Antiepileptic Medications - PowerPoint Presentation

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Antiepileptic MedicationsThe GoodThe Badand theScary

Carolyn Zook Lewis, CPNP, AC/PC, PMHS

UNC Child Neurology

Chapel Hill, NC

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Learning ObjectivesDescribe the factors that would guide selection of a specific antiepileptic drug for an individual patientDiscuss general considerations and patient/parent counseling regarding black box warnings and antiepileptic medicationDescribe the role of therapeutic drug monitoring in the management of a patient with epilepsy

Understand the cognitive effects of various antiepileptic medications

Formulate appropriate counseling information regarding hormonal/reproductive health considerations of antiepileptic drug treatment

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2017 ILAE Seizure Classification SystemStep OneClassifying seizure typeIdentify onsetGeneralized

Focal

Unknown

Specify level of awareness

Aware

Impaired awareness

Motor or non-motor onset

Sensory

Autonomic

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2017 ILAE Seizure Classification SystemStep TwoClassify epilepsy based on seizure typeFocal-replaces partial onset to describe epilepsy associated with seizures that arise from clinical or EEG data localizing to one hemisphere

Generalized-seizures originate within or rapidly spread to both hemispheres

Combined generalized and focal-epilepsies that have both generalized and focal seizures. Includes most severe epilepsy syndromes

Unknown-epilepsies with seizures in which it cannot be clearly determined whether onset is focal or generalized.

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2017 ILAE Seizure Classification SystemStep ThreeDiagnosis of epilepsy syndromeIncorporates seizure types, EEG, and imaging featuresConsiders age-dependent features such as age at onset and remission (where applicable)

Seizure triggers

Diurnal variation

Prognosis

Comorbidities

Imaging findings

Implications for etiology and treatment

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2017 ILAE Seizure Classification SystemStep FourDetermine etiology and potential treatment implicationsStructural (genetic or acquired or both)Genetic

Infectious

Metabolic

Immune

Unknown

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Management OptionsPrevention Antiepileptic medicationsDietary DevicesTreatment

Abortive medications

Treatment of status epilepticus

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Risk of Reoccurrence Risk of seizure recurrence — A developmentally normal child with no history of a neurologic d/o

and has first unprovoked seizure has a 24% risk of having another seizure in the next year and a 45% over the next 14 years

Clinical factors associated with an increased risk of recurrent seizures include:

Prior neurologic insult

Significant magnetic resonance imaging (MRI) findings

Abnormal electroencephalogram (EEG)

Practice parameter for the treatment of a child with a first unprovoked seizure published by the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society provides the following recommendations:

Treatment with AEDs is not indicated for the prevention of the development of epilepsy

Treatment with AEDs may be considered when the benefits of reducing the risk of a second seizure are greater than the risks of pharmacologic and psychosocial side effects

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Starting AEDsAfter first unprovoked seizure- decision to start medication is based onRisks of recurrent seizure vs potential risks and benefits of medication

Risks of not treating which include prolonged seizure/status epilepticus

Risks of long term use of AEDs, which include possible effects on school performance, behavior, and allergic reactions

Cost and financial burden of AEDs, office visits, laboratory tests, and struggles associated with administering medication should also be considered

Most children who present with a second unprovoked seizure are usually started on an AED. 2 or more unprovoked seizures is the diagnosis of epilepsy and indicates an increased risk for additional seizures

Some parents may choose not start AEDs if the seizures are infrequent and/or mild

Children with absence and atonic seizures, drop attacks, and infantile spasms are always treated as they almost always present with multiple seizures

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Choosing the Right MedicationMonotherapy is the goal of epilepsy treatment as it is associated withbetter compliance

fewer adverse effects

less potential for teratogenicity

lower cost

Medications are divided into “older”

and "newer" based upon approval time and availability

Optimal choice of AED is one that is

highly effective for type of seizure and the epilepsy syndrome

has least number of side effects

easy to give and long lasting

cost effective

does not require lab monitoring

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Older MedicationsCarbamazepine

Used for partial seizures

Need to monitor blood levels, CBC and LFTs as can rarely cause leukopenia,

thromocytopenia

, pancreatitis, elevated liver enzymes

Increased risk for severe allergic reaction in Asian population (and recently in Northern Europeans) so FDA recommends HLA genetic testing prior to staring

Ethosuxamide

Used for absence seizures only. Rarely causes agranulocytosis, pancytopenia, leukopenia, blood

dyscrasias

Phenobarbital

Used for generalized and partial seizures

Monitor blood levels. Can cause behavior problems and slowed development

Valproic

Acid

Used for generalized and partial seizures

Need to monitor blood levels, CBC and LFTs as can rarely cause aplastic anemia, thrombocytopenia, pancreatitis, hepatotoxicity. Increased risk for birth defects.

