Transcript Morning Keynote Address - FACES (Finding a Cure for Epilepsy and

Controlling Seizures
Staying Health
Orrin Devinsky, M.D.
Department of Neurology
NYU Langone School of Medicine
What is Epilepsy?
 Occasional,
sudden, excessive, rapid, and
local discharge of grey matter (Jackson, 1890)
 We focus on what we see, not what is missing
 Sudden
– there are continuous disorders of neural
functioning
 Excessive – there is often deficient inhibition of
neuronal activity
 Rapid – changes may be fast at the human sensory
level but slow at the cellular level
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?
Fooled by Experience:
Tom’s Seizure
9
am Saturday morning – Tonic-clonic
seizure, witnessed by his children
 My first question: any provocative
factor?
 Missed
meds, sleep deprivation, alcohol?
 “Nothing
 Missed
really”
meds, but can’t be that – I do it all
the time
Risks, Rewards, Perfect Storms
 Known
provocative factors
 Missed
medications
 Sleep deprivation/time zone Δ’s
 Excess alcohol (> 2 drinks)
 Physical or emotional stress
 Factors
are not additive but
synergistic
 Linear
 Many
or non-linear
factors unknown
Seeing patterns, Finding Meaning
 WWII
– V2 rockets in London
 Germans precisely targeted
areas &avoided spies
 Cancer clusters – in CA 5000
census areas, 2,750 with
statistically significant but
random elevations of some
cancer
 Your idea: find evidence it is
wrong, not only right
Missing Patterns
Our mind sees stability
It fills in holes from your visual blindspot to
the sentences you hear
On chronic AED therapy – and this may only
be months – one may start to forget how they
felt or their relative behaved before the
medicine
This is especially problematic when
medicine dose is increased slowly and
other factors (eg, seizures, stress) are
present
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 Selection of AEDs

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
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
What is Seizure Control?
Relative term
Are there things to encourage the resolution of
epilepsy?
Epileptogenesis – the process by which epilepsy
develops, for example, after a head injury
Anti-epileptogenesis – preventing the process
by which epilepsy develops
Reverse epileptogenesis – reversing the process
by which epilepsy develops
Why is Seizure Control
Important?
Quality of life
Prevention of injury, accident, SUDEP
Prevention of progression
The longer you are seizure free, the longer you
stay seizure free
The longer you are seizure free, the greater the
chances of staying seizure free off medication
Progression of Epilepsy
For some, epilepsy is a progressive disorder
MRI – progressive hippocampal atrophy with
continued seizures
41 years old
44 years old
75 Partial Seizures & 5 GTCS in 3 years
Fuerst et al, Ann Neurol 2003
Mental Status and Seizures in TSC
Mental
Status
No
Epilepsy
With
Epilepsy
Total
Normal
19
40
59
MR
0
89
89
Total
19
129
148
Gomez M 1979;18-19.
Mental Status and Seizures in TSC
Age (yr) Sz
Onset
Normal
Intelligence
Mentally
Retarded
0-1
7
72
2-4
13
9
5-9
6
3
10-14
2
1
=>15
11
2
Total
39
87
Gomez M 1979;18-19.
Histological Studies of TLE
 Dendritic
spine density remote
from seizure focus reduced with
increased epilepsy duration
 Multani
et al, Epilepsia 1994;35:728-36
 Hippocampal
neuron density
declines with chronic habitual
seizures
 Mathern
et al, Brain 1995 Epilepsy Res 1996
PET Temporal Hypometabolism
 Results
from neuronal loss and functional
factors. Can occur without atrophy.
Extends beyond seizure focus.
 Associated with epilepsy duration
Extratemporal Volume Loss &
Hypometabolism in TLE
 Whole
brain volumes reduced
 In TLE, thalamic volumes & metabolism are
reduced
 Thalamic reduction ipsilateral to focus
 epilepsy duration cerebellar metabol
Normalization of PET
Abnormalities after
Successful TLE Surgery
Metabolism normalizes in contralateral
mesial temporal lobe and in ipsilateral
frontal cortex and thalamus after
temporal lobectomy!
Normalization of MRS Abnormalities
after Temporal Lobectomy
 NAA/Cr
increased to normal
range on side of surgery in seizure
free patients
 NAA/Cr (Ipsilateral &
Contralateral) increased 50% by
6mos and 95% by 25 mos in
seizure-free patients
 Contralateral hippocampus NAA
improves
Cross Sectional Neuropsychological
Studies in Epilepsy Patients
Relationship of Epilepsy Duration & Mental Deterioration
STRONG
MODERATE
Lennox & Lennox (1960)
Dikman & Matthews (1977)
Dodrill & Troupin (1976)
Jokeit & Ebner (1999)
Gomez (1979)
Jokeit et al (2000)
Dodrill (1986)
Hermann et al (2002)
Oyegbile et al (2004)
MILD
Trimble (1988)
Jokeit et al (1999)
NONE BUT + AGE ONSET
Strauss et al (1995)
Helmstaedter & Elger (1999)
The Value of Exercise
 Exercise
is good for your brain, whether you
are a mouse or person
 Salk studies – mice given access to running
wheels produce more brain cells in a vital
memory area of the brain
 Women age 70-80 with mild cognitive
impairment, brisk walking or weight training
prevents memory decline and in some cases,
improvements (compared with toning)
Exercise & Epilepsy
 Animal
studies – aerobic exercise
increases the threshold to evoke
epilepsy in several animal models
(Airda)
 Swedish military recruits – individuals
who entered military and had low
cardiovascular fitness had a 79%
increase of developing epilepsy after
controlling for education, heredity, and
other factors (Ben-Menachem)
The Value of Sleep
 Mental
 Improved
mood, memory, attention,
judgment and reasoning
 Cardiovascular
– lower risk of disease
 Immune suppression
 Growth suppression
 Obesity
 Adult onset diabetes
Sleep & Epilepsy
 Sleep
deprivation – reliable
method to evoke seizures
 Circadian shifts – can lower
seizure threshold without ‘sleep
deprivation’
 Sudden shifts – need a plane
Diet & Epilepsy
 Ketogenic
 Modified
Atkins
 Low glycemic
Dietary Supplements & Epilepsy
?
Less restrictive carbohydrate diets
 No evidence that any supplement reduces seizure
frequency outside rare genetic/nutritional disorders
 Pyridoxine & Vitamin E deficiencies
ALTERNATIVE THERAPIES






