Transcript Advances in Adult Epilepsy Treatment

Advances in Adult Epilepsy Treatment
What to know as primary care physicians
Practical Approach
Dai Takahashi DO FACP SFHM
Disclosure
• I have nothing to disclose.
• This presentation is geared toward Primary
Care Providers.
• I am a board certified internists, not
neurologists.
Practical Approach to Epilepsy
• Difficulty accessing neurologists
• More and more primary care physicians are
managing Epilepsy
• Review some practical approach to Epilepsy
using current evidence. But…
• Remember “evidence based medicine” is not
everything
• “Let’s talk about practical approach.”
Epilepsy - Epidemiology
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More than 2 episodes of unprovoked seizure
65 million people have epilepsy worldwide
Just over 2 million people have epilepsy in the USA
1 in 26 people in the USA will develop epilepsy at
some point in their life time.
• ½ of epilepsy patients live with uncontrolled epilepsy.
Olafsson et al: Incidence of unprovoked seizures and epilepsy in
Iceland and assessment of the epilepsy syndrome classification: a
prospective study. Lancet Neurol 2005;4(10):627–634
Topics
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Social Consequence of Epilepsy
“Go to AEDs” for Primary Care Providers
Women and Seizure
Surgical Treatment of Epilepsy
Cannabis and Epilepsy
Case – Doc, I am really depressed.
• Matt is a 28 year old man presents at your clinic
with chief complaint of depression and wants to
establish a new primary care provider. He was
diagnosed with epilepsy after resection of AVM.
• He now lives with uncontrolled epilepsy.
• He had a successful career as an engineer and
lost his job. He no longer has a driver’s license.
He lost his fiancé and moved back with his
parents. He spends most of his day watching
movies and dazing. He gained 40 lbs.
Case – Doc, I am depressed.
• He has a neurologist that he sees every year.
• According to him, his neurologists seems to be
too busy with other patients. “Well, you are
justly lucky to be alive.”
• What can you do as a primary care doctor?
Living with un-controlled epilepsy
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Depression
Work / School performance
Family – Caregiver burn out issues
Driving
Cognitive Decline
Substance Abuse
“Osteopathic Principle”
Support System
• Establish rapport with patients
– Don’t just refer patients to specialists
– Frequent office visits
– (my opinion) monthly – just to check on them
• Possible referral to a psychotherapist including family
members. (I personally prefer psychotherapists over
psychiatry).
• Give resource
– Community support group
– Epilepsy foundation
– Monthly visits can be easily justified with AED level
check and lab monitoring.
Medication Management
Depression
• Many anti-depressants lower seizure thresh-hold.
• Choice depends on side effect profile
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SSRI – Know side effect profile
SNRI – Venlafaxine!
TCA
MAOI (if refractory)
Other Anti-depressants (mirtazapine)
Antipsychotic agents (aripiprazole, olanzapine)
Lithium
Benzodiazepines
Stimulants (overall better mood, amphetamine, modanafil…)
NO Bupropion
THD
• Depression Screening (Recommended once a year at least)
Cochrane review: 2014
Driving!
• One of the hardest thing to do as a doctor is
to take away driving license
– You don’t have to take license away but you can.
• Wisconsin law states
– Any medical conditions that include loss of
consciousness.
– 3 months.
– (OT can evaluate driving skills)
Other things to note at each PMD visit
• Vitamin Levels – Vitamin B12 level, Folic Acid, B6, Vitamin K (useless)
• Bone disorder - Vitamin D, Dexa scan?
• Serum AED level
– Therapeutic Level is different for each patient
– To check compliance
– Toxicity
• Check CBC, BMP, LFT (not required for newer agents)
• Review of Seizure Calendar
– Helps identify triggering effects
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Exercise?
Alcohol?
Illicit drugs
Lack of sleep
Stress Level
Hormonal Level
• Alcohol use
Case – what do I do with Keppra that
hospitalists started in the hospital?
• 45 yo man, alcoholic, here for follow up from
hospital for alcohol withdrawal.
Hospitalization was complicated with multiple
seizure events.
• He swears that he does not drink any more.
• Pt was sent home with Keppra 1 gram twice
daily and asks you “what should I do with
Keppra?”
Provoked Seizure
• Focus on stopping offending agents / triggering
disorder?
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Stroke
Brain Tumor
Substance abuse
Medical Illness
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Alcohol / Drug Withdrawal or Intoxication
Hypoglycemia
Electrolytes Abnormalities
Uremia
Porphyria
Genetic disorders
Alcohol Related Seizure
• Consider use of Gabapentin
– Shown to reduce cravings, reduce number of
alcohol consumed, depression, sleeplessness
– Acutely, prevents seizure
– DOSE: 1800mg per day vs 900mg per day
• Alcohol related encephalopathy
• Stop alcohol intake
(Side note: use of baclofen)
Barbara J: JAMA 2013
American Public Health Association 138th Annual Meeting:
Abstract 4225.0-4. Presented November 9, 2010.