Benzodiazepams

(diazepam, lorazepam,

chlorazepate

)

Usually used as a short term treatment for increased seizures

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Newer MedicationsLamotrigine-Used for generalized and partial seizures. Can have a severe allergic reaction with Steven’s-Johnson rash so started very slowlyLevetiracetam

-Used for generalized and partial seizures. Can cause irritability

Oxcarbazepine-

Used for partial seizures. May cause dizziness and double vision

Topiramate

-

Used for generalized and partial seizures. Can cause kidney stones, glaucoma, weight loss, inability to sweat, memory problems, and difficulty with concentration

Zonisamide

-

Used for generalized and partial seizures. Can cause loss of appetite, upset stomach, headache, dizziness, fatigue, kidney stones, and decreased sweating

Rufinamide

-

FDA approved in 2008 to be used as an adjunctive medicine in children

>

4 years and adults with Lennox-

Gastaut

syndrome

Lacosamide

-

FDA approved 2008 to be used as an adjunctive medicine in adults with partial-onset epilepsy

Clobazam

-

Approved 1/12 for adjunctive treatment of seizures associated with Lennox-

Gastaut

syndrome (LGS) in patients two years and older

Vigabatrin

-

Approved in 1/09 for infantile spasms, but with very strict stipulations. Approved in many other countries for many years. 25 % of patients who take it for a long time suffer damage to the retina of the eye which affects the visual fields

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Prevention MedicationsFocal OnsetCarbamazepine

Oxcarbazepine

Lacosamide

Generalized Onset

Ethosuxamide

Special uses

Benzodiazepams

(diazepam, lorazepam,

chlorazepate

)-Usually used as a short term treatment for increased seizures

Vigabatrin

Used for both focal and generalized

Phenobarbital

Valproic

Acid

Lamotrigine

Levetiracetam

Topiramate

Zonisamide

Clobazam

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Medications to Treat a SeizureRectal Diazepam

Used to treat a prolonged seizure

Dosed according to age

2-5 years 0.5mg/kg

6-11 years 0.3mg/kg

12+ years 0.2mg/kg

Intranasal/

intrabucchal

Midazolam

Not yet FDA approved but being studied

Studies show works as well as Diastat

Less invasive, less expensive

Currently have to use IV version

Intrabucchal

Ativan

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Treatment OutcomesAbout 50% of people with seizures never have another seizure after starting AEDsAbout 80% eventually have seizure under control with standard treatment

The remaining 20% continue to have seizures despite trials of several medications. They are considered intractable

If a patient fails 2-3 drugs at maximally tolerated doses(intractable) there is about a 5% chance that further medications will be successful

That is when other options are considered

Ketogenic diet

Biomechanical devices (VNS, RNS)

Epilepsy surgery

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AlternativesKetogenic diet-High fat, adequate protein, very low carbohydrate diet (ratio of fat to

carbohydrates+protein

)

Places body into ketosis which is thought to improve seizure control

Have to consider all sources of sugar, including OTC and RX medications, toothpaste, etc. Need “sugar free” medications, usually can not take liquid antibiotics or

chewables

, will need capsules or tablets

Vagus

Nerve Stimulator-(VNS) prevent seizures by sending pulses of electrical energy to the brain via the

vagus

nerve. Pulses are supplied by a device similar to a pacemaker (generator) implanted into chest with wire extending into the neck and attaching to the

vagus

nerve

Responsive

Neurostimulation

-(RNS)-

neurostimulator

placed under the scalp and within the skull with one or two leads placed at the seizure target and connected to the

neurostimulator

. The

neurostimulator

continuously monitors the brain’s activity and is programmed to detect and record

atterns

that could lead to a seizure. When patterns are detected, the

neurostimulator

responds with brief pulses of electricity intended to disrupt the abnormal brain activity before a seizure occurs. Detection and stimulation settings are individualized for each patient’s patterns and so that stimulation is not felt. Patient gets a take-home monitor so that brain activity data can be sent to Neurologist between visits

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Prevention DevicesVagus Nerve Stimulator

Responsive

Neurostimulation

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Cannabidiol (CBD)Cannabidiol(CBD)- one of the chemicals in the cannabis sativa plant (marijuana). There are over 60 cannabinoids(chemicals in the cannabis plant) of which

cannabidiol

and THC are present in greatest concentrations.

