epilepsy: knowledge is power patient education conference april 28, 2012 1

Epilepsy:Knowledge is Power

Patient Education Conference

April 28, 2012

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Treating Epilepsy

Antiepileptic Medications and

New Treatments

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Northeast Regional Epilepsy Group

Christos Lambrakis M.D.

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‘The goal of therapy is to help the person with epilepsy lead a

full and productive life….’

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‘…with minimal effects from the condition or its treatment.’

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What is a Seizure?

• A seizure begins when one or more cells send electrical messages that cause an inappropriate burst of electrical activity.

• This can cause surrounding neurons to generate their own electrical discharges which can spread throughout the entire brain.

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What is a Seizure?

• Abnormal discharge of brain cells resulting in a change of behavior, movement, sensation or awareness.

• During a seizure a person may feel, move, think or act differently. This is because a seizure can temporarily disturb many of the brains normal functions.

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EEG (Normal)

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EEG (Seizure)

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What is Epilepsy?

• Epilepsy is the term applied to the state of recurrent seizures.

• A condition of the brain, of various causes, which predisposes the patient to recurrent epileptic seizures.

• Epilepsy is a tremendously variable condition in terms of its cause, seizure types and response to treatment.

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Epilepsy

• Our understanding of epilepsy has increased dramatically over the last 20 years.

• Accurate seizure characterization has aided in determining prognosis and selection of medication

• Several new anti-epileptic medications provide excellent seizure control with less side effects than older medications.

• Advances in surgery and vagal nerve stimulation.

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EpilepsyStatistics

• Epilepsy is one of the most common neurologic diseases.

• Affects approximately 1% of the population (2 million people in the USA).

• Approximately 10% of the population will have a seizure at some point in their lifetime.

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Treatment Strategies

• Medications

• Surgical

• Dietary

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Antiepileptic Medications

• Decreases the frequency or severity of seizures in people with epilepsy.

• Treats the symptom of the epilepsy (the seizure) and not the underlying condition (the epilepsy).

• Goal is to improve quality of life by reducing the frequency of seizures with minimal side effects.

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History of Antiepileptic Medications

1912

• Phenobarbital was the primary medication used for seizures.

• Used for generalized tonic-clonic and to a lesser extent partial seizures. No effect on absence seizures.

• Sedative effect occurred in many people. Hyperactivity noted in children.

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History of Antiepileptic Medications

1938

• Diphenylhydantoin (Dilantin) was discovered to have antiepileptic properties.

• Similar effectiveness to phenobarbital.

• Less sedative side effects.

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History of Antiepileptic Medications1960-1974

• U.S. Food and Drug Administration (FDA) imposed new regulations on pharmaceutical companies.

• Medications were now required not only to be safe but they had to be proven effective against the illness it was designed to treat.

• Only one medication for seizures was developed during this time. Valium was found to be an effective treatment for status epilepticus.

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History of Antiepileptic Medications

• 1974: Carbamazepine (Tegretol)• 1978: Valproic acid (Depakote)• 1993: Felbamate, Gabapentin (Neurontin)• 1995: Lamotrigine (Lamictal)• 1996: Fosphenytoin (Cerebyx)• 1997: Topiramate (Topamax), Tiagabine (Gabitril)• 1999: Levetiracetam (Keppra)• 2000: Oxcarbazepine (Trileptal), Zonisamide

(Zonegran)21

History of Antiepileptic Medications

• 2007: Lyrica (Pregabalin)

• 2008: Lacosamide (Vimpat)

• 2008: Rufinamide (Banzel)

• 2009: Vigabatrin (Sabril)

• 2011: Clobazam (Onfi)

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History of Antiepileptic Medications

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History of Antiepileptic Medications

Extended Release Formulations

• 1996: Tegretol XR (Carbamazepine)

• 2001: Phenytek (Phenytoin)

• 2002: Depakote ER (Divalproex sodium)

• 2008: Keppra XR (Levetiracetam)

• 2009: Lamictal XR (Lamotrigine)

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Extended Release Formulations

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Antiepileptic MedicationsHow they work?

