Orrin Devinsky, M.D.

Orrin Devinsky, M.D.
  No
seizures, no side effects
  If patients had their choice:
 No doctors, No Medicines
  In general, would rather see doctor than
take medication
  Ongoing
assessment: consequences of
seizures and therapy
  Aggressively pursue seizure control?
  Do we treat interictal EEG?
  How to assess effects of long-term
therapies?
 
Misdiagnosis
Is it epilepsy?
  Which epilepsy syndrome?
  Reliance on prior diagnosis
 
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Incorrect medication choice
 
AEDs can exacerbate seizures
Failure to reassess or
consider VNS or surgery
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AED relative efficacy:toxicity
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Knowledge
 
Published studies
 
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Randomized v. open-label
Dose range, methodology
Statistical v. clinical significance
Information from colleagues
  Personal experience
  Belief, Bias, & Comfort Zone
 
 
Human nature sees patterns and assigns meaning
 
WWII – V2 rockets in London
  Newspapers published impact site maps; Germans
precisely targeted areas and avoided spies’ homes
  Cancer
clusters – in CA 5000 census tracks,
2,750 with statistically significant but random
elevations of some cancer
  Once you have an idea, look for evidence that it is
wrong, as well as that it is right
The human mind loves defaults
  The 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
  56
absence epilepsy v. 61 JRA patient
  Absence
epilepsy group had more
academic, personal, and behavioral
disorders (p<.001)
  Recurrent
complex partial seizures
similar to repetitive mild head injuries
  Memory
  Are
& other cognitive impairments
tonic-clonic seizures bad? - Yes!
 
Full explanation of AEs
Impossible
  Not known
 
 
Doctors understanding of AEs
 
Biased; literature & experience
Older MDs - favor older AEDs
  Younger MDs - favor newer AEDs
 
 
 
Based on giving - not taking
MDs often fail to appreciate chronic or longstanding problems
 
 
Idiosyncratic AE’s
Dose-related AE’s
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Cognitive
Behavioral
Quality of life
Chronic AE’s
Teratogenic AE’s
Drug interactions
 
Rash
 
 
 
Internal organs (liver, pancreas, kidneys)
 
 
LTG is related to rapid increase
LEV, GBP, PBG, LEV – very low rash risk
Many drugs but very rare (1/30-50,000)
  Felbatol – bone marrow and liver
  Valproic acid before age 6 mos – 2 years
COMMON MISPERCEPTION – AEDs cause chronic
organ dysfunction – WRONG!
  GI
(eg, nausea) (eg, FBM, CBZ, VPA)
  Liver (many drugs - increased LFTs)
  Blood Cells (eg, CBZ - lowered WBC)
  Coagulation (eg, VPA - platelets)
  Increased
cholesterol (eg, CBZ)
  Weight
gain (eg, VPA, GBP, PGB, CBZ)
  Weight
loss (eg, FBM, TPX, ZNG, RUF)
Obesity Trends* Among U.S. Adults
BRFSS, 1990, 1998, 2006
(*BMI ≥30, or about 30 lbs. overweight for 5’4” person)
1998
1990
2006
No Data
<10%
10%–14%
15%–19%
20%–24%
25%–29%
≥30%
Weight Gain (kg)
Disease
Risk Increase
1
Heart disease
Hypertension
3%
5%
2-5
Hypertension
30%
5-8
Hypertension
Type 2 diabetes
75%
100%
8 - 11
Ischemic stroke
25%
11 - 20
Ischemic stroke
Hypertension
Type 2 diabetes
50%
165%
400%
>20
Ischemic stroke
Hypertension
Type 2 diabetes
100%
300%
>1000%
Nurse’s Health Study
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Sedation/Lethargy (most drugs)
Insomnia (eg, FBM, LTG)
Dizziness (most drugs)
Slowed reaction time (most drugs)
Impaired thinking (eg, PB, TOP)
Mood changes (eg, PB, TOP, LEV, ZNG)
Tremor (eg, VPA, LTG)
Libido (eg, PB)
 
Decrease Ca/Vit D levels
CBZ (?OXC), PRM, PB, PHT, VPA
  New AEDs appear safer
 
 
Risk factors
 
 
Diagnosis
 
 
Dose, polytherapy, & duration
Suspicion; bone densitomety
Treatment - Vit D/Ca, sun, alendrodate,
estrogen supp after menopause
  Peripheral
neuropathy – PHT
  Polycystic ovarian syndrome - VPA
  Soft tissue disorders – PB, MYS
  Joint
pain
  Contractures in the palm with nodules
  Frozen shoulder
  Heel & knuckle pads
  Increased
frequency of urination - LTG
  Migraine & other headaches - CBZ
  Aggressiveness - PB, PRM, ETX, LEV
  Movement disorders - PHT, CBZ
  Tics – LTG, CBZ
  Death
  A
with:
history of epilepsy (generally having a
seizure in the last 5 years)
  Sudden
  Unexpected (meaning no life threatening
illness concurrently present)
  Pulmonary and cardiac causes suspected
General population (2.5)
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)
Tomson T. Walczak T. Sillanpaa M. Sander JW. Epilepsia. 46 Suppl 11:54-61, 2005
  2
retrospective & descriptive studies
  Estimated
incidence of 1-2/10,000
person-years
  No
unique risk factors found
  High
seizure frequency
  Tonic-clonic seizures
  Longer duration of epilepsy
  Number of AEDs
  Age over 20 years
  DD (IQ<70)
È  46%of
all SUDEP vs.18% of controls
Tomson T. Walczak T. Sillanpaa M. Sander JW. Epilepsia. 46 Suppl 11:54-61, 2005
Risk factors
Preventive strategy
• Uncontrolled
• Optimize AED treatment,
• Tonic-clonic seizures
• Optimize AED treatment,
epilepsy
• Low serum AED
concentrations
• Polytherapy
• Frequent AED adjustments
• Substance abuse
• Mental retardation
consider epilepsy surgery
consider epilepsy surgery;
supervise; ? Seizure alarm
• Improve compliance &
monitoring
• AED reduction
• Stabilize regimen
• Avoidance
• Supervision
CP1203130-1
  Risks
and benefits of AEDs & seizures
must be carefully weighed
  People often under- and overestimate
risks and benefits of both
  The challenge is systematic and
objective observation individual cases
and review of published literature