapentin, pregabalin
Weight loss-topiramate, zonisamide
Altered blood counts- carbamazepine,
valproate
Headaches-topiramate, carbamazepine,
valproate, levetiracetam
Side Effects
Phenobarbital-sedation
Valproate-weight gain, liver toxicity,
decreased platelets, pancreatitis
Sodium abnormalities-ox-carbazepine
Lamotrigine-Steven’s Johnson syndrome
Topiramate-weight loss, language
dysfunction, kidney stones, glaucoma
Levetiracetam-irritability,agitation
Pediatric formulations
Liquid
Sprinkle
Chewable tab
Phenobarbital
** Divalproate (Depakote)
** carbamazepine
(Tegretol)
Ethosuximide (Zarontin)
Topiramate (Topamax)
Lamotrigine (Lamictal)
** carbamazepine (Tegretol)
Zonisamide (Zonegran)
valproic acid (Depakene)
Vigabatrin (Sabril)
sachet powder
Ox-carbazepine (Trileptal)
Levetiracetam
(Keppra)
Felbatol (Felbamate)
** 3-4 times per day
Treatment Goal
Single medication at a dose with NO side
effects
If first medication does not work-trial of
another single medication
If second medication alone is not effective,
trial of polytherapy (2 or more drugs)
Rarely are 3 medications better than 2
Side effects increase
Outcomes
Most children with epilepsy do VERY well
One study 83% required a single AED in
first year of treatment
61% of these were seizure free off meds
at end of study---REMISSION
Only 4% with favorable response in first
year developed intractable epilepsy
17% with inadequate control
42% still achieved remission
29% develop intractable epilepsy
Camfield, PR et.al., J Pediatr, 1997:131:821-24
Long Term Follow-up
37 year f/u of 144 patients
31% enter remission in first year of Rx
19% are resistant from the beginning
Overall 67% achieve terminal remission
14% on AED’s
86% off AED’s
Sillanpaa, M & Schmidt, D Brain 2006, 129, 671-624
When to wean?
Seizure free for 2 years
Single seizure type
Normal EEG on AED’s
Normal IQ
Normal neurologic examination
Less “favorable” factors
Age greater than 12 years
Family history of epilepsy
Frequency of seizures at onset (>21)
Slowing on EEG
Remote etiology
“At-risk” population
Remission rates are much less than
those with developmental disabilities
Should still consider if sz free>2 years
Recurrence risks:
Spastic hemiplegic CP-61%
DD only 52%
The “nightmare”-relatively rare
2/41 children with DD
Camfield, C, et.al., J Pediatr 1993;122:861-8
Delgado, MR, et.al. Pedaitrics 1996;97:192-197
Neuropsychological Status in
children
Distinct neuropsychological profiles in
different epilepsy syndromes
Often confounded by seizure burden and
medication side effects
What about children with “new-onset
epilepsy”
New-onset Epilepsy
Prospective study of 53 children with
recent-onset idiopathic epilepsy
Diagnosis of epilepsy within the past 12 months
No other developmental or neurologic disorder
Normal MRI
Neuropsychological assessment performed
& compared to age/gender matched firstdegree cousins.
Hermann, B, Children with new-onset
epilelpsy:neuropsychological status and brain
structure,Brain:129, 2609-2619
Results
Epilepsy patients exhibited poorer performance across all measures
Hermann, B, Children with new-onset
epilelpsy:neuropsychological status and brain
structure,Brain:129, 2609-2619
LRE vs PGE
LRE but NOT PGE differ from controls in language and memory
Hermann, B, Children with new-onset
epilelpsy:neuropsychological sstatus and brain
structure,Brain:129, 2609-2619
Academic Achievement
26% presented with history of academic problems (AP)
No relationship with epilepsy syndrome, age, number of
medications
MR volumetrics reveal no differences in white matter
volume when compared to controls
In those with AP-significant volume reductions in left
parietal and left occipital grey matter.
Hermann, B, Children with new-onset
epilelpsy:neuropsychological sstatus and brain
structure,Brain:129, 2609-2619
Social Consequences
Nova Scotia population-based cohort
56 patients with CAE
61 patients with JRA
Inteviewed at mean age of 23 years
Terminal remission
CAE=57%
JRA=28%
Wirrell et al, Long-term psychosocial outcome in typical
absence epilepsy.