Mechanisms To Target

• Excitation (Too much)

- Flow of Sodium or Calcium into neuron

- Neurotransmitters (Glutamate, Aspertate)

• Inhibition (Too little)

-Flow of Chloride in, or Potassium out of neuron

-Neurotransmitter (GABA) 26

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Mechanisms Of Action

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Mechanisms To TargetExamples

• Dilantin: Blocks sodium channels

• Depakote: Blocks sodium channels Increases GABA

transmission

• Zarontin: Blocks calcium channels

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When to Treat?

• Are the episodes really seizures?

• EEG: Normal or abnormal?

• Frequency and type of episodes?

• Are there other neurologic problems?

• What is the cause of the seizures? Can the underlying problem be treated rather then treating the symptom (i.e. the seizure)?

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When Not to Treat

• Single seizure

• No history

• Neurologically normal

• Young age

• Side effect concerns

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First Seizure

• Studies have shown that a otherwise normal child who had a single seizure has a 15% chance of having a second seizure if left untreated.

• Physicians will typically wait until a second or third seizure before initiating treatment with antiepileptic medication.

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First Seizure

• For a child who is neurologically abnormal or has an abnormal EEG- the risk of subsequent seizures is substantially increased to between 50-60%.

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When to Treat?Risk-Benefit Ratio

• In determining whether to treat physicians consider many factors.

• The benefits of further seizure activity is weighed against the potential side effects of the antiepileptic medications.

• The decision to treat is a highly individualized one.

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Key Concepts in Antiepileptic Treatment -Metabolism-

• The process by which medications are broken down and eliminated by the body.

• Most antiepileptic medications are metabolized by the liver.

• Some antiepileptic medications are metabolized by the kidneys.

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Key Concepts in Antiepileptic Treatment -Metabolism-

• Children generally have a faster metabolism and thus require higher then expected dosages of medications to maintain adequate blood levels.

• Older people typically have slower metabolisms and thus require less medication. Often they can become toxic on normal dosages of medication.

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Key Concepts in Antiepileptic TreatmentHalf-life

• The time it takes your body to eliminate half the medication in your body.

• After one half-life the amount of medication in your body will decrease by 50 %.

• After 5 half-lives 95% of the medication will be removed from your body.

• Half-lives vary greatly among seizure medications.

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Key Concepts in Antiepileptic Treatment

Steady State• A balance obtained when the amount of

medication you take into your body equals the amount being eliminated.

• May take days to reach a steady state when starting or changing doses of medications.

• Full therapeutic effect of a medication is not reached until steady state is achieved.

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Key Concepts in Antiepileptic Treatment

Therapeutic Range• The blood levels of medication that for

most people will provide an adequate seizure reducing effect without excessive side effects.

• Treat the person not the range! Everyone responds differently. Some people can be effectively treated with blood levels above or below the therapeutic range.

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Key Concepts in Antiepileptic Treatment

Mechanism of Action• How do medications work? For many

medications this is still not well understood

• Proposed mechanisms involve increasing the amount of inhibitory neurotransmitters or changes in the flow of ions (sodium or chloride) across the neuron cell membrane.

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Factor Influencing Drug Selection

• Many antiepileptic medications are effective against specific seizure types.

• It is very important to know the specific type or types of seizures a patient is having so that the appropriate medication can be chosen.

• On occasion the wrong medication can actually make seizures worse.

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Factor Influencing Drug Selection

• Seizure type

• Syndrome

• Side effects

• Patient age

• Lifestyle

• Childbearing potential

• Other medications 43

Factor Influencing Drug Selection

Monotherapy or Polytherapy• Monotherapy is usually the preferred

treatment.• A single drug is prescribed in increasing

increments until seizures are controlled or toxicity occurs.

• If the drug is ineffective or side effects occur, the drug is slowly withdrawn while another medication is slowly introduced.

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Advantages of Monotherapy

• 70-80% of patients are controlled on monotherapy.

• Fewer side effects.

• No drug interactions.

• Easier dosing = Greater compliance

• Lower cost.

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Antiepileptic Medication Response

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Advantages of Polytherapy

• May control an additional 30% of patients that could not be controlled with monotherapy.

• May provide synergistic effects. (1+1=3)

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Side Effects

• All seizure medications can have side effects.

• Side effects can be grouped as:– Dose related– Dose unrelated (occur at any dosage)– Idiosyncratic

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Side EffectsDose related

• Some effects are dose related. That is they become more likely as the amount of medication is increased.