Other provoked seizure
– Metabolic Derangements
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Alcohol / Drug Withdrawal or Intoxication
Hypoglycemia
Electrolytes Abnormalities
Uremia
Porphyria
– Stroke / Intracranial Abnormalities
– Syncope
Imitators
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●Syncope
●Psychological disorders
●Sleep disorders
●Paroxysmal movement disorders
●Migraine
●Miscellaneous neurologic events
●Transient ischemic attack
●Transient global amnesia
●Drop attacks
Women and Seizure
• Women are people with high level and
fluctuation of estrogen and progesterone.
• Catamenial Seizure
– Hormonal Fluctuation
• Pregnancy
• Birth Control
Case – I don’t want to be pregnant
• First thing to do: Seizure diary
• Recommendation (WHO)
– Against systemic oral contraceptives if possible
– But still better than barrier methods
• Hormonal based oral contraceptives
– Enzyme inducing AEDs decrease estrogen levels.
– Phenytoin, Carbamazepine, Phenobarbital, Primidone, Oxcarbazipine, and Topiramate.
– Acceptable but patient needs to be educated that
failure rate goes from 0.7 / 100 to 3.1 / 100
– Consider using higher dose estrogen containing
product (at least 50mcg) - Unproven
So? What is the answer?
• IUD
– Both Mirena (progestin based) and Paraguard
(copper based)
– Maybe covered by insurance
• Depo Provera
Case – Can you give me Morning After Pill?
• Enzyme inducing agents actually lower levels
of morning after pill as well.
– Two ways to attack this
– Double the dose
– Single dose q12 for 2 doses
Case – I want to be pregnant
• Let’s plan for babies!
• Major congenital malformation happens between
3 to 8 weeks when vital organs are being
developed. So, PLAN for babies. Main goal: Avoid
Tetragenicity
• General Population
– Risk of Major Congenital Malformation 1.6%
• Risk of Seizure
– 50% no change
– 25% Increase in frequency
– 25% Decrease in frequency
I NEED TO BE PREGNANT
• (1) major congenital malformations (MCMs) that
affect the development of major anatomic
structures and significantly impair function
• (2) minor anomalies that may affect appearance
but do not interfere with function
• (3) developmental deficits that impact cognition
and/or behavior but are not necessarily
associated with visible structural changes.
Overview
• Valproic Acid, Polypharmacy, Phenobarbital seems to have
the greatest risk for tetragenicity.
• Tetragenic Effect is increased in patients on AED vs No AED.
• Tetragenic Effect is increased in patients on polypharmacy.
• Seizure risks mom and baby – not well defined
• Seizure control is predictive – if patient has well controlled
epilepsy (sz free) for 9 mo prior to preganancy, 90%
remains sz free.
• MCM does not seem to be increased with AED use except
Neural Tube Defect except for Valproic Acid and
Polypharmacy.
Overview
• Many AEDs lower levels of Folic Acid
• 4mg of Folic Acid daily reduce NTD by 70% and
increase IQ level. (Mawer, Seizure, 2010)
• Many AEDs lower levels of Vit K
– Give Vit K at birth
• Benefit of Breast Feeding overweighs the Risk of AEDs
– AEDs that are protein-bound do not cross (PB, PHT, VPA,
CBZ)
– LEV, LTG, GBP, TPM do cross over
– Breastfeeding presents no additional risk to cognitive
status if in utero exposure (Meador, NEAD study,
Neurology, 2010)
Management of AEDs
During Pregnancy
• BASELINE AED LEVEL with Sz Free Time for 9
mo (Ideal).
• Many AEDs level goes down during pregnancy
• Quickly taper down after delivery
• Having seizure during pregnancy vs
Benzodiazapine
Valproic Acid
• Tetragenicity 10.9% vs 2.9% (North American
Registry)
• NERD study (Neurodevelopmental Effects of
Antiepileptic Drugs) – 2006
– (20.3% with VPA vs. 10.7% in phenytoin, 8.2% in
carbamazepine, and 1% in lamotrigine)
Phenobarbital
• The North American Pregnancy Registry
– 6.5% risk among 77 phenobarbital monotherapy
exposures
– 2.9% rate among other AEDs
– background population rate of 1.6%
• Of note, Phenobarbital is cheap! ? Effect
from socio economic status.
Benzodiazepine
• Confusing Data
• It appears “BENZO” is safer than we thought
• A large meta-analysis of 12 cohort studies, representing over 1000
exposed pregnancies, found no increased risk of MCMs or cleft lip
versus controls (OR 0.9; 95% CI, 0.61 to 1.35), including two studies
of patients with epilepsy.
• A meta-analysis of case control studies from the same paper found
an increased risk of MCMs (OR 3.01; 95% CI, 1.32 to 6.84).
– Note case-control studies may be more sensitive to rare outcomes,
they also suffer from biases (e.g., recall bias). Moreover, several of
these case-control studies allowed the use of other medications,
making the increased risk reported tenuous at best.