Cannabidiol

is hypothesized to have anti seizure properties.

THC(tetrahydrocannabinol)- also one of the main chemicals in marijuana. It is the part that makes people high. Hemp has very low levels of THC. The effect of THC on seizures is unknown

Marijuana and hemp are both varieties of the same plant but the marijuana plant has been bred to have high amounts of THC, and the hemp plant has very low levels of THC, but higher levels of

cannabidiol

(the component that is thought to be possibly effective at treating seizures)

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Cannabidiol (CBD)Hemp oil is produced by pressing the seeds, stalks or leaves from the hemp plant. There is little to no THC in hemp oil and larger amounts

cannabidiol

. Most commercially available hemp oils do not have enough

cannabidiol

to have a therapeutic effect on seizures

Cannabidiol

oil(CBD) is made from a cannabis plant that has a higher concentration of CBD. It can also be made from different extraction processes to make it more concentrated

“Charlotte’s Web” is a particular strain of the cannabis sativa plant that was originally grown in Colorado that claims to be high in

cannabidiol

and has anecdotally helped children who have difficult to control seizures gain better seizure control

THERE ARE CURRENTLY NO PUBLISHED EVIDENCE BASED TRIALS TO DATE ESTABLISHING EFFICACY OR SAFETY OF CANNABIDIOL

Cannabidiol

oil and hemp oil are not regulated and anyone can make them. There are varying amounts (if any) of

cannabidiol

in these products making it difficult to know the correct amount or side effects. Since the oils are not regulated by the FDA there may be contaminants in them that are harmful (pesticides, solvents, molds)

There are studies in progress using a pharmacy grade form of

cannabidiol

(

Epidiolex

) that are showing positive results and some side effects. No FDA approval yet. States have different laws about use

NC Law: SESSION LAW 2015-154 and HOUSE BILL 766

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Management of AEDsIf a patient continues to have seizures at maximally tolerated dose another AED is startedIf patient has good seizure control after completing taper up on new AED then wean of old medication is consideredStudies have shown best time frame to wean off AEDs is 6-8 weeks

If a patient is seizure free for a minimum of 2-3 years on AEDs it is time to consider weaning off

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Role of Genetic TestingOf approx. 20,000 different genes at least 1/3 are expressed in the brain Influence development and function of the brain

Combined with environmental factors gene changes can also determine risk for disease and course the disease will follow

It is now thought that genetic factors account for about 40% of the etiologic causes of epilepsy

Current studies showing up to 500 different genes are associated with epilepsy

Genetic changes associated with epilepsy

Encode subunits of ion channels involved in stabilizing or propagating neuronal activity, including components of the voltage gated sodium, potassium, and calcium channels and gated gamma aminobutyric (GABA) and nicotinic acetylcholine receptor channels

Non ion channel genes associated with a variety of neurotransmitter, storage and other

neurometabolic

disorders,

Genes causing syndromic forms of epilepsy, many of which are involved in transcriptional activation or repression

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Pros and Cons of Genetic Testing ProsYield up to 35 % if FH epilepsy or child has DD, drug resistant epilepsy, abnormal neuro findings

Chance of finding potentially treatable conditions (vitamin responsive epilepsy)

Helps explain prognosis and family acceptance

Helps with choice of AED

Avoidance of AED

Diagnoses conditions such as glucose transporter d/o leading to treatment with ketogenic diet

Leads to development of novel therapies

Cons

Yield of usual cases is so low does not justify cost unless family history of epilepsy, child has DD, drug resistant epilepsy, or abnormal neuro findings

Cost

Variants of unknown significance

(1/3 of results)

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ImplicationsSodium channel abnormalities such as SCN1ASevere type associated with Dravet

syndrome and Lennox

Gastaut

(called epileptic encephalopathies)

