Download Epilepsy

Epilepsy: Challenges & Therapies
Orrin Devinsky, M.D.
NYU Epilepsy Center
Diagnostic Challenges

Define epilepsy syndrome


Understand the cause of epilepsy



High resolution MRI
Genetic studies (GEFS+, Chromosomal microarrays)
Define factors that provoke seizures


Video-EEG monitoring
FAILURE
Identify long-term effects of epilepsy &s its treatment
Therapeutic Challenges
 No
seizures, no side effects
 If patients had their choice:
No doctors, No Medicines
 In general, would rather see doctor than
take medication
Therapeutic Challenges
 Ongoing
assessment: consequences of
seizures and therapy
 How aggressive to pursue seizure
control?
 Do we treat interictal EEG?
? Benign rolandic epilepsy
 How to assess effects of long-term
therapies?
Alternative Therapies for Epilepsy
 Diverse
group
 Osteopathy,
chiropractic, homeopathy,
herbs, EEG feedback (neurotherapy), stress
reduction, magnetic stimulation, carbon
dioxide therapy, fatty acids
 We
need data!
Common Errors that
Doctors Make

Misdiagnosis
 Is
it epilepsy?
 Which epilepsy syndrome?
 Not noticing change
 Incorrect
 AEDs
medication choice
can exacerbate seizures
Failure to reassess or
consider VNS or surgery

Mistakes I’ve Made
 Relying
on prior diagnosis
 Becoming “invested” in a course of
action
 Not listening to the information
 Not challenging one’s own conclusion
 Finding
information that supports
 Explaining information that doesn’t fit
Physician Issues in
Selecting AED
 AED
relative efficacy:toxicity
 Knowledge

Published studies



Randomized v. open-label
Dose range, methodology
Statistical v. clinical significance
 Information
from colleagues
 Personal experience
 Belief, Bias, & Comfort Zone
Quality of Life:
The Traditional View
 Medical
Education - MD perspective
 Medical
literature, clinical experience
 Disorders
- signs & symptoms
 Evaluation - history, PE, Lab
 Therapy - studies of medical outcome
QOL:
A Different View
 QOL
- Defined by patient not MD
 Should patient’s perspective be filtered
through “objective medical lens”? - NO
 QOL is about listening, changing
perspective, and using the patients’
view as the ultimate measure of
outcome
QOL:
Relevance to Epilepsy?
 QOL
issues most relevant to chronic
disorders, problems beyond disease
symptoms
 Epilepsy is the paradigm of such a
disorder
 Seizures are infrequent,AED effects &
psychosocial problems are chronic
A Case Study
 29
y.o. woman
 monthly


CPS, rare GTCs
 Routine 6 mo. Checkup: complains of some
tiredness, blurred vision, nausea
 Exam - mild nystagmus, tremor
 Labs - slightly elevated LFTs
MD’s perspective - doing great
Woman’s perspective - doing poorly; not driving,
underemployed, fearful of seizures, troubled by AEs
Cognitive & Behavioral
Changes in Epilepsy
 Must
diagnose to treat
 Cognitive-behavioral disorders are
often overlooked - “under appreciated”
 Not
spontaneously reported
 Not asked about by MD/RN
 Noted, but considered minor
 Noted, but considered untreatable
Seizure Burden:
The Great Lie
 Are
complex partial seizures bad?
 Memory
- long-term consequences
 Personality changes
 Affective changes
 Psychosis
 Are
tonic-clonic seizures bad?
 You
bet!
PGE and Behavior:
Absence Epilepsy
(Wirrell et al, 1997)
 56
absence epilepsy v. 61 JRA patient
 Pts
with absence epilepsy had more
academic, personal, and behavioral
disorders (p<.001)
 Those with ongoing seizures had worse
outcomes
Epilepsy: Progressive
Cognitive Decline
 Tuberous
Sclerosis (Gomez)
 Relation
of Seizure and MR
 Of
140 pts with Szs - 89 MR
 Of 19 pts w/o Szs - none MR
 Age of seizure onset and MR related:
MR in 72/79 with seizures before age 1y
 MR in 6/25 with seizures after age 4 y

?
Role of CNS pathology vs. Seizures
 ? Younger brain protected or at risk
Issues with AED Safety


Idiosyncratic AE’s
Dose-related AE’s



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Cognitive
Behavioral
Quality of life
Chronic AE’s
Teratogenic AE’s
Drug interactions
Uncommon Side Effects