• A more recent study of 52 mothers taking clonazepam found one
MCM (3%) in a patient on monotherapy and none with
polytherapy.56
Phenytoin
• Even more confusing
• Risk has been estimated to be 2 to 3 times that of
mothers not taking phenytoin as has been
confirmed in several recent studies.
• these results are still debatable and may be due
to confounds of dosage and maternal IQ.
• It is still unknown if phenytoin has a higher risk
than newer AEDs because of insufficient sample
sizes in most newer studies (possibly due to the
avoidance of phenytoin in young women for
cosmetic reasons).
Carbamazepine and Oxcarbazepine
The risks similar to phenytoin, with the exception of a higher
incidence of NTDs.
There are greater numbers of patients taking carbamazepine in
recent registries, these data do not consistently demonstrate a
differential risk.
While there is less clinical experience with oxcarbazepine, a
review of reported studies representing over 300 pregnancies
exposed to oxcarbazepine found no evidence of an increased risk
of MCMs with monotherapy (2.4%), except when used in
polytherapy (6.6%).
Lamictal (Lamotrigine)
• The latest report concluded that there is no evidence
for an increased risk of MCMs with lamotrigine
exposure based on a rate of 2.9% over 800 exposures.
– International Lamotrigine Pregnancy Registry
• NERD study
– lamotrigine compared favorably to other AEDS with a 1%
risk of MCMs and appeared to have no increased risk
compared with mothers not taking AEDs.
• Of note, lamictal level frequently goes down with
pregnancy. (Ex: My patient was “eating” 1200mg of
lamictal every day.)
Other AEDs
• Data is minimal
• The largest study of levetiracetam (117 patients) found no
evidence of an increased risk of MCMs.
• To date, only 26 pregnancy outcomes have been reported
for zonisamide, with 2 MCMs (7.7%), both in women on
polytherapy.
• A study of 51 pregnancies exposed to gabapentin found no
increased risk of MCM (2%).
• gabapentin, topiramate, vigabatrin, may have teratogenic
potential.
– However, caution must be applied when interpreting these
results, particularly as many of the doses used were
supratherapeutic.
Case – Doc, I am still having seizure.
• Don’t just add other medications!
• Again, basic tools such as seizure diary is very useful.
• Are there additional imitators present?
– ? Seizure
– ? Drop Syndrome
– ? Migraine
• Check AED Level
• Are they drinking more? Started using cocaine? New
medications that is lowering seizure thresh-hold?
Infections? Dehydration? Sleep deprived?
• Hmmm Radiate patient with CT scan?
I AM HAVING SEIZURES!
• Well… you sure?
• If you are sure… adding another medication is
totally acceptable.
• If you are not sure, consider…
– Ambulatory EEG monitoring
– Inpatient continuous EEG monitoring
– Rule out Pseudo-seizure
• Use of that EEG…..
Which Medications should primary
care should know.
• Lamotrigene – No IV form. Have to slowly titrate medications.
• Levetiracetam – IV form. Easy to load up
• Phenytoin, Carbamazapine, Valproic Acid – IV from. Cheap.
Easy to load up.
• Topiramate
• Zonisomide
• Gabapentin (narrow spectrum)
Case – I am still having seizures
• When is surgery effective?
– It needs to be able to identify seizure foci.
– Try – seizure monitoring in inpatient or outpatient
– If you can identify seizure foci, send patient to
epilepsy center for surgical consideration.
– Two step vs One step surgery (These epileptologists
are doing crazy things)
- Preparing for surgery
- Functional MRI
- Wada Test
- Neuropsych evaluation (Baseline)
Case – I heard marijuana stops epilepsy
• The anticonvulsant properties of marijuana may be the
oldest of its known medical benefits.
• Marijuana was used as a medicine for epilepsy by
ancient societies in China, Africa, India, Greece and
Rome.
• 1980, a study appeared in Pharmacology involving 16
patients with grand mal epilepsy who had not
responded well to treatment with standard
antiepileptic drugs and showed improvement in
epilepsy control.
• Studies have been inconclusive.
• Use of CBD vs THC/CBD
• At the Academy of Neurology, April 22, 2015,
Washington DC, open-label included safety
data from 213 patients at 11 different
sites. Epidiolex (99% CBD) was generally well
tolerated. Side effects that occurred in 10% or
more of people included: sleepiness (21%),
diarrhea (17%), fatigue (17%), and decreased
appetite (16%).
• APA and AEF are asking government to make marijuana
schedule II so that we can do more research.
• AEF actually statement in their website
“When conventional treatments do not work, as is the
case for roughly 30% of people with epilepsy, it is not
unreasonable to consider cannabis. This is why some
states have approved it for “compassionate
access.” However, this should only be considered after a
thorough evaluation at a specialized epilepsy center and
once conventional treatments (pharmacologic and
nonpharmacologic) have been reasonably tried.”
• My take on Marijuana and Seizure
– Yet Another AED that can be useful
– Favorable Side Effect profile (Anti Depression, Anti
Anxiety..)
• Any questions?
• [email protected]
• [email protected]