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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
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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
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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
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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
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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
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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
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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
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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
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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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