Treating Epilepsy Antiepileptic Medications and New Treatments

Northeast Regional Epilepsy Group Christos Lambrakis M.D.

‘The goal of therapy is to help the person with epilepsy lead a full and productive life….’

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

Treatment Strategies Medications Surgical Dietary

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.

History of Antiepileptic Medications 1938 Diphenylhydantoin (Dilantin) was discovered to have antiepileptic properties. Similar effectiveness to phenobarbital. Less sedative side effects.

History of Antiepileptic Medications 1960-1974 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.

History of Antiepileptic Medications 1974: Carbamazepine (Tegretol) 1978: Valproic acid (Depakote) 1993-Present: Rapid emergence of very effective seizure medications.

History of Antiepileptic Medications 1993-Present: Rapid emergence of very effective seizure medications. Neurontin, Felbatol, Topamax, Lamictal, Gabitril, Zonegran, Keppra, Trileptal, Lyrica, Sabril, Banzel, Vimpat.

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)?

When Not to Treat Single seizure No history Neurologically normal Young age Side effect concerns

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.

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%.

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.

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.

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.

Key Concepts in Antiepileptic Treatment Half-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.

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.

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.

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.

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.

Factor Influencing Drug Selection Seizure type Syndrome Side effects Patient age Lifestyle Childbearing potential Other medications

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.

Advantages of Monotherapy 70-80% of patients are controlled on monotherapy. Fewer side effects. No drug interactions. Easier dosing = Greater compliance Lower cost.

Advantages of Polytherapy May control an additional 20% of patients that could not be controlled with monotherapy. May provide synergistic effects. (1+1=3)

Side Effects All seizure medications can have side effects. Side effects can be grouped as: Dose related Dose unrelated (occur at any dosage) Idiosyncratic

Side Effects Dose 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.

Side Effects Dose 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.

Side Effects Idiosyncratic 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).

Side Effects Warning Signs Prolonged fever Rash Severe sore throat Mouth ulcers Easy bruising Pinpoint bleeding Weakness Excessive fatigue Swollen glands Lack of appetite Increased seizures

Side Effects Pregnancy 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.

Side Effects Pregnancy 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.

Side Effects Pregnancy 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.

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.

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 directions

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.

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.

Factors Associated with Seizure Recurrence Abnormal EEG Hard to control seizures Neurologic deficits Epilepsy type

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

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

Newer Treatments Antiepileptic Medications Sabril (Vigabatrin) Banzel (Rufinamide) Vimpat (Lacosamide)

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).

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

Vimpat (Lacosamide) Approved as add-on treatment in adults with partial onset seizures. Unique mechanism of action. Low side effect profile.

Newer Treatments Medications in Development Clobazam (Lennox-Gastaut) Eslicarbazepine (Partial seizures) Perampanel (Partial seizures)

Newer Treatments Neuro-stimulators Deep Brain Stimulation

Newer Treatments Neuro-stimulators Deep Brain Stimulation Promising new technology for medically-refractory seizures. Stimulator electrodes are placed deep within the brain and are connected to a pacemaker-like device in the chest.

Newer Developments MEG (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 functions