Sometimes a wolf in sheeps’
clothing, Arch Pediatr Adoles Med, 1997 151(2);152-8
Social Outcomes
CAE patients (%)
JRA patients (%)
Odds ratio (CI)
No high school
graduation
36
14
3.7 (1.3-10.4)
Special classes
16
3
5.7 (1.1-40.5)
Repeated a grade
before diagnosis
20
3
7.6 (1.4-52.8)
Ever considered a
behavior problem
41
10
6.4 (2.2-19.9)
Unplanned pregnancy
34
3
19.3 (2.3-426.1)
Psychiatric or
emotional problems
54
31
2.6 (1.1-5.9)
Unskilled laborer
53
16
5.9 (1.6-24.0)
Manager or
professional
0
36
undefined
Not employed in area
of training
50
14
5.7 (1.2-33.9)
Autism and Epilepsy
75% of children with autism will have
abnormal EEG
25-30% will have epilepsy
Absence of MR- 2-8%
Presence of MR- 7-27%
Remission rates low- 16%
Tuchman, RF, et.al. Pediatrics 1991;88:1219-1225
14% of 155 children with autistic
regression had abnormal EEG vs 6%
without regression
No difference in incidence of AR
between those with and without
epilepsy
Significance is unclear and very
controversial
Treat patients NOT EEG abnormalities
Abortive medications
A medication that is given for a prolonged
seizure or seizures that cluster
Rectal vs. buccal
Diastat is studied and approved for rectal
administration
Buccal/nasal delivery of midazolam
Intermittant diazepam or lorazepam for
children who cluster in setting of
fever/illness
Beyond Medications
5% of patients per year will become seizure
free with additional AED trials
Consider alternative measures
Ketogenic/Atkin’s Diet
Surgery
Ketogenic Diet
Described in New Testament and by
Hippocrates
Starvation was noted to improve “fits”
High fat, low carbohydrate diet mimics
starvation
Very effective
Reports of between 20-45% seizure free
67% have >50% reduction in seizures
Very restrictive
Modified Atkin’s Diet
Less restrictive but still only 10-20 g
carbs/day
Liberalize protein and fat
5-15% may become seizure free
60% may have >50% reduction
If some effect, can always transition to
classic ketogenic diet
Pre-surgical evaluation
First tier
Video EEG for ictal recording
High-resolution MRI
Second tier
Magnetoencephalography (MEG)
Positron emission tomography (PET)
Single photon emission computed
tomography (SPECT)
Lesional epilepsy
Complete resection of lesion AND
electrographically abnormal region
92% have good outcome
sz free or >90% reduction
Electrographically abnormal region
Electrocortiography
Chronic subdural grid recordings
Palocchi, JM, et.al, Neurology 2000 54(3):642-47
Non-lesional epilepsy
Subdural grid/strip recordings are
mandatory
At 2 year follow-up
44% seizure free
15% >90% reduction
17% >50% reduction
10 year follow-up
33% seizure free
Jayakar, P et.al., Epilepsia 2008 49(5) 758-64
VNS
Implanted under chest wall and wire
wrapped around left vagus nerve
Unclear mechanism of action
Vagus nerve projects widely throughout
cerebrum
Higher incidence of cardiac related side
effects if implanted on right side
VNS complications
Hoarseness
Cough
Reflux
<1% symptomatic bradycardia
VNS efficacy
<5% seizure free
50% experience 50% reduction of
seizures
magnet swipes may shorten/abort
prolonged seizures
Comprehensive Epilepsy Center
Team approach
Pediatric epileptologist
High-quality neuroimaging
High field MRI, fMRI, MEG, PET
Experienced neuroradiologists
Pediatric neuropsychologist
Pediatric epilepsy surgeon
Experienced EEG technologists
Nursing
Questions?
Febrile Seizures
An event in infancy or childhood, usually
occuring between 3 months and 5 years,
associated with fever but without evidence
of intracranial infection or other definable
cause.
Febrile Seizures
Simple-primarily generalized seizure
lasting <15 mins and not recurring in 24
hours
Complex-focal, prolonged, or more than 1
seizure in 24 hours
Epilepsy-recurrent, non-febrile/unprovoked
seizures
Febrile Seizures
2-5% of children
Epilepsy 0.5-1%
Clinical Characteristics
16-35% of initial FS are complex
Risk factors for 1st FS-FHx of FS, delayed
development, daycare attendance
Laboratory Evaluation
“The workup of a child who has had a
febrile seizure and has recovered consists
solely of the work-up of the fever (Vining
& Freeman, 1985)
Lumbar Puncture
How many children with meningitis present
with seizure and fever
503 cases of meningitis
115(23%) had seizures
105 were obtunded or comatose
other 10 had nuchal rigidity (6),
prolonged seizure(1), petechial rash
(1), viral meinigities (2)
Lumbar Puncture
Mental status is highly predictive
79% of meningitis cases had complex FS
Pretreatment with Abx may be a concern
Recent FEBSTAT study
80% of 102 pts had LP
8% had more than 5 WBC’s
All traumatic
Lumbar Puncture
FEBSTAT study
80% of 102 pts had LP
30%-0, 40%-1, 15%-2, 5%-3, 1%-4
8% had more than 5 WBC’s
All traumatic
Normal protein and glucose
Finding of >5 WBC’s in a non-traumatic LP
should be a concern
Imaging
No good studies
FEBSTAT-some hippocampal signal
abnormalties in first 72 hours, in those with
febrile status
Also finding hippocampal malrotation
(17% >30 mins, 9% <30 mins, 1% simple
FS)
EEG
Hypothesized reasons for obtaining EEG
Help with estimating risk of recurrence
Help stratifying those that will go on to develop epilepsy
3-4% will show spikes or spike-wave activity
close to the 1-9% incidence of focal sharp activity in
normal young children
Factors affecting
recurrence risk
Age at onset
Simple vs. Complex
Neurodevelopmental exam
Duration of fever
Height of Temperature
Family History of Febrile Seizures
Age at onset
Less than 12 mos of age has increased risk of
developing recurrence of febrile seizure
48.4% vs. 29.6% in older group
Different or longer period of time at risk
Laboratory Evaluation
Does not affect risk of recurrence for febrile seizures
30% vs. 37%
Does affect risk of developing epilepsy
Overall risk of developing epilepsy with a simple
febrile seizure is approx 2%
If initial seizure is complex this is increased
Combining Risk Factors
Epilepsy risk & complex features
per/1000
Duration of fever
Height of fever
Treatment?
Phenobarb will decreased recurrence to as
low at 5%
Side effects including irritability, agression,
neurodevelopmental effects
Antipyretics?
Ibuprofen 5mg/kg, not effective
Acetominophen 10 mg/kg also not
effective
Did reduce mean temp, but not max
van Stuijvenberg et al 1998
Uhari et al, 1995
What to do?
Seizure often first sign of fever
Difficult to argue against, but warn parents
that it still may not work!
Conclusions
Most FS are benign events
Stratification allows identification of high
risk groups
Work-up need not be extensive
Very few treatment options
Treatment should be reserved for special
situations