• Sleepiness, slurred speech, and unsteadiness are common effects of seizure medications at higher doses.

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Side EffectsDose unrelated

(Common at any dose)

• Some side effects can occur at any dosage.• Examples include double vision, weight gain,

hyperactivity, sleep disturbances, irritability, hair growth, gum growth, and changes in mood.

• On occasion these effects are seen at the start of treatment and gradually get better with time.

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Side EffectsIdiosyncratic

• A rare side effect that occurs because of a patients individual sensitivity or allergic reaction to a particular medication.

• Examples include: Liver failure, aplastic anemia, severe rashs (Steven Johnson Syndrome).

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Side EffectsWarning Signs

• Prolonged fever• Rash• Severe sore throat• Mouth ulcers• Easy bruising• Pinpoint bleeding

• Weakness• Excessive fatigue• Swollen glands• Lack of appetite• Increased seizures

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Side EffectsPregnancy

• All seizures medication pose some risk to the developing fetus.

• None of the commonly used seizure medication are absolutely contraindicated in pregnancy.

• Possible side effects include cleft palate/lips, cardiac abnormalities, and spinal tube defects.

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Side EffectsPregnancy

• Antiepileptic medications can reduce the effectiveness of certain birth control pills.

• It is important to tell your doctors about all the medications you are taking so that potential interactions can be discussed and avoided.

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Side EffectsPregnancy

• Folic acid is frequently prescribed to all women of child baring age as it is believed to protect against some birth defects.

• Good news! 90% of women with epilepsy who become pregnant will give birth to normal healthy babies.

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FDA Pregnancy Risk

Category C• Zonisamide• Gabapentin• Oxcarbazepine• Felbamate• Levetiracetam• Lamotrigine• Tiagabine

Category D• Phenytoin• Valproic acid• Carbamazepine • Phenobarbital

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Compliance

• The degree to which the patient follows the physicians directions on how and when medications should be taken.

• 73% of people with epilepsy were found to be compliant with medications.

• Compliance is very important in epilepsy treatment as blood levels of medications will fall low if dosages are missed.

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Reasons for non-compliance

• Do not need so much medication

• Unpleasant side effects

• Making the drug last longer because of cost

• Forgetfulness

• Confusion about dosages and times

• Inconvenience of schedule

• Misunderstand directions58

Effectiveness of Treatment

• 75-80% of patients with epilepsy will have reliable long term control of their seizures with currently available medications.

• For the remainder of patients with intractable seizures other options exist such as epilepsy surgery, neuro-stimulators and the ketogenic diet.

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Discontinuing Antiepileptic Medications

• Antiepileptic medications may not have to be taken for a lifetime.

• When seizures have been controlled over a period of time (usually one to two years), there is a good chance that withdrawal of medication will be successful.

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Factors Associated with Seizure Recurrence

• Abnormal EEG

• Hard to control seizures

• Neurologic deficits

• Epilepsy type

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Factors Associated with Non-Recurrence in Adults

• Primary generalized seizure type

• Under 30 years of age

• Prompt initial control

• 2-5 years of seizure freedom

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Discontinuing Antiepileptic Medications

• 65-70% of children who are free of seizures on antiepileptic medications will remain seizure free after the drugs are withdrawn.

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Newer TreatmentsAntiepileptic Medications

• Research has provided insight into the pathophysiology of epilepsy at the molecular and genetic level enabling medications to be developed that target these mechanisms

• Not just ‘more of the same’

• Unique mechanisms of action

• Improved pharmacokinetics

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Newer Antiepileptic Medications

• Similar effectiveness to established AEDs in the treatment of partial seizures

• All AEDs have adverse effects

• Not appropriate for all seizure types

• Possible teratogenicity

• Limited data available for efficacy and safety

• Most used as adjunctive therapy

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Newer TreatmentsAntiepileptic Medications

• Sabril (Vigabatrin)

• Banzel (Rufinamide)

• Vimpat (Lacosamide)

• Onfi (Clobazam)

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Sabril (Vigabatrin)

• Approved as monotherapy for patients 1 month to 2 years of age with infantile spasms.

• Approved as add-on therapy for adults with complex partial seizures.