Avoid sodium channel AEDs (carbamazepine, lamotrigine) makes seizures worse

Poor prognosis

Milder version –GEFS+ (generalized epilepsy with febrile seizures plus afebrile seizures

Better prognosis

Avoid sodium channel drugs

POLG-gene that codes mitochondrial DNA polymerase gamma

Poor prognosis

Avoid

valproic

acid and

Depakoke

-can cause severe liver problems and death

HLA- US FDA recommends HLA testing prior to treatment with carbamazepine (

Tegretaol

) in Asian patients due to high risk for SJS

Potassium channel abnormalities KCNQ2 and KCNQ3- associated with BECTS (BRE)

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Label WarningSuicideIn 2008 FDA issued a warning about increased risk of suicidal thoughts when taking AEDsRecommended patients being treated with antiepileptic drugs for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior

Data from pharmaceutical companies reviewed information from 199 placebo controlled trials of 11 AEDs used for various indications (25% epilepsy patients, 27% psychiatric patients and 48% other conditions). Included 28,000 people taking AEDs and over 16,000 people taking placebo

Found that patients taking AEDs had about twice the risk of suicidal behavior compared with patients taking a placebo.

The absolute risk amounted to about 1 added case of suicidal thoughts or behaviors for every 500 patients taking the antiepileptic drugs versus placebo.

The mechanism linking antiepileptic drugs with potential suicide risk remains unknown

As a result of the analysis, the FDA required that all manufacturers of drugs in this class include a warning in their labeling and develop a medication guide for patients, informing them of the risks of suicidal thoughts or actions

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Black Box WarningsLamotrigine (Lamictal)-serious skin rashes (and SJS) can occur. Rate is 8/1000. Usually happens in first 8 weeks of therapy but can occur later with dose increases

Carbamazepine (

Tegretol

)-can cause serious skin reactions such as toxic epidermal necrolysis and Stevens Johnson Syndrome, especially in Asian population. Also associated with aplastic anemia and agranulocytosis. CBC with platelets recommended prior to starting and periodically based on clinical judgement

Valproic

Acid (Depakote)- hepatotoxicity, teratogenicity, and pancreatitis. Education important in females of childbearing age before starting. Monitor LFTs

Felbamate

-

aplasitic

anemia-parents have to sign a consent form

Perampanel

(

Fycompa

)-serious or life-threatening psychiatric and behavioral adverse reactions including aggression, hostility, irritability, anger, and homicidal ideation and threats, even in patients without prior psychiatric history, or aggressive behavior

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Therapeutic Drug MonitoringTDM is used when trying to optimize dosage to get best clinical efficacy while minimizinge side effects

Reference ranges are only guidelines that to indicate range of likely therapeutic response, however many patients may require target concentrations outside the reference range.

Clinical decisions about dosing are based on multiple factors including

type and severity of epilepsy

pathological and physiological states

drug interactions

variability of

pharmacogenetics

Many factors can effect serum concentration of medication

timing of taking medication and blood draw- even trough levels fluctuate up to 15 to 20 percent in many patients who take the drug on a consistent schedule.

patients who are frequently noncompliant may take enough medication shortly before the test to attain a therapeutic level

laboratory errors

generic substitution for brand-name AEDs

variable potency of pills (following improper storage, for example)

menstrual cycle (

midcycle

levels may be higher than during the premenstrual period or menses)

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Mood Disorders and EpilepsyPsychiatric comorbidities occur in 37%-77% of pediatric patients with epilepsyAttention deficit hyperactivity disorder is most common in children

Depression was the most common psychiatric comorbidity in adolescent

Studies have shown prevalence of depression ranging between 30% to 50% in all people with epilepsy

Meta-analysis of 12 studies showed people with epilepsy are more than 5 times as likely to commit suicide than the general population

AEDs have mechanisms of action responsible for anti-seizure activity and effect on mood and behavior

A number of studies have suggested some AEDs are associated with symptoms of depression while others act as antidepressants

Anxiety, panic, and phobic disorders also occur more frequently especially in patients with frontal or temporal lobe seizures (areas involved in memory and emotion)

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Cognitive Effects of AEDsAntiepileptic drugs (AEDs) as well as seizures are known to affect learning, education, social development and behavior20-30% of children with epilepsy have learning difficulties

