Advances in Adult Epilepsy TreatmentWhat 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

• 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

• 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

• 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 ManagementDepression

• Many anti-depressants lower seizure thresh-hold.• Choice depends on side effect profile

• 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• 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?– Stroke– Brain Tumor– Substance abuse– Medical Illness

• 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 2013American Public Health Association 138th Annual Meeting: Abstract 4225.0-4. Presented November 9, 2010.

Other provoked seizure

– Metabolic Derangements• Alcohol / Drug Withdrawal or Intoxication• Hypoglycemia• Electrolytes Abnormalities• Uremia• Porphyria

– Stroke / Intracranial Abnormalities– Syncope

Imitators

• ●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 AEDsDuring 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?• daitakahashi@gmail.com• dtakahas@mcw.edu