• Can cause eye injury (Retinal damage).

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Banzel (Rufinamide)

• Approved for the treatment of seizures for children and adults (> 4 years old) with Lennox-Gastaut Syndrome (2008).

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Vimpat (Lacosamide)

• Approved as add-on treatment in adults with partial onset seizures (2008).

• Unique mechanism of action.

• Low side effect profile.

• Rapid effectiveness

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Onfi (Clobazam)

• Approved in 2011

• Adjunctive (add-on) treatment for seizures associated with Lennox-Gastaut syndrome in adults and children 2 years of age and older.

• Atonic (“drop seizures”), tonic, or myoclonic seizures

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Newer TreatmentsMedications in Development

• Carisbamate (Partial seizures)

• Retigabine (Partial seizures)

• Eslicarbazepine (Partial seizures)

• Perampanel (Partial seizures)

• Brivaracetam (Generalized tonic seizures)

• Fluorofelbamate

• JZP-4, PID, Valrocemide, Ganaxolone71

New TreatmentsDevices/Surgical

• Vagus Nerve Stimulator

• Deep Brain Stimulation

• Neuropace

• Epilepsy Surgery

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Vagus Nerve Stimulator

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Vagus Nerve Stimulator

• FDA approved in 1997 (Seizures),

2005 (Depression)

• Electrical stimulus applied to the Vagus Nerve and has been found to reduce seizure frequency

• Typically reserved for patients with difficult to control epilepsy.

• Implantation takes 1-2 hours under general anesthesia.

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Vagus Nerve Stimulator

• Patients/Caregivers can turn the device on by using hand held magnet

• Low side effects: Cough/ deepening of voice during stimulation.

• After one year:

1/3 have excellent response (90% reduction)

1/3 have good response (50% reduction)

1/3 little to no response75

Newer TreatmentsNeuro-stimulators

Deep Brain Stimulation

• Promising new technology for medically-refractory seizures.

• Stimulator electrodes are placed deep within the brain (thalamus or cerebellum) which are then connected to a pacemaker-like device in the chest.

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Newer TreatmentsNeuro-stimulators

NeuroPace

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Neuro-stimulatorsNeuroPace

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Newer TreatmentsEpilepsy Surgery

• Certain patients in whom medication has failed to provide seizure control are evaluated for epilepsy surgery

• Surgery is restricted to those patients whose seizures originate from an identifiable focus in the brain.

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Epilepsy Surgery

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Epilepsy Surgery

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Newer DevelopmentsMEG

(Magnetoencephalography)

• Measures the small electrical currents arising inside the neurons of the brain.

• Similar to EEG but provides greater accuracy.

• Used to locate where seizures are coming from within the brain.

• Can be used to map brain functions84

Alternative TreatmentsKetogenic Diet

• Developed in the 1920’s

• High fat, low carbohydrate, adequate protein diet (4:1 ratio)

• Forces body to burn fats producing ketones

• Effective in half the patients who try it

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Alternative TreatmentsKetogenic Diet

• Not easy. Requires careful weighing and calculating of food calories

• Complications: Growth delay, bone fractures, kidney stones and elevated cholesterol levels

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Alternative TreatmentsBiofeedback

• Method of using relaxation or imagery to change body functions such as breathing, heart rate, and blood pressure

• These functions are monitored

• A stressful situation is presented and relaxation techniques are utilized

• Patient is able to view these functions and the see the differences between stressed and relaxed states 87

Alternative TreatmentsBiofeedback

• Has been shown to help people with high blood pressure, headaches, and pain.

• Patients who have seizures triggered by anxiety or stressful situations may benefit

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Alternative TreatmentsRelaxation Techniques

• Reiki

• Yoga

• Hypnosis

• Deep breathing exercises

• Massage therapy

• Meditation

• Muscle relaxation techniques89

Alternative TreatmentsMelatonin

• Natural hormone produced by the pineal gland in the brain

• Frequently used as a sleep aid

• Study results with respect to helping seizures have been inconclusive.

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Alternative TreatmentsVitamins

• Necessary for good health, however……

• Large doses of vitamins have not been shown to be of any benefit in reducing seizure frequency

• Patients on seizure medication may require supplements of calcium and Vitamin D for bone health.

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