No AED is free from unfavorable cognitive or behavioral effects, although some (phenobarbital) cause more than others (Depakote, carbamazepine, lamotrigine)

Some AEDs interfere with processing and memory and some cause fatigue which interferes with the ability to learn

Word-finding difficulty observed with

topiramate

does not occur with other AEDs

Use of a single drug (monotherapy) is better that polypharmacy

Levitiracitam

does not cause learning difficulties but can cause irritability and aggressive behavior

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How to Help Children with Epilepsy in SchoolBased on seizure focus, frequency of seizures, and medication, the child with epilepsy may experience trouble with

Executive function

Language-speech, communication, comprehension

Attention and concentration

Processing speed

memory

Child may also have

intermittent disruptions in their learning that specifically relate to their seizures, sleep patterns, and medications. These disruptions in their ability to attend and learn can change from day to day, or even hour to hour

Night-time seizures or poor sleep patterns caused by abnormal brain activity can increase fatigue during the school day. As a result the child is less attentive and less available to learn

Subclinical seizures which can interfere with processing, consolidation, and retrieval of information recently learned

Seizures during the school day can cause disruptions in memory that result in

forgeting

what they have just learned

In some cases they cannot remember much about what happened just before or for some time after the seizure

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Adolescence Puberty appears to have an effect on epilepsyEtiology not completely understood but appears to be

multifactoral

and both males and females are affected

As puberty is reached hepatic metabolism slows to a rate similar to adults which may lead to a rise in AED levels

Pubertal growth spurts result in rapid weight changes and can lower AED levels

More frequent monitoring of plasma levels and dose adjustments may be needed

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ContraceptionInteractions between AEDs and oral contraceptives are common

No increased seizure activity with addition of contraceptives but enzyme inducing AEDs (EIAEDs) decrease the effectiveness of contraceptives

WHO recommends women taking EIAEDs including lamotrigine use a method of contraception other than hormonal pill, patch, or ring contraceptives Long-acting reversible contraceptives (LARC), including copper or

levonogestrel

intrauterine devices and

etonogestrel

implants are highly effective alternatives that carry no or much less potential for drug-drug interactions

Oral estrogen-progestin contraceptives can increase the metabolism of lamotrigine and reduce plasma drug concentration by about 50% percent. Levels can rise significantly upon discontinuation of oral contraceptive, even during the 7-day pill free interval. Continuous dosing is preferred

Higher estrogen doses (at least 50mcg) is recommended for women talking EIAEDs

Progestin only contraception not recommended

IM Medroxyprogesterone (Depo Provera) is ok, but may need to give more frequently in patients on EIAEDs. Long term use should be avoided due to association with decreased bone mineral density. Because of inhibitory effect is being studied as treatment for

catmenial

epilepsy

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ContraceptivesEnzyme InducersCarbamazepinePhenobarbitalPhenytoin

Felbamate(mild)

Oxcarbazepine (mild)

Topamax (mild)

Non Enzyme Inducers

Gabapentin

Lamotrigine

Levetiracetam

Tiagabine

Valproate

Zonisamide

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Pre-pregnancy CounselingPreconception information should be offered to all females with childbearing potentialFolic acid supplementation should be provided to all women of child bearing potential

Women with epilepsy have a slightly increased risk of fetal malformation in comparison with the general population

This is somewhat due to AED used (3% greater risk with CBZ or LMT, 7% with VPA, 15% with 2 or more AEDs)

Most major malformations occur in the early stages of pregnancy

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Common MalformationsMAJOR4-8% of all pregnancies-in comparison to 2-4% in general population

Usually associated with older drugs

Cleft palate and lip

VSD

Neural tube deficits

MINOR

7-15% of all pregnancies-about 2 times general population

Frequently involve face and digits

Learning and behavior problems

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Bone HealthFemales and males with epilepsy are at higher risk for bone disease (osteoporosis and osteopenia) that general populationMetabolic bone disease is a recognized consequence of EIAEDs

Mechanism thought to be caused by reduced levels of vitamin D, with subsequent decrease calcium absorption and increased parathyroid concentrations

Valproate is not an enzyme inducer but has been linked to impaired bone health

Recommend patients on AEDS take a vitamin D and calcium supplement and check levels routinely