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ACUPUNCTURE
HYPNOSIS
AROMATHERAPY
BIOFEEDBACK &
NEURO-EEG
FEEDBACK
MEDITATION
CHIROPRACTIC
REFLEXOLOGY







COUNSELING /
PSYCHOTHERAPY
NUTRITIONAL
HERBAL REMEDIES
OSTEOPATHY
HOMEOPATHY
YOGA
MASSAGE
Alternative Therapies for
Epilepsy
 What
to do: medicine fails, problems persist?
 Limits of proving any efficacy
 Doctors get it wrong
 Internal
 Patients
get it wrong
 Autism
 Need
know
mammary artery bypass
and vaccine
really good data – otherwise, impossible to
EVIDENCE: HEIGHT OF ABSURDITY
 Parachute
to prevent death & trauma
related to gravitational challenge:
systematic review of randomized
controlled trials1
 No
RCTs of parachute use
 Basis for parachute use is purely
observational; apparent efficacy could be
explained by a “healthy cohort” effect
 Individuals who insist that all
interventions need to be validated by a
RCT need to come down to earth with a
bump
1Smith, GCS, Pell, JP BMJ 2003
Stopping Prolonged Seizures
&Seizure Clusters
 How
much water to put out a fire?
 Prolonged febrile seizures
 Lessons from Dravet – if you know there is a
tendency to have prolonged seizures, hit
them early, and hard if needed
 Options



Diastat (rectal diazepam)
Buccal midozalam
Intranasal midazolam
Double-Blind, Placebo-Controlled
Randomized Trial
Doctors and patients are biased
–Internal mammary artery bypass
–Beta blockers vs. ACE inhibitors for
hypertension
•Motivated reasoning
•Confirmational bias
–If you support the Death Penalty, can you
objectively evaluate new data?
•The Myth of Associationism-Causation
–Vaccines and seizures
–Mercury and autism
•
Concluding Thoughts
 Think
healthy - we largely are who we
decide we will be
 Act health – work hard to be physically
active, eat healthy, limit alcohol, sleep
well, avoid stressors
 Take your own pulse – as patient, as
caregiver
 Search hard to understand, be humble