Increased frequency of urination - lamotrigine
High blood pressure, migraines - carbamazepine
Aggressiveness - phenobarb, ethosuximide,
levetiracetam
Severe sedation, coma - valproic acid
Movement disorders - phenytoin, carbamazepine
Kidney stones - topiramate, zonisamide,
acetazolamide
Getting Off AEDs


Everyone’s goal
Must balance risk - benefit





Lifestyle factors such as driving
Potential side effects
How long do you wait for seizure freedom
Do you ever try when EEG has spikes or sharp waves, or if
auras/minor seizures persist
Middle road is often reasonable - gradual taper over
months or often years
Chronic Adverse Effects:
Bone Disorders
 Decrease
Ca/Vit D levels
 CBZ
(?OXC), PRM, PB, PHT, VPA
 New AEDs appear safer, but ?
 Risk
factors
 Dose,
polytherapy, & duration
 Diagnosis
 Suspicion;
 Treatment
bone densitomety
- Vit D/Ca, sun, alendrodate,
estrogen supp after menopause
Rapist Roosters
Grandin - Animals in Translation
 Observed
chicken pecked to death
 Chicken farmer - we see this; roosters
rape and murder, lots of them
 Breeding for single traits
 Large
breasts & rapid growth
 Roosters lost their mating dance
 We
get used to abnormal, and think its
normal
Long Term Side Effects:
? Drugs v. Disease v. Person
 After
several years, hard to determine if
something really exists - ? personality/person
versus disease process versus AED
 Can be impossible to determine
 Reducing or changing drugs may be only
way to answer, but may be dangerous
 Young woman, PB, and memory
Depression



Common
Underdiagnosed
Undertreated



Doctors and patients are at fault
Major factor in reducing quality of life
Polycystic ovarian syndrome
100
70
80
60
Total QOLIE-89
QOLIE-89 Total Score
Depression and QOL in Epilepsy
60
Gilliam
et al., 2002
40
50
Johnson et al.,
2004
40
30
20
20
0
-5
0
5
10
15
20
25
30
35
30
40
40
50
60
70
80
90
Depression (SCL-90-R)
Beck Depression Inventory Score
100
100
90
Cramer
et al, 2003
Quality of Life (QOLIE-31)
QOLIE-31
80
60
40
20
80
70
Boylan et al.,
2004
60
50
40
30
20
10
0
0
0
10
20
30
40
50
60
70
-5
0
5
10
15
2
0
25
30
Depression (BDI)
35
40
45
50
Sudden Unexplained Death
in Epilepsy (SUDEP)
 SUDEP
incidence increases with
epilepsy severity
 Community
sample -- 0.35/1000 pt-yrs
24X general populate rate
 Epilepsy centers -- 1.0/1000 pt-yrs
 AED/VNS trials -- 3.75/1000 pt-yrs
Sudden Unexplained Death
in Epilepsy (SUDEP)
General population (2–3)
Epilepsy incidence population (5)
Epilepsy prevalence population (7)
Patients in clinical trials (30–50)
Patients undergoing vagus nerve stimulation (41)
Patients referred to epilepsy centers (50–60)
Surgical candidates (90)
Surgical failures (150)
0
25
50
75
100
125
150
Annual incidence per 10,000 population
175
200
Developmental Disabilities &
Epilepsy


Never lose sight of the person behind the frail frame
or cognitive impairment
Put yourself in their shoes



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We relate to those like us
Teachers favor good looking students, what of doctors?
Lower expectations
Don’t tolerate side effects, seizures, lower QOL
Neurologic disorders close doors of normality, but
open new ones
New Therapies in Epilepsy:
AED Pipeline

Novel mechanisms

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New Relatives of known drugs

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Potassium channels - retigabine,
Functionalized amino acid (glycine; NMDA antagonist) lacosamide
GABAA receptor modifiers - neuroctive steroid (ganaxalone)
Synaptic vesical 2A ligands (levetericetam relatives)
Sodium channel - oxcarbazepine relative
Valproate relatives - valrocamide, isovaleramide
Felbamate relative - flourofelbamate
Nasal midazolam - new rescue medication!

More rapid onset, quicker offset than rectal diazepam
Closing Thoughts

Health care is a partnership
Knowldege is power
 Communication is essential
 QOL is yours

Never accept seizures and side effects
 The